Entecavir Interacts with Influx Transporters hOAT1, hCNT2, hCNT3, but Not with hOCT2: The Potential for Renal Transporter-Mediated Cytotoxicity and Drug-Drug Interactions

Czech Academy of Sciences Publication Activity Database

Mandíková, J.; Volková, M.; Pávek, P.; Navrátilová, L.; Hyršová, L.; Janeba, Zlatko; Pavlík, J.; Bárta, P.; Trejtnar, F.

2016-01-01

Roč. 6, Jan 5 (2016), č. článku 304. ISSN 1663-9812 Institutional support: RVO:61388963 Keywords : antivirals * nephrotoxicity * renal disposition * drug-drug interactions Subject RIV: CC - Organic Chemistry Impact factor: 4.400, year: 2016 http://journal.frontiersin.org/article/10.3389/fphar.2015.00304/full

77 FR 12062 - Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting

Science.gov (United States)

2012-02-28

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-N-0001] Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting AGENCY: Food and Drug Administration, HHS... of Committee: Cardiovascular and Renal Drugs Advisory Committee. General Function of the Committee...

77 FR 43093 - Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting

Science.gov (United States)

2012-07-23

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-N-0001] Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting AGENCY: Food and Drug Administration, HHS...: Cardiovascular and Renal Drugs Advisory Committee. General Function of the Committee: To provide advice and...

78 FR 38717 - Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting

Science.gov (United States)

2013-06-27

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2013-N-0001] Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting AGENCY: Food and Drug Administration, HHS...: Cardiovascular and Renal Drugs Advisory Committee. General Function of the Committee: To provide advice and...

75 FR 35496 - Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting

Science.gov (United States)

2010-06-22

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2010-N-0001] Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting AGENCY: Food and Drug Administration, HHS...: Cardiovascular and Renal Drugs Advisory Committee. General Function of the Committee: To provide advice and...

77 FR 43600 - Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting

Science.gov (United States)

2012-07-25

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-N-0001] Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting AGENCY: Food and Drug Administration, HHS...: Cardiovascular and Renal Drugs Advisory Committee. General Function of the Committee: To provide advice and...

75 FR 1395 - Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting

Science.gov (United States)

2010-01-11

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2009-N-0664] Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting AGENCY: Food and Drug Administration, HHS...: Cardiovascular and Renal Drugs Advisory Committee. General Function of the Committee: To provide advice and...

78 FR 36787 - Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting

Science.gov (United States)

2013-06-19

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2013-N-0001] Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting AGENCY: Food and Drug Administration, HHS...: Cardiovascular and Renal Drugs Advisory Committee. General Function of the Committee: To provide advice and...

75 FR 52762 - Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting

Science.gov (United States)

2010-08-27

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2010-N-0001] Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting AGENCY: Food and Drug Administration, HHS...: Cardiovascular and Renal Drugs Advisory Committee. General Function of the Committee: To provide advice and...

75 FR 30839 - Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting

Science.gov (United States)

2010-06-02

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2010-N-0001] Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting AGENCY: Food and Drug Administration, HHS...: Cardiovascular and Renal Drugs Advisory Committee. General Function of the Committee: To provide advice and...

76 FR 82310 - Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting

Science.gov (United States)

2011-12-30

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2011-N-0002] Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting AGENCY: Food and Drug Administration, HHS...: Cardiovascular and Renal Drugs Advisory Committee. General Function of the Committee: To provide advice and...

76 FR 39404 - Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting

Science.gov (United States)

2011-07-06

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2011-N-0002] Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting AGENCY: Food and Drug Administration, HHS...: Cardiovascular and Renal Drugs Advisory Committee. General Function of the Committee: To provide advice and...

Identification and Quantitative Assessment of Uremic Solutes as Inhibitors of Renal Organic Anion Transporters, OAT1 and OAT3.

Science.gov (United States)

Hsueh, Chia-Hsiang; Yoshida, Kenta; Zhao, Ping; Meyer, Timothy W; Zhang, Lei; Huang, Shiew-Mei; Giacomini, Kathleen M

2016-09-06

One of the characteristics of chronic kidney disease (CKD) is the accumulation of uremic solutes in the plasma. Less is known about the effects of uremic solutes on transporters that may play critical roles in pharmacokinetics. We evaluated the effect of 72 uremic solutes on organic anion transporter 1 and 3 (OAT1 and OAT3) using a fluorescent probe substrate, 6-carboxyfluorescein. A total of 12 and 13 solutes were identified as inhibitors of OAT1 and OAT3, respectively. Several of them inhibited OAT1 or OAT3 at clinically relevant concentrations and reduced the transport of other OAT1/3 substrates in vitro. Review of clinical studies showed that the active secretion of most drugs that are known substrates of OAT1/3 deteriorated faster than the renal filtration in CKD. Collectively, these data suggest that through inhibition of OAT1 and OAT3, uremic solutes contribute to the decline in renal drug clearance in patients with CKD.

Renal sympathetic nerve, blood flow, and epithelial transport responses to thermal stress.

Science.gov (United States)

Wilson, Thad E

2017-05-01

Thermal stress is a profound sympathetic stress in humans; kidney responses involve altered renal sympathetic nerve activity (RSNA), renal blood flow, and renal epithelial transport. During mild cold stress, RSNA spectral power but not total activity is altered, renal blood flow is maintained or decreased, and epithelial transport is altered consistent with a sympathetic stress coupled with central volume loaded state. Hypothermia decreases RSNA, renal blood flow, and epithelial transport. During mild heat stress, RSNA is increased, renal blood flow is decreased, and epithelial transport is increased consistent with a sympathetic stress coupled with a central volume unloaded state. Hyperthermia extends these directional changes, until heat illness results. Because kidney responses are very difficult to study in humans in vivo, this review describes and qualitatively evaluates an in vivo human skin model of sympathetically regulated epithelial tissue compared to that of the nephron. This model utilizes skin responses to thermal stress, involving 1) increased skin sympathetic nerve activity (SSNA), decreased skin blood flow, and suppressed eccrine epithelial transport during cold stress; and 2) increased SSNA, skin blood flow, and eccrine epithelial transport during heat stress. This model appears to mimic aspects of the renal responses. Investigations of skin responses, which parallel certain renal responses, may aid understanding of epithelial-sympathetic nervous system interactions during cold and heat stress. Copyright © 2016 Elsevier B.V. All rights reserved.

75 FR 70933 - Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting

Science.gov (United States)

2010-11-19

...] Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting AGENCY: Food and Drug Administration, HHS... of Committee: Cardiovascular and Renal Drugs Advisory Committee. General Function of the Committees... appropriate clinical study design for thromboxane receptor antagonists for prevention of cardiovascular events...

Renal Side Effects of Non-Steroidal Anti-Inflammatory Drugs in Neonates

Directory of Open Access Journals (Sweden)

Marc Gewillig

2010-02-01

Full Text Available Non-steroidal anti-inflammatory drugs like ibuprofen or indomethacin are commonly prescribed drugs to induce pharmacologic closure of a patent ductus arteriosus in preterm neonates. Based on a recently published Cochrane meta-analysis, both drugs are equally effective to induce closure. Drug choice can therefore be based on differences in side effects or pharmaco-economic arguments. The current review quantifies the negative impact of either ibuprofen or indomethacin on renal function, including diuresis, glomerular filtration rate and renal tubular function. Both ibuprofen and indomethacin have a quantifiable impact on renal function. However, compared to ibuprofen, the negative impact of indomethacin is more pronounced.

78 FR 76307 - Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting

Science.gov (United States)

2013-12-17

...] Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting AGENCY: Food and Drug Administration, HHS...: Cardiovascular and Renal Drugs Advisory Committee. General Function of the Committee: To provide advice and... combined endpoint of cardiovascular death, MI, stroke, and urgent coronary revascularization. FDA intends...

Renal denervation decreases blood pressure and renal tyrosine hydroxylase but does not augment the effect of hypotensive drugs.

Science.gov (United States)

Skrzypecki, Janusz; Gawlak, Maciej; Huc, Tomasz; Szulczyk, Paweł; Ufnal, Marcin

2017-01-01

The effect of renal denervation on the efficacy of antihypertensive drugs has not yet been elucidated. Twenty-week-old spontaneously hypertensive rats were treated with metoprolol, losartan, indapamide, or saline (controls) and assigned to renal denervation or a sham procedure. Acute hemodynamic measurements were performed ten days later. Series showing a significant interaction between renal denervation and the drugs were repeated with chronic telemetry measurements. In the saline series, denervated rats showed a significantly lower mean arterial blood pressure (blood pressure) than the sham-operated rats. In contrast, in the metoprolol series denervated rats showed a significantly higher blood pressure than sham rats. There were no differences in blood pressure between denervated and sham rats in the losartan and indapamide series. In chronic studies, a 4-week treatment with metoprolol caused a decrease in blood pressure. Renal denervation and sham denervation performed 10 days after the onset of metoprolol treatment did not affect blood pressure. Denervated rats showed markedly reduced renal nerve tyrosine hydroxylase levels. In conclusion, renal denervation decreases blood pressure in hypertensive rats. The hypotensive action of metoprolol, indapamide, and losartan is not augmented by renal denervation, suggesting the absence of synergy between renal denervation and the drugs investigated in this study.

Tubular transport and metabolism of cimetidine in chicken kidneys

International Nuclear Information System (INIS)

Rennick, B.; Ziemniak, J.; Smith, I.; Taylor, M.; Acara, M.

1984-01-01

Renal tubular transport and renal metabolism of [ 14 C]cimetidine (CIM) were investigated by unilateral infusion into the renal portal circulation in chickens (Sperber technique). [ 14 C]CIM was actively transported at a rate 88% that of simultaneously infused p-aminohippuric acid, and its transport was saturable. The following organic cations competitively inhibited the tubular transport of [ 14 C]CIM with decreasing potency: CIM, ranitidine, thiamine, procainamide, guanidine and choline. CIM inhibited the transport of [ 14 C]thiamine, [ 14 C]amiloride and [ 14 C]tetraethylammonium. During CIM infusion, two renal metabolites, CIM sulfoxide and hydroxymethylcimetidine, were found in urine. When CIM sulfoxide was infused, its transport efficiency was 32% and not saturable. CIM sulfoxide did ot inhibit the simultaneous renal tubular transport of p-aminohippuric acid or tetraethylammonium. CIM is transported by the organic cation transport system and the kidney metabolizes CIM. Transport of CIM and other cationic drugs could produce a drug interaction to alter drug excretion

78 FR 76308 - Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting

Science.gov (United States)

2013-12-17

...] Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting AGENCY: Food and Drug Administration, HHS...: Cardiovascular and Renal Drugs Advisory Committee. General Function of the Committee: To provide advice and..., Inc., for the proposed indication to reduce the risk of thrombotic cardiovascular events in patients...

75 FR 57474 - Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting

Science.gov (United States)

2010-09-21

...] Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting AGENCY: Food and Drug Administration, HHS...: Cardiovascular and Renal Drugs Advisory Committee. General Function of the Committee: To provide advice and... analyses of the TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) study of ARANESP...

77 FR 21982 - Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting

Science.gov (United States)

2012-04-12

...] Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting AGENCY: Food and Drug Administration, HHS...: Cardiovascular and Renal Drugs Advisory Committee. General Function of the Committee: To provide advice and...., to reduce the risk of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS...

Drug-interaction-induced hemodynamically mediated acute renal failure in postsurgical patient

Directory of Open Access Journals (Sweden)

Arup K Misra

2014-01-01

Full Text Available Acute renal failure is a life threatening condition. Nonsteroidal antiinflammatory drugs (NSAIDs and cephalosporins are widely used postoperative drugs. NSAID-induced acute renal failure has been reported in the past. In this case, drug interaction and decompensated state of the patient precipitate the condition. NSAIDs inhibit prostaglandins synthesis and thus aggravate ischemia to the kidney that is already facing volume crisis due to surgery. Due to renal dysfunction, plasma ceftriaxone level increases due to decrease clearance and it also acts as nephrotoxic by unknown mechanism. On the other hand, ceftriaxone on its interaction with diclofenac for renal tubular clearance also increases the level of diclofenac and thus further aggravate the ischemia. It is a reversible condition with excluding diclofenac from the treatment regimen and giving adequate hydration to the patient. This highlights the importance of hydration and knowledge of drugs interactions in a postsurgical patient.

Water transport by the renal Na(+)-dicarboxylate cotransporter

DEFF Research Database (Denmark)

Meinild, A K; Loo, D D; Pajor, A M

2000-01-01

. This solute-coupled influx of water took place in the absence of, and even against, osmotic gradients. There was a strict stoichiometric relationship between Na(+), substrate, and water transport of 3 Na(+), 1 dicarboxylate, and 176 water molecules/transport cycle. These results indicate that the renal Na......This study investigated the ability of the renal Na(+)-dicarboxylate cotransporter, NaDC-1, to transport water. Rabbit NaDC-1 was expressed in Xenopus laevis oocytes, cotransporter activity was measured as the inward current generated by substrate (citrate or succinate), and water transport...... was monitored by the changes in oocyte volume. In the absence of substrates, oocytes expressing NaDC-1 showed an increase in osmotic water permeability, which was directly correlated with the expression level of NaDC-1. When NaDC-1 was transporting substrates, there was a concomitant increase in oocyte volume...

Pregnancy Increases the Renal Secretion of N1-methylnicotinamide, an Endogenous Probe for Renal Cation Transporters, in Patients Prescribed Metformin.

Science.gov (United States)

Bergagnini-Kolev, Mackenzie C; Hebert, Mary F; Easterling, Thomas R; Lin, Yvonne S

2017-03-01

N 1 -methylnicotinamide (1-NMN) has been investigated as an endogenous probe for the renal transporter activity of organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins 1 and 2-K (MATE1 and MATE2-K). As pregnancy increased the renal secretion of metformin, a substrate for OCT2, MATE1, and MATE2-K, we hypothesized that the renal secretion of 1-NMN would be similarly affected. Blood and urine samples collected from women prescribed metformin for type 2 diabetes, gestational diabetes, and polycystic ovarian syndrome during early, mid, and late pregnancy ( n = 34 visits) and postpartum ( n = 14 visits) were analyzed for 1-NMN using liquid chromatography-mass spectrometry. The renal clearance and secretion clearance, using creatinine clearance to correct for glomerular filtration, were estimated for 1-NMN and correlated with metformin renal clearance. 1-NMN renal clearance was higher in both mid (504 ± 293 ml/min, P pregnancy (557 ± 305 ml/min, P pregnancy (269± 267, P pregnancy compared with postpartum (342 ± 283 versus 76 ± 92 ml/min, P Metformin renal clearance and 1-NMN renal clearance were positively correlated (r s = 0.68, P pregnancy due to increased glomerular filtration and net secretion by renal transporters. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

The dual-gate lumen model of renal monoamine transport

Directory of Open Access Journals (Sweden)

Marty Hinz

2010-07-01

Full Text Available Marty Hinz1, Alvin Stein2, Thomas Uncini31Clinical Research, NeuroResearch Clinics, Inc. Cape Coral, Florida, USA; 2Stein Orthopedic Associates, Plantation, Florida, USA; 3DBS Labs, Duluth, Minnesota, USAAbstract: The three-phase response of urinary serotonin and dopamine in subjects ­simultaneously taking amino acid precursors of serotonin and dopamine has been defined.1,2 No model exists regarding the renal etiology of the three-phase response. This writing outlines a model explaining the origin of the three-phase response of urinary serotonin and dopamine. A “dual-gate lumen transporter model” for the basolateral monoamine transporters of the kidneys is proposed as being the etiology of the three-phase urinary serotonin and dopamine responses.Purpose: The purpose of this writing is to document the internal renal function model that has evolved in research during large-scale assay with phase interpretation of urinary serotonin and dopamine.Patients and methods: In excess of 75,000 urinary monoamine assays from more than 7,500 patients were analyzed. The serotonin and the dopamine phase were determined for specimens submitted in the competitive inhibition state. The phase determination findings were then correlated with peer-reviewed literature.Results: The correlation between the three-phase response of urinary serotonin and dopamine with internal renal processes of the bilateral monoamine transporter and the apical monoamine transporter of the proximal convoluted renal tubule cells is defined.Conclusion: The phase of urinary serotonin and dopamine is dependent on the status of the serotonin gate, dopamine gate, and lumen of the basolateral monoamine transporter while in the competitive inhibition state.Keywords: serotonin, dopamine, basolateral, apical, kidney, proximal

Use of nonsteroidal anti-inflammatory drugs and renal failure in nursing home residents-results of the study "Inappropriate Medication in Patients with Renal Insufficiency in Nursing Homes".

Science.gov (United States)

Dörks, Michael; Herget-Rosenthal, Stefan; Schmiemann, Guido; Hoffmann, Falk

2016-04-01

Use of potentially inappropriate medications may result in increased morbidity, mortality and resource utilisation. Due to polypharmacy and age-related decline in renal function the elderly population is at particular risk. Therefore, the Beers Criteria include use of nonsteroidal anti-inflammatory drugs in chronic renal failure stage 4 and 5 as these drugs may worsen renal function. According to the summary of product characteristics, the nonsteroidal anti-inflammatory drugs ibuprofen and diclofenac are contraindicated in these patients. Objective was to assess the extent of nonsteroidal anti-inflammatory drug use in nursing homes with a focus on residents with severe renal failure. Multi-centre cross-sectional study in 21 German nursing homes. The study population comprised residents for whom at least one serum creatinine value and information about sex were available, so that creatinine clearance rate could be estimated. In all, 685 of 852 residents were included as they fulfilled the abovementioned criteria. Renal failure was severe (estimated creatinine clearance rate renal failure (20.8 %). With one exception, all residents prescribed nonsteroidal anti-inflammatory drugs with severe renal failure were treated with at least one nonsteroidal anti-inflammatory drug that was contraindicated due to the underlying renal function. Notwithstanding their classification as potentially inappropriate medications and underlying contraindications, use of nonsteroidal anti-inflammatory drugs is common among nursing home residents with severe renal failure.

Renal denervation for treatment of drug-resistant hypertension.

Science.gov (United States)

Esler, Murray

2015-02-01

At the seven-year anniversary of the first catheter-based renal denervation procedure for resistant hypertension, it is timely to reflect on the past, present, and future of the development and clinical application of this treatment. Unresolved procedural and technical questions are central: How much renal denervation is optimal? How can this level of denervation be achieved? What test for denervation can be applied in renal denervation trials? Will renal denervation show a "class effect," with the different energy forms now used for renal nerve ablation producing equivalent blood pressure lowering? When I have assessed renal denervation efficacy, using measurements of the spillover of norepinephrine from the renal sympathetic nerves to plasma, the only test validated to this point, denervation was found to be incomplete and non-uniform between patients. It is probable that the degree of denervation has commonly been suboptimal in renal denervation trials; this criticism applying with special force to the Symplicity HTN-3 trial, where the proceduralists, although expert interventional cardiologists, had no prior experience with the renal denervation technique. Recently presented results from the Symplicity HTN-3 trial confirm that renal denervation was not achieved effectively or consistently. Given this, and other difficulties in the execution of the trial relating to drug adherence, an idea mooted is that the US pivotal trial of the future may be in younger, untreated patients. Copyright © 2015 Elsevier Inc. All rights reserved.

Development of novel, 384-well high-throughput assay panels for human drug transporters: drug interaction and safety assessment in support of discovery research.

Science.gov (United States)

Tang, Huaping; Shen, Ding Ren; Han, Yong-Hae; Kong, Yan; Balimane, Praveen; Marino, Anthony; Gao, Mian; Wu, Sophie; Xie, Dianlin; Soars, Matthew G; O'Connell, Jonathan C; Rodrigues, A David; Zhang, Litao; Cvijic, Mary Ellen

2013-10-01

Transporter proteins are known to play a critical role in affecting the overall absorption, distribution, metabolism, and excretion characteristics of drug candidates. In addition to efflux transporters (P-gp, BCRP, MRP2, etc.) that limit absorption, there has been a renewed interest in influx transporters at the renal (OATs, OCTs) and hepatic (OATPs, BSEP, NTCP, etc.) organ level that can cause significant clinical drug-drug interactions (DDIs). Several of these transporters are also critical for hepatobiliary disposition of bilirubin and bile acid/salts, and their inhibition is directly implicated in hepatic toxicities. Regulatory agencies took action to address transporter-mediated DDI with the goal of ensuring drug safety in the clinic and on the market. To meet regulatory requirements, advanced bioassay technology and automation solutions were implemented for high-throughput transporter screening to provide structure-activity relationship within lead optimization. To enhance capacity, several functional assay formats were miniaturized to 384-well throughput including novel fluorescence-based uptake and efflux inhibition assays using high-content image analysis as well as cell-based radioactive uptake and vesicle-based efflux inhibition assays. This high-throughput capability enabled a paradigm shift from studying transporter-related issues in the development space to identifying and dialing out these concerns early on in discovery for enhanced mechanism-based efficacy while circumventing DDIs and transporter toxicities.

Effect of diuretics on renal tubular transport of calcium and magnesium.

Science.gov (United States)

Alexander, R Todd; Dimke, Henrik

2017-06-01

Calcium (Ca 2+ ) and Magnesium (Mg 2+ ) reabsorption along the renal tubule is dependent on distinct trans- and paracellular pathways. Our understanding of the molecular machinery involved is increasing. Ca 2+ and Mg 2+ reclamation in kidney is dependent on a diverse array of proteins, which are important for both forming divalent cation-permeable pores and channels, but also for generating the necessary driving forces for Ca 2+ and Mg 2+ transport. Alterations in these molecular constituents can have profound effects on tubular Ca 2+ and Mg 2+ handling. Diuretics are used to treat a large range of clinical conditions, but most commonly for the management of blood pressure and fluid balance. The pharmacological targets of diuretics generally directly facilitate sodium (Na + ) transport, but also indirectly affect renal Ca 2+ and Mg 2+ handling, i.e., by establishing a prerequisite electrochemical gradient. It is therefore not surprising that substantial alterations in divalent cation handling can be observed following diuretic treatment. The effects of diuretics on renal Ca 2+ and Mg 2+ handling are reviewed in the context of the present understanding of basal molecular mechanisms of Ca 2+ and Mg 2+ transport. Acetazolamide, osmotic diuretics, Na + /H + exchanger (NHE3) inhibitors, and antidiabetic Na + /glucose cotransporter type 2 (SGLT) blocking compounds, target the proximal tubule, where paracellular Ca 2+ transport predominates. Loop diuretics and renal outer medullary K + (ROMK) inhibitors block thick ascending limb transport, a segment with significant paracellular Ca 2+ and Mg 2+ transport. Thiazides target the distal convoluted tubule; however, their effect on divalent cation transport is not limited to that segment. Finally, potassium-sparing diuretics, which inhibit electrogenic Na + transport at distal sites, can also affect divalent cation transport. Copyright © 2017 the American Physiological Society.

Selective pharmacological modulation of renal peripheral-type benzodiazepine binding by treatment with diuretic drugs

International Nuclear Information System (INIS)

Lukeman, D.S.; Vaughn, D.A.; Fanestil, D.D.

1988-01-01

The authors have assessed the effects of in vivo administration of different classes of diuretic drugs on the expression of the peripheral-type benzodiazepine binding site (PBBS) in crude membranes derived from the cortex and outer medulla of rat kidney by saturation analysis with the PBBS-selective ligands [ 3 H]RO5-4864 and [ 3 H]PH 11195 in cortex and [ 3 H]RO5-4864 in outer medulla. Administration for 14-15 days of furosemide, a drug that blocks NaCl-KCl coupled transport in the thick ascending limb of the loop of Henle, produced a significant doubling in the PBBS density (B/sub max/) in outer medulla, a region of the kidney rich in thick ascending limbs, and produced a lesser but significant increase in PBBS density in the cortex. Conversely, administration for 14-15 days of the carbonic anhydrase inhibitor acetazolamide, which acts predominantly in the proximal tubule, and hydrochlorothiazide, which acts predominantly in the early distal tubule, elicited statistically significant increases in PBBS density in renal cortex but not in renal outer medulla. Furthermore, all drug treatments were without effect on the equilibrium dissociation constants (K/sub d/s) of [ 3 H]RO5-4864 and [ 3 H]PK 11195 binding to cortical and outer medullary membrane preparations. These findings demonstrate that the PBBS can be selectively up-regulated in different regions of the kidney by diuretic drugs with different modes/sites of action. 50 references, 1 table

Impact on creatinine renal clearance by the interplay of multiple renal transporters: a case study with INCB039110.

Science.gov (United States)

Zhang, Yan; Warren, Mark S; Zhang, Xuexiang; Diamond, Sharon; Williams, Bill; Punwani, Naresh; Huang, Jane; Huang, Yong; Yeleswaram, Swamy

2015-04-01

Serum creatinine is commonly used as a marker of renal function, but increases in serum creatinine might not represent changes in glomerular filtration rate (GFR). INCB039110 (2-(3-(4-(7H-pyrrolo[2,3-day]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile) is an inhibitor of the Janus kinases (JAKs) with selectivity for JAK1. In a phase 1 study, a modest and reversible increase in serum creatinine was observed after treatment with INCB039110. However, a dedicated renal function study with INCB039110, assessed by iohexol plasma clearance, conducted in healthy volunteers indicated no change in GFR. In vitro studies were therefore conducted to investigate the interaction of INCB039110 with five transporters that are likely involved in the renal clearance of creatinine. Cell systems expressing individual or multiple transporters were used, including a novel quintuple-transporter model OAT2/OCT2/OCT3/MATE1/MATE2-K. INCB039110 potently inhibited OCT2-mediated uptake of creatinine as well as MATE1-/MATE2-K-mediated efflux of creatinine. Given the interactions of INCB039110 with multiple transporters affecting creatinine uptake and efflux, an integrated system expressing all five transporters was sought; in that system, INCB039110 caused a dose-dependent decrease in transcellular transport of creatinine with weaker net inhibition compared with the effects on individual transporters. In summary, a molecular mechanism for the increase in serum creatinine by INCB039110 has been established. These studies also underline the limitations of using serum creatinine as a marker of renal function. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Effect of nephrotoxicants on renal membrane transport: In vitro studies

International Nuclear Information System (INIS)

Ansari, R.A.; Berndt, W.O.

1990-01-01

It is possible to study the effects of nephrotoxicants on membrane function free of other cellular influences. By the use of Percoll gradient centrifugation, highly purified preparations of right-side-out basolateral (BL) and brush border (BB) membrane vesicles can be obtained from rat (male, Sprague-Dawley) renal cortex. Membrane function can be monitored by evaluation of sodium driven transport: 14 C-p-aminohippurate (PAH) for BL and 14 C-glucose for BB. Transport was measured by the rapid filtration technique. Each vesicle preparation was preincubated with the nephrotoxicant for five minutes before initiation of transport. Control vesicles showed a prominant overshoot 1 to 2 minutes after start of transport. Mercuric ion (Hg) had no effect on transport by BB at concentrations as high as 10μM. Transport by BL was reduced significantly at Hg concentrations as low as 100 nM. Chromate (Cr) also reduced BL transport at 100 nM and had no effect on BB transport. Citrinin significantly reduced both BB and BL transport, but the sensitivity of the membrane preparations differed. These data are consistent with the hypothesis that some nephrotoxicants may act on either side of the renal tubular cell membrane

Role of drug transporters and drug accumulation in the temporal acquisition of drug resistance

International Nuclear Information System (INIS)

Hembruff, Stacey L; Laberge, Monique L; Villeneuve, David J; Guo, Baoqing; Veitch, Zachary; Cecchetto, Melanie; Parissenti, Amadeo M

2008-01-01

Anthracyclines and taxanes are commonly used in the treatment of breast cancer. However, tumor resistance to these drugs often develops, possibly due to overexpression of drug transporters. It remains unclear whether drug resistance in vitro occurs at clinically relevant doses of chemotherapy drugs and whether both the onset and magnitude of drug resistance can be temporally and causally correlated with the enhanced expression and activity of specific drug transporters. To address these issues, MCF-7 cells were selected for survival in increasing concentrations of doxorubicin (MCF-7 DOX-2 ), epirubicin (MCF-7 EPI ), paclitaxel (MCF-7 TAX-2 ), or docetaxel (MCF-7 TXT ). During selection cells were assessed for drug sensitivity, drug uptake, and the expression of various drug transporters. In all cases, resistance was only achieved when selection reached a specific threshold dose, which was well within the clinical range. A reduction in drug uptake was temporally correlated with the acquisition of drug resistance for all cell lines, but further increases in drug resistance at doses above threshold were unrelated to changes in cellular drug uptake. Elevated expression of one or more drug transporters was seen at or above the threshold dose, but the identity, number, and temporal pattern of drug transporter induction varied with the drug used as selection agent. The pan drug transporter inhibitor cyclosporin A was able to partially or completely restore drug accumulation in the drug-resistant cell lines, but had only partial to no effect on drug sensitivity. The inability of cyclosporin A to restore drug sensitivity suggests the presence of additional mechanisms of drug resistance. This study indicates that drug resistance is achieved in breast tumour cells only upon exposure to concentrations of drug at or above a specific selection dose. While changes in drug accumulation and the expression of drug transporters does occur at the threshold dose, the magnitude of

Renal myoglobin in drug addicts: occurrence and significance in a postmortem study

DEFF Research Database (Denmark)

Kock, Kirsten Friis; Simonsen, Kirsten Wiese

1994-01-01

In a 3-year period (1989–1991) a non-selected, consecutive series of 62 deaths in drug addicts was autopsied at the Forensic Institute in Odense. The kidney sections from these addicts were examined for the presence of renal myoglobin using immunohistochemical methods. A reference group consisting......, immobilization, hypovolemia). In sufficient amounts, renal myoglobin may be of importance as a cause of death or a contributing factor to death in both drug addicts and non-addicts....

Usefulness of zebrafish larvae to evaluate drug-induced functional and morphological renal tubular alterations.

Science.gov (United States)

Gorgulho, Rita; Jacinto, Raquel; Lopes, Susana S; Pereira, Sofia A; Tranfield, Erin M; Martins, Gabriel G; Gualda, Emilio J; Derks, Rico J E; Correia, Ana C; Steenvoorden, Evelyne; Pintado, Petra; Mayboroda, Oleg A; Monteiro, Emilia C; Morello, Judit

2018-01-01

Prediction and management of drug-induced renal injury (DIRI) rely on the knowledge of the mechanisms of drug insult and on the availability of appropriate animal models to explore it. Zebrafish (Danio rerio) offers unique advantages for assessing DIRI because the larval pronephric kidney has a high homology with its human counterpart and it is fully mature at 3.5 days post-fertilization. Herein, we aimed to evaluate the usefulness of zebrafish larvae as a model of renal tubular toxicity through a comprehensive analysis of the renal alterations induced by the lethal concentrations for 10% of the larvae for gentamicin, paracetamol and tenofovir. We evaluated drug metabolic profile by mass spectrometry, renal function with the inulin clearance assay, the 3D morphology of the proximal convoluted tubule by two-photon microscopy and the ultrastructure of proximal convoluted tubule mitochondria by transmission electron microscopy. Paracetamol was metabolized by conjugation and oxidation with further detoxification with glutathione. Renal clearance was reduced with gentamicin and paracetamol. Proximal tubules were enlarged with paracetamol and tenofovir. All drugs induced mitochondrial alterations including dysmorphic shapes ("donuts", "pancakes" and "rods"), mitochondrial swelling, cristae disruption and/or loss of matrix granules. These results are in agreement with the tubular effects of gentamicin, paracetamol and tenofovir in man and demonstrate that zebrafish larvae might be a good model to assess functional and structural damage associated with DIRI.

Projecting ADME Behavior and Drug-Drug Interactions in Early Discovery and Development: Application of the Extended Clearance Classification System.

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El-Kattan, Ayman F; Varma, Manthena V; Steyn, Stefan J; Scott, Dennis O; Maurer, Tristan S; Bergman, Arthur

2016-12-01

To assess the utility of Extended Clearance Classification System (ECCS) in understanding absorption, distribution, metabolism, and elimination (ADME) attributes and enabling victim drug-drug interaction (DDI) predictions. A database of 368 drugs with relevant ADME parameters, main metabolizing enzymes, uptake transporters, efflux transporters, and highest change in exposure (%AUC) in presence of inhibitors was developed using published literature. Drugs were characterized according to ECCS using ionization, molecular weight and estimated permeability. Analyses suggested that ECCS class 1A drugs are well absorbed and systemic clearance is determined by metabolism mediated by CYP2C, esterases, and UGTs. For class 1B drugs, oral absorption is high and the predominant clearance mechanism is hepatic uptake mediated by OATP transporters. High permeability neutral/basic drugs (class 2) showed high oral absorption, with metabolism mediated generally by CYP3A, CYP2D6 and UGTs as the predominant clearance mechanism. Class 3A/4 drugs showed moderate absorption with dominant renal clearance involving OAT/OCT2 transporters. Class 3B drugs showed low to moderate absorption with hepatic uptake (OATPs) and/or renal clearance as primary clearance mechanisms. The highest DDI risk is typically seen with class 2/1B/3B compounds manifested by inhibition of either CYP metabolism or active hepatic uptake. Class 2 showed a wider range in AUC change likely due to a variety of enzymes involved. DDI risk for class 3A/4 is small and associated with inhibition of renal transporters. ECCS provides a framework to project ADME profiles and further enables prediction of victim DDI liabilities in drug discovery and development.

Deregulated Renal Calcium and Phosphate Transport during Experimental Kidney Failure.

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Wilco P Pulskens

Full Text Available Impaired mineral homeostasis and inflammation are hallmarks of chronic kidney disease (CKD, yet the underlying mechanisms of electrolyte regulation during CKD are still unclear. Here, we applied two different murine models, partial nephrectomy and adenine-enriched dietary intervention, to induce kidney failure and to investigate the subsequent impact on systemic and local renal factors involved in Ca(2+ and Pi regulation. Our results demonstrated that both experimental models induce features of CKD, as reflected by uremia, and elevated renal neutrophil gelatinase-associated lipocalin (NGAL expression. In our model kidney failure was associated with polyuria, hypercalcemia and elevated urinary Ca(2+ excretion. In accordance, CKD augmented systemic PTH and affected the FGF23-αklotho-vitamin-D axis by elevating circulatory FGF23 levels and reducing renal αklotho expression. Interestingly, renal FGF23 expression was also induced by inflammatory stimuli directly. Renal expression of Cyp27b1, but not Cyp24a1, and blood levels of 1,25-dihydroxy vitamin D3 were significantly elevated in both models. Furthermore, kidney failure was characterized by enhanced renal expression of the transient receptor potential cation channel subfamily V member 5 (TRPV5, calbindin-D28k, and sodium-dependent Pi transporter type 2b (NaPi2b, whereas the renal expression of sodium-dependent Pi transporter type 2a (NaPi2a and type 3 (PIT2 were reduced. Together, our data indicates two different models of experimental kidney failure comparably associate with disturbed FGF23-αklotho-vitamin-D signalling and a deregulated electrolyte homeostasis. Moreover, this study identifies local tubular, possibly inflammation- or PTH- and/or FGF23-associated, adaptive mechanisms, impacting on Ca(2+/Pi homeostasis, hence enabling new opportunities to target electrolyte disturbances that emerge as a consequence of CKD development.

Towards a system-based pharmacology approach to predict developmental changes in renal drug clearance in children

NARCIS (Netherlands)

De Cock, Roosmarijn Frieda Wilfried

2014-01-01

Renal clearance is responsible for the elimination of a large number of water-soluble drugs and metabolites and is therefore of large importance when characterizing the pharmacokinetics of drugs. Renal clearance includes glomerular filtration, tubular secretion and reabsorption and each of these

Influence of multidrug resistance and drug transport proteins on chemotherapy drug metabolism.

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Joyce, Helena; McCann, Andrew; Clynes, Martin; Larkin, Annemarie

2015-05-01

Chemotherapy involving the use of anticancer drugs remains an important strategy in the overall management of patients with metastatic cancer. Acquisition of multidrug resistance remains a major impediment to successful chemotherapy. Drug transporters in cell membranes and intracellular drug metabolizing enzymes contribute to the resistance phenotype and determine the pharmacokinetics of anticancer drugs in the body. ATP-binding cassette (ABC) transporters mediate the transport of endogenous metabolites and xenobiotics including cytotoxic drugs out of cells. Solute carrier (SLC) transporters mediate the influx of cytotoxic drugs into cells. This review focuses on the substrate interaction of these transporters, on their biology and what role they play together with drug metabolizing enzymes in eliminating therapeutic drugs from cells. The majority of anticancer drugs are substrates for the ABC transporter and SLC transporter families. Together, these proteins have the ability to control the influx and the efflux of structurally unrelated chemotherapeutic drugs, thereby modulating the intracellular drug concentration. These interactions have important clinical implications for chemotherapy because ultimately they determine therapeutic efficacy, disease progression/relapse and the success or failure of patient treatment.

Alteration of renal excretion pathways in gentamicin-induced renal injury in rats.

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Ma, Yan-Rong; Luo, Xuan; Wu, Yan-Fang; Zhang, Tiffany; Zhang, Fan; Zhang, Guo-Qiang; Wu, Xin-An

2018-02-20

The kidney plays a major part in the elimination of many drugs and their metabolites, and drug-induced kidney injury commonly alters either glomerular filtration or tubular transport, or both. However, the renal excretion pathway of drugs has not been fully elucidated at different stages of renal injury. This study aimed to evaluate the alteration of renal excretion pathways in gentamicin (GEN)-induced renal injury in rats. Results showed that serum cystatin C, creatinine and urea nitrogen levels were greatly increased by the exposure of GEN (100 mg kg -1 ), and creatinine concentration was increased by 39.7% by GEN (50 mg kg -1 ). GEN dose-dependently upregulated the protein expression of rOCT1, downregulated rOCT2 and rOAT1, but not affected rOAT2. Efflux transporters, rMRP2, rMRP4 and rBCRP expressions were significantly increased by GEN(100), and the rMATE1 level was markedly increased by GEN(50) but decreased by GEN(100). GEN(50) did not alter the urinary excretion of inulin, but increased metformin and furosemide excretion. However, GEN(100) resulted in a significant decrease of the urinary excretion of inulin, metformin and p-aminohippurate. In addition, urinary metformin excretions in vivo were significantly decreased by GEN(100), but slightly increased by GEN(50). These results suggested that GEN(50) resulted in the induction of rOCTs-rMATE1 and rOAT3-rMRPs pathway, but not changed the glomerular filtration rate, and GEN(100)-induced acute kidney injury caused the downregulated function of glomerular filtration -rOCTs-rMATE1 and -rOAT1-rMRPs pathway. Copyright © 2018 John Wiley & Sons, Ltd.

Roles of Akt and SGK1 in the Regulation of Renal Tubular Transport

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Nobuhiko Satoh

2015-01-01

Full Text Available A serine/threonine kinase Akt is a key mediator in various signaling pathways including regulation of renal tubular transport. In proximal tubules, Akt mediates insulin signaling via insulin receptor substrate 2 (IRS2 and stimulates sodium-bicarbonate cotransporter (NBCe1, resulting in increased sodium reabsorption. In insulin resistance, the IRS2 in kidney cortex is exceptionally preserved and may mediate the stimulatory effect of insulin on NBCe1 to cause hypertension in diabetes via sodium retention. Likewise, in distal convoluted tubules and cortical collecting ducts, insulin-induced Akt phosphorylation mediates several hormonal signals to enhance sodium-chloride cotransporter (NCC and epithelial sodium channel (ENaC activities, resulting in increased sodium reabsorption. Serum- and glucocorticoid-inducible kinase 1 (SGK1 mediates aldosterone signaling. Insulin can stimulate SGK1 to exert various effects on renal transporters. In renal cortical collecting ducts, SGK1 regulates the expression level of ENaC through inhibition of its degradation. In addition, SGK1 and Akt cooperatively regulate potassium secretion by renal outer medullary potassium channel (ROMK. Moreover, sodium-proton exchanger 3 (NHE3 in proximal tubules is possibly activated by SGK1. This review focuses on recent advances in understanding of the roles of Akt and SGK1 in the regulation of renal tubular transport.

The anti-epileptic drug substance vigabatrin inhibits taurine transport in intestinal and renal cell culture models

DEFF Research Database (Denmark)

Plum, Jakob Munk; Nøhr, Martha Kampp; Hansen, Steen H

2014-01-01

, such evidence does not preclude the involvement of other transporters. The aim of the present study was, therefore, to investigate if vigabatrin interacts with taurine transport. The uptake of taurine was measured in intestinal human Caco-2 and canine MDCK cell monolayers in the absence or presence of amino...... acids such as GABA and vigabatrin. Vigabatrin inhibits the uptake of taurine in Caco-2 and MDCK cells to 34±3 and 53±2%, respectively, at a concentration of 30mM. In Caco-2 cells the uptake of vigabatrin under neutral pH conditions is concentration-dependent and saturable with a Km-value of 27mM (log......Km is 1.43±0.09). In conclusion, the present study shows that vigabatrin was able to inhibit the uptake of taurine in intestinal and renal cell culture models. Furthermore, uptake of vigabatrin in Caco-2 cells under neutral pH conditions was concentration-dependent and saturable and suggesting...

Renal transport and metabolism of nicotinic acid

International Nuclear Information System (INIS)

Schuette, S.; Rose, R.C.

1986-01-01

Renal metabolism and brush-border transport of nicotinic acid were studied in renal cortical slices and brush-border membrane vesicles exposed to a physiological concentration of vitamin (2.2-3.5 microM). Vesicle transport of [ 3 H]nicotinic acid was found to be Na+ dependent and concentrative. The presence of a Na+ gradient resulted in a fivefold increase in the rate of nicotinic acid uptake over that observed with mannitol and caused a transient nicotinic acid accumulation two- to fourfold above the equilibrium value. The effects of membrane potential, pH, and elimination of Na+-H+ exchange were also studied. Cortical slices and isolated tubules exposed to 2.2 microM [ 14 C]nicotinic acid took up vitamin and rapidly metabolized most of it to intermediates in the Preiss-Handler pathway for NAD biosynthesis; little free nicotinic acid was detectable intracellularly. The replacement of Na+ with Li+ in the bathing medium reduced total accumulation of 14 C label primarily as a result of reduced nicotinic acid uptake. Cortical tissue concentrated free nicotinic acid only when the involved metabolic pathways were saturated by levels of nicotinic acid far in excess of what occurs in vivo

The effect of screening for cardio-renal risk factors on drug use in the general population

NARCIS (Netherlands)

Atthobari, J.; Gansevoort, R.T.; Visser, S.T.; De Jong, P.E.; de Jong-van den Berg, L.T.

2007-01-01

Aims To evaluate the effect of a cardio-renal screening programme on desired and undue drug use. Methods Data from the PREVEND cohort (Prevention of REnal and Vascular ENd-stage Disease) were used. The drug use of screened (randomly) selected subjects (n = 2650) was compared with unscreened

Drug Dosing and Estimated Renal Function-Any Step Forward from Effersoe?

DEFF Research Database (Denmark)

Hornum, Mads; Feldt-Rasmussen, Bo

2017-01-01

Drug dosing in accordance with the renal function is a long-standing challenge to clinicians. For many years it has been evident that in many clinical situations there is no easy way to correctly dose any drug that is mainly cleared by the kidneys. Despite the development of many formulas...

Drug disposition and drug-drug interaction data in 2013 FDA new drug applications: a systematic review.

Science.gov (United States)

Yu, Jingjing; Ritchie, Tasha K; Mulgaonkar, Aditi; Ragueneau-Majlessi, Isabelle

2014-12-01

The aim of the present work was to perform a systematic review of drug metabolism, transport, pharmacokinetics, and DDI data available in the NDAs approved by the FDA in 2013, using the University of Washington Drug Interaction Database, and to highlight significant findings. Among 27 NMEs approved, 22 (81%) were well characterized with regard to drug metabolism, transport, or organ impairment, in accordance with the FDA drug interaction guidance (2012) and were fully analyzed in this review. In vitro, a majority of the NMEs were found to be substrates or inhibitors/inducers of at least one drug metabolizing enzyme or transporter. However, in vivo, only half (n = 11) showed clinically relevant drug interactions, with most related to the NMEs as victim drugs and CYP3A being the most affected enzyme. As perpetrators, the overall effects for NMEs were much less pronounced, compared with when they served as victims. In addition, the pharmacokinetic evaluation in patients with hepatic or renal impairment provided useful information for further understanding of the drugs' disposition. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

Drug-drug interactions of antifungal agents and implications for patient care.

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Gubbins, Paul O; Amsden, Jarrett R

2005-10-01

Drug interactions in the gastrointestinal tract, liver and kidneys result from alterations in pH, ionic complexation, and interference with membrane transport proteins and enzymatic processes involved in intestinal absorption, enteric and hepatic metabolism, renal filtration and excretion. Azole antifungals can be involved in drug interactions at all the sites, by one or more of the above mechanisms. Consequently, azoles interact with a vast array of compounds. Drug-drug interactions associated with amphotericin B formulations are predictable and result from the renal toxicity and electrolyte disturbances associated with these compounds. The echinocandins are unknown cytochrome P450 substrates and to date are relatively devoid of significant drug-drug interactions. This article reviews drug interactions involving antifungal agents that affect other agents and implications for patient care are highlighted.

Testosterone increases urinary calcium excretion and inhibits expression of renal calcium transport proteins.

NARCIS (Netherlands)

Hsu, Y.J.; Dimke, H.; Schoeber, J.P.H.; Hsu, S.C.; Lin, S.H.; Chu, P.; Hoenderop, J.G.J.; Bindels, R.J.M.

2010-01-01

Although gender differences in the renal handling of calcium have been reported, the overall contribution of androgens to these differences remains uncertain. We determined here whether testosterone affects active renal calcium reabsorption by regulating calcium transport proteins. Male mice had

Evidence of active transport of cadmium complexing dithiocarbamates into renal and hepatic cells in vivo

International Nuclear Information System (INIS)

Gale, G.R.; Smith, A.B.; Jones, M.M.; Singh, P.K.

1992-01-01

A study was made of the effects of certain inhibitors of transport systems on the actions of four cadmium (Cd) complexing N,N-disubstituted dithiocarbamates (DTCs) in mobilizing murine renal and hepatic Cd in vivo. Probenecid, the prototypical antagonist of organic anion transport in the kidney, when given 1 hr prior to each DTC, sharply suppressed the DTC-induced reduction of renal Cd but was virtually without effect on mobilization of Cd from liver. Sulfinpyrazone, which blocks tubular reabsorption of uric acid and also inhibits transport of a variety of organic acids, inhibited markedly the mobilization of both renal and hepatic Cd by DTCs. Phlorizin, an inhibitor of tubular sugar reabsorption, did not affect the Cd mobilizing actions of DTCs in any consistent fashion. We propose that the high degree of selectivity of DTCs in mobilizing renal hepatic Cd is dependent, at lest in part, upon active transport of DTCs into these tissues via the organic anion transport systems. This report presents the first evidence that compounds of the (R) 2 NCSS - class may gain access to intracellular space by an active, carrier-mediated process. (au)

78 FR 76308 - Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting

Science.gov (United States)

2013-12-17

...: Cardiovascular and Renal Drugs Advisory Committee. General Function of the Committee: To provide advice and... enter through Building 1. Contact Person: Kristina Toliver, Center for Drug Evaluation and Research... system atrophy, or pure autonomic failure), dopamine beta-hydroxylase deficiency, and non-diabetic...

Augmented Renal Clearance in Critical Illness: An Important Consideration in Drug Dosing

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Sherif Hanafy Mahmoud

2017-09-01

Full Text Available Augmented renal clearance (ARC is a manifestation of enhanced renal function seen in critically ill patients. The use of regular unadjusted doses of renally eliminated drugs in patients with ARC might lead to therapy failure. The purpose of this scoping review was to provide and up-to-date summary of the available evidence pertaining to the phenomenon of ARC. A literature search of databases of available evidence in humans, with no language restriction, was conducted. Databases searched were MEDLINE (1946 to April 2017, EMBASE (1974 to April 2017 and the Cochrane Library (1999 to April 2017. A total of 57 records were included in the present review: 39 observational studies (25 prospective, 14 retrospective, 6 case reports/series and 12 conference abstracts. ARC has been reported to range from 14–80%. ARC is currently defined as an increased creatinine clearance of greater than 130 mL/min/1.73 m2 best measured by 8–24 h urine collection. Patients exhibiting ARC tend to be younger (<50 years old, of male gender, had a recent history of trauma, and had lower critical illness severity scores. Numerous studies have reported antimicrobials treatment failures when using standard dosing regimens in patients with ARC. In conclusion, ARC is an important phenomenon that might have significant impact on outcome in critically ill patients. Identifying patients at risk, using higher doses of renally eliminated drugs or use of non-renally eliminated alternatives might need to be considered in ICU patients with ARC. More research is needed to solidify dosing recommendations of various drugs in patients with ARC.

Interaction of Drug or Food with Drug Transporters in Intestine and Liver.

Science.gov (United States)

Nakanishi, Takeo; Tamai, Ikumi

2015-01-01

Oral bioavailability (F) is determined as fraction of the drug dose absorbed through the gastrointestinal membranes (Fa), the unmetabolized fraction of the absorbed dose that passes through the gut into the portal blood (Fg), and the hepatic first pass availability (Fh), namely F is expressed as the product of Fa, Fg and Fh (F = Fa.Fg.Fh). Current evidence suggests that transporter proteins play a role in intestinal absorption and hepatobiliary clearance of drugs. Among those transporters, this review will focus on PEPT1 and OATP2B1 as influx transporter and p-glycoprotein (P-gp) and BCRP as efflux transporter in intestinal epithelial cells, and on OATP1B1 and 1B3 as influx transporter and MRP2 as efflux transporter in hepatocytes, respectively, because drug-drug (DDI) and -food (DFI) interactions on these transporter are considered to affect bioavailability of their substrate drugs. DDI and DFI may reduce systemic exposure to drug by blocking influx transporters in intestine, but increase it by modulating influx and efflux transporters in liver and efflux transporters in intestines. Namely, drug disposition and efficacy are likely affected by DDI and DFI, resulting in treatment failures or increase in adverse effect. Therefore, it is of significantly importance to understand precise mechanism of DDI and DFI. This review will present information about transporter-based DDI and DFI in the processes of intestinal absorption and hepatic clearance of drugs, and discuss about their clinical implication.

Hepatic and renal Bcrp transporter expression in mice treated with perfluorooctanoic acid

International Nuclear Information System (INIS)

Eldasher, Lobna M.; Wen, Xia; Little, Michael S.; Bircsak, Kristin M.; Yacovino, Lindsay L.; Aleksunes, Lauren M.

2013-01-01

Highlights: ► PFOA increased liver weight and Cyp4a14 mRNA and protein expression in mice. ► PFOA increased kidney Cyp4a14 mRNA in mice. ► PFOA increased Bcrp mRNA and protein in livers, but not kidneys, of mice. ► PFOA inhibited activation of human BCRP ATPase activity in vitro. ► PFOA inhibited human BCRP transport in inverted membrane vesicles. - Abstract: The breast cancer resistance protein (Bcrp) is an efflux transporter that participates in the biliary and renal excretion of drugs and environmental chemicals. Recent evidence suggests that pharmacological activation of the peroxisome proliferator activated receptor alpha (PPARα) can up-regulate the hepatic expression of Bcrp. The current study investigated the regulation of hepatic and renal Bcrp mRNA and protein in mice treated with the PPARα agonist perfluorooctanoic acid (PFOA) and the ability of PFOA to alter human BCRP function in vitro. Bcrp mRNA and protein expression were quantified in the livers and kidneys of male C57BL/6 mice treated with vehicle or PFOA (1 or 3 mg/kg/day oral gavage) for 7 days. PFOA treatment increased liver weights as well as the hepatic mRNA and protein expression of the PPARα target gene, cytochrome P450 4a14. Compared to vehicle-treated control mice, PFOA increased hepatic Bcrp mRNA and protein between 1.5- and 3-fold. Immunofluorescent staining confirmed enhanced canalicular Bcrp staining in liver sections from PFOA-treated mice. The kidney expression of cytochrome P450 4a14 mRNA, but not Bcrp, was increased in mice treated with PFOA. Micromolar concentrations of PFOA decreased human BCRP ATPase activity and inhibited BCRP-mediated transport in inverted membrane vesicles. Together, these studies demonstrate that PFOA induces hepatic Bcrp expression in mice and may inhibit human BCRP transporter function at concentrations that exceed levels observed in humans

Di/tri-peptide transporters as drug delivery targets

DEFF Research Database (Denmark)

Nielsen, C U; Brodin, Birger

2003-01-01

-dependent, and the transporters thus belong to the Proton-dependent Oligopeptide Transporter (POT)-family. The transporters are not drug targets per se, however due to their uniquely broad substrate specificity; they have proved to be relevant drug targets at the level of drug transport. Drug molecules such as oral active beta....../tri-peptide transporters from vesicular storages 3) changes in gene transcription/mRNA stability. The aim of the present review is to discuss physiological, patho-physiological and drug-induced regulation of di/tri-peptide transporter mediated transport....

Predicting transporter-mediated drug interactions: Commentary on: "Pharmacokinetic evaluation of a drug transporter cocktail consisting of digoxin, furosemide, metformin and rosuvastatin" and "Validation of a microdose probe drug cocktail for clinical drug interaction assessments for drug transporters and CYP3A".

Science.gov (United States)

Zhang, L; Sparreboom, A

2017-04-01

Transporters, expressed in various tissues, govern the absorption, distribution, metabolism, and excretion of drugs, and consequently their inherent safety and efficacy profiles. Drugs may interact with a transporter as a substrate and/or an inhibitor. Understanding transporter-mediated drug-drug interactions (DDIs), in addition to enzyme-mediated DDIs, is an integral part of risk assessment in drug development and regulatory review because the concomitant use of more than one medication in patients is common. © 2016 ASCPT.

Distribution of glucose transporters in renal diseases

OpenAIRE

Szablewski, Leszek

2017-01-01

Kidneys play an important role in glucose homeostasis. Renal gluconeogenesis prevents hypoglycemia by releasing glucose into the blood stream. Glucose homeostasis is also due, in part, to reabsorption and excretion of hexose in the kidney. Lipid bilayer of plasma membrane is impermeable for glucose, which is hydrophilic and soluble in water. Therefore, transport of glucose across the plasma membrane depends on carrier proteins expressed in the plasma membrane. In humans, there are three famil...

Effect of Diuretics on Renal Tubular Transport of Calcium and Magnesium

DEFF Research Database (Denmark)

Alexander, R Todd; Dimke, Henrik

2017-01-01

are important for both forming divalent cation permeable pores and channels, but also for generating the necessary driving forces for Ca2+ and Mg2+ transport. Alterations in these molecular constituents lead to profound effects on tubular Ca2+ and Mg2+ handling. Diuretics are used to treat a large range...... of clinical conditions, but most commonly for the management of blood pressure and fluid balance. The pharmacological targets of diuretics generally directly facilitate sodium (Na+) transport, but also indirectly affect renal Ca2+ and Mg2+ handling, i.e. by establishing a prerequisite electrochemical gradient....... It is therefore not surprising that substantial alterations in divalent cation handling can be observed following diuretic treatment. The effects of diuretics on renal Ca2+ and Mg2+ handling are reviewed in the context of the current understanding of basal molecular mechanisms of Ca2+ and Mg2+ transport...

Use of nonsteroidal anti-inflammatory drugs prior to chronic renal replacement therapy initiation

DEFF Research Database (Denmark)

Kristensen, Søren Lund; Fosbøl, Emil L; Kamper, Anne-Lise

2012-01-01

PURPOSE: Nonsteroidal anti-inflammatory drugs (NSAIDs) may be associated with severe renal complications, including acute renal failure, reduced glomerular filtration rate and interstitial nephritis. Caution against NSAIDs is therefore recommended in advanced chronic kidney disease. In this study......, we examined NSAID use, aetiology and comorbidity among a national cohort of patients before the initiation of chronic renal replacement therapy (RRT). METHODS: Patients initiated on chronic RRT in the period 1997-2006 were identified in the Danish National Registry on Regular Dialysis...

Potential beneficial effects of sacubitril-valsartan in renal disease: a new field for a new drug.

Science.gov (United States)

Gervasini, Guillermo; Robles, Nicolas Roberto

2017-05-01

Patients with renal dysfunction are at a higher risk of cardiovascular disease (CVD), which often shares manifestations with heart failure (HF). Last year, the FDA approved the use of sacubitril-valsartan in patients with HF. This dual-acting agent enhances the functions of natriuretic peptides and inhibits the renin-angiotensin system. Areas covered: This review summarizes the existing preclinical and clinical studies carried out with sacubitril-valsartan (and other drugs with similar pharmacological mechanisms) in HF and hypertensive patients. We put the focus on the renal data provided by these studies. Data were obtained from English peer-reviewed articles on PubMed and clinical trials registered in ClinicalTrials.gov. Expert opinion: Overall, sacubitril-valsartan might be a promising therapeutic approach in patients with renal dysfunction. Renal conditions with marked CV risk, such as arterionephrosclerosis, could constitute a particular setting where to evaluate the impact of the drug. Nevertheless, large, randomized trials are needed to confirm the beneficial effects and safety profile of the drug in renal patients, as well as to elucidate some concerns observed in HF trials, such as the slight increase in proteinuria.

Update on the renal toxicity of iodinated contrast drugs used in clinical medicine

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Andreucci M

2017-05-01

Full Text Available Michele Andreucci,1 Teresa Faga,1 Raffaele Serra,2 Giovambattista De Sarro,3 Ashour Michael1 1Renal Unit, Department of Health Sciences, 2Interuniversity Center of Phlebolymphology (CIFL, International Research and Educational Program in Clinical and Experimental Biotechnology, Department of Medical and Surgical Sciences, 3Pharmacology Unit, Department of Health Sciences, Magna Graecia University, Catanzaro, Italy Abstract: An important side effect of diagnostic contrast drugs is contrast-induced acute kidney injury (CI-AKI; a sudden decrease in renal function occurring 48–72 hours after injection of a contrast drug that cannot be attributed to other causes. Its existence has recently been challenged, because of some retrospective studies in which the incidence of AKI was not different between subjects who received a contrast drug and those who did not, even using propensity score matching to prevent selection bias. For some authors, only patients with estimated glomerular filtration rate <30 mL/min/1.73 m2 are at significant risk of CI-AKI. Most agree that when renal function is normal, there is no CI-AKI risk. Many experimental studies, however, are in favor of the existence of CI-AKI. Contrast drugs have been shown to cause the following changes: renal vasoconstriction, resulting in a rise in intrarenal resistance (decrease in renal blood flow and glomerular filtration rate and medullary hypoxia; epithelial vacuolization and dilatation and necrosis of proximal tubules; potentiation of angiotensin II effects, reducing nitric oxide (NO and causing direct constriction of descending vasa recta, leading to formation of reactive oxygen species in isolated descending vasa recta of rats microperfused with a solution of iodixanol; increasing active sodium reabsorption in the thick ascending limbs of Henle’s loop (increasing O2 demand and consequently medullary hypoxia; direct cytotoxic effects on endothelial and tubular epithelial cells (decrease

Acute renal failure secondary to drug-related crystalluria and/or drug reaction with eosinophilia and systemic symptom syndrome in a patient with metastatic lung cancer

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Saime Paydas

2017-01-01

Full Text Available Drug reaction with eosinophilia and systemic symptoms (DRESS or drug-induced hypersensitivity is a severe adverse drug-induced reaction. Aromatic anticonvulsants, such as phenytoin, phenobarbital, and carbamazepine, and some drugs, can induce DRESS. Atypical crystalluria can be seen in patients treated with amoxycillin or some drugs and can cause acute renal failure. We describe a 66-year-old man who presented fever and rash and acute renal failure three days after starting amoxycillin. He was also using phenytoin because of cerebral metastatic lung cancer. Investigation revealed eosinophilia and atypical crystalluria. The diagnosis of DRESS syndrome was made, amoxicillin was stopped, and dose of phenytoin was reduced. No systemic corticosteroid therapy was prescribed. Symptoms began to resolve within three to four days. The aim of this paper is to highlight the importance of microscopic examination of urine in a case with acute renal failure and skin lesions to suspect DRESS syndrome.

Characterization of Organic Anion Transporter 2 (SLC22A7): A Highly Efficient Transporter for Creatinine and Species-Dependent Renal Tubular Expression.

Science.gov (United States)

Shen, Hong; Liu, Tongtong; Morse, Bridget L; Zhao, Yue; Zhang, Yueping; Qiu, Xi; Chen, Cliff; Lewin, Anne C; Wang, Xi-Tao; Liu, Guowen; Christopher, Lisa J; Marathe, Punit; Lai, Yurong

2015-07-01

The contribution of organic anion transporter OAT2 (SLC22A7) to the renal tubular secretion of creatinine and its exact localization in the kidney are reportedly controversial. In the present investigation, the transport of creatinine was assessed in human embryonic kidney (HEK) cells that stably expressed human OAT2 (OAT2-HEK) and isolated human renal proximal tubule cells (HRPTCs). The tubular localization of OAT2 in human, monkey, and rat kidney was characterized. The overexpression of OAT2 significantly enhanced the uptake of creatinine in OAT2-HEK cells. Under physiologic conditions (creatinine concentrations of 41.2 and 123.5 µM), the initial rate of OAT2-mediated creatinine transport was approximately 11-, 80-, and 80-fold higher than OCT2, multidrug and toxin extrusion protein (MATE)1, and MATE2K, respectively, resulting in approximately 37-, 1850-, and 80-fold increase of the intrinsic transport clearance when normalized to the transporter protein concentrations. Creatinine intracellular uptake and transcellular transport in HRPTCs were decreased in the presence of 50 µM bromosulfophthalein and 100 µM indomethacin, which inhibited OAT2 more potently than other known creatinine transporters, OCT2 and multidrug and toxin extrusion proteins MATE1 and MATE2K (IC50: 1.3 µM vs. > 100 µM and 2.1 µM vs. > 200 µM for bromosulfophthalein and indomethacin, respectively) Immunohistochemistry analysis showed that OAT2 protein was localized to both basolateral and apical membranes of human and cynomolgus monkey renal proximal tubules, but appeared only on the apical membrane of rat proximal tubules. Collectively, the findings revealed the important role of OAT2 in renal secretion and possible reabsorption of creatinine and suggested a molecular basis for potential species difference in the transporter handling of creatinine. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Pharmacotherapy in pregnancy; effect of ABC and SLC transporters on drug transport across the placenta and fetal drug exposure.

Science.gov (United States)

Staud, Frantisek; Cerveny, Lukas; Ceckova, Martina

2012-11-01

Pharmacotherapy during pregnancy is often inevitable for medical treatment of the mother, the fetus or both. The knowledge of drug transport across placenta is, therefore, an important topic to bear in mind when deciding treatment in pregnant women. Several drug transporters of the ABC and SLC families have been discovered in the placenta, such as P-glycoprotein, breast cancer resistance protein, or organic anion/cation transporters. It is thus evident that the passage of drugs across the placenta can no longer be predicted simply on the basis of their physical-chemical properties. Functional expression of placental drug transporters in the trophoblast and the possibility of drug-drug interactions must be considered to optimize pharmacotherapy during pregnancy. In this review we summarize current knowledge on the expression and function of ABC and SLC transporters in the trophoblast. Furthermore, we put this data into context with medical conditions that require maternal and/or fetal treatment during pregnancy, such as gestational diabetes, HIV infection, fetal arrhythmias and epilepsy. Proper understanding of the role of placental transporters should be of great interest not only to clinicians but also to pharmaceutical industry for future drug design and development to control the degree of fetal exposure.

A bioartificial renal tubule device embedding human renal stem/progenitor cells.

Directory of Open Access Journals (Sweden)

Anna Giovanna Sciancalepore

Full Text Available We present a bio-inspired renal microdevice that resembles the in vivo structure of a kidney proximal tubule. For the first time, a population of tubular adult renal stem/progenitor cells (ARPCs was embedded into a microsystem to create a bioengineered renal tubule. These cells have both multipotent differentiation abilities and an extraordinary capacity for injured renal cell regeneration. Therefore, ARPCs may be considered a promising tool for promoting regenerative processes in the kidney to treat acute and chronic renal injury. Here ARPCs were grown to confluence and exposed to a laminar fluid shear stress into the chip, in order to induce a functional cell polarization. Exposing ARPCs to fluid shear stress in the chip led the aquaporin-2 transporter to localize at their apical region and the Na(+K(+ATPase pump at their basolateral portion, in contrast to statically cultured ARPCs. A recovery of urea and creatinine of (20±5% and (13±5%, respectively, was obtained by the device. The microengineered biochip here-proposed might be an innovative "lab-on-a-chip" platform to investigate in vitro ARPCs behaviour or to test drugs for therapeutic and toxicological responses.

Impact of renal aging on drug therapy.

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Musso, Carlos G; Belloso, Waldo H; Scibona, Paula; Bellizzi, Vincenzo; Macías Núñez, Juan F

2015-08-01

Elderly patients (age ≥ 65 years old) use up to 30% of all commonly prescribed medication, and they suffer more their adverse effects than the general population. In order to minimize this risk, physicians should avoid polypharmacy, dangerous pharmacological interactions and take into account pharmacodynamic and senile pharmacokinetic changes before prescribing any medication to the elderly. The present review article originally describes how renal physiology changes secondary to aging such as dysautonomia, glomerular filtration rate reduction, tubular back-filtration, sodium, calcium and magnesium loss, potassium retention, altered dilution-concentration capability, tubular frailty, genetics, internal milieu and body composition are senile changes that when combined predispose elderly people to suffer from pharmacological adverse effects. Knowledge of these physiological modifications associated with aging and their impact on the pharmacology of particular drugs may help to optimize drug use and to avoid complications in this age group.

Divide and conquer: processive transport enables multidrug transporters to tackle challenging drugs

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Nir Fluman

2014-09-01

Full Text Available Multidrug transporters are membrane proteins that catalyze efflux of antibiotics and other toxic compounds from cells, thereby conferring drug resistance on various organisms. Unlike most solute transporters that transport a single type of compound or similar analogues, multidrug transporters are extremely promiscuous. They transport a broad spectrum of dissimilar drugs and represent a serious obstacle to antimicrobial or anticancer chemotherapy. Many challenging aspects of multidrug transporters, which are unique, have been studied in detail, including their ability to interact with chemically unrelated drugs, and how they utilize energy to drive efflux of compounds that are not only structurally but electrically different. A new and surprising dimension of the promiscuous nature of multidrug transporters has been described recently: they can move long molecules through the membrane in a processive manner.

Interplay of drug metabolizing enzymes with cellular transporters.

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Böhmdorfer, Michaela; Maier-Salamon, Alexandra; Riha, Juliane; Brenner, Stefan; Höferl, Martina; Jäger, Walter

2014-11-01

Many endogenous and xenobiotic substances and their metabolites are substrates for drug metabolizing enzymes and cellular transporters. These proteins may not only contribute to bioavailability of molecules but also to uptake into organs and, consequently, to overall elimination. The coordinated action of uptake transporters, metabolizing enzymes, and efflux pumps, therefore, is a precondition for detoxification and elimination of drugs. As the understanding of the underlying mechanisms is important to predict alterations in drug disposal, adverse drug reactions and, finally, drug-drug interactions, this review illustrates the interplay between selected uptake/efflux transporters and phase I/II metabolizing enzymes.

A role for the organic anion transporter OAT3 in renal creatinine secretion in mice

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Eraly, Satish A.; Rao, Satish Ramachandra; Gerasimova, Maria; Rose, Michael; Nagle, Megha; Anzai, Naohiko; Smith, Travis; Sharma, Kumar; Nigam, Sanjay K.; Rieg, Timo

2012-01-01

Tubular secretion of the organic cation, creatinine, limits its value as a marker of glomerular filtration rate (GFR) but the molecular determinants of this pathway are unclear. The organic anion transporters, OAT1 and OAT3, are expressed on the basolateral membrane of the proximal tubule and transport organic anions but also neutral compounds and cations. Here, we demonstrate specific uptake of creatinine into mouse mOat1- and mOat3-microinjected Xenopus laevis oocytes at a concentration of 10 μM (i.e., similar to physiological plasma levels), which was inhibited by both probenecid and cimetidine, prototypical competitive inhibitors of organic anion and cation transporters, respectively. Renal creatinine clearance was consistently greater than inulin clearance (as a measure of GFR) in wild-type (WT) mice but not in mice lacking OAT1 (Oat1−/−) and OAT3 (Oat3−/−). WT mice presented renal creatinine net secretion (0.23 ± 0.03 μg/min) which represented 45 ± 6% of total renal creatinine excretion. Mean values for renal creatinine net secretion and renal creatinine secretion fraction were not different from zero in Oat1−/− (−0.03 ± 0.10 μg/min; −3 ± 18%) and Oat3−/− (0.01 ± 0.06 μg/min; −6 ± 19%), with greater variability in Oat1−/−. Expression of OAT3 protein in the renal membranes of Oat1−/− mice was reduced to ∼6% of WT levels, and that of OAT1 in Oat3−/− mice to ∼60%, possibly as a consequence of the genes for Oat1 and Oat3 having adjacent chromosomal locations. Plasma creatinine concentrations of Oat3−/− were elevated in clearance studies under anesthesia but not following brief isoflurane anesthesia, indicating that the former condition enhanced the quantitative contribution of OAT3 for renal creatinine secretion. The results are consistent with a contribution of OAT3 and possibly OAT1 to renal creatinine secretion in mice. PMID:22338083

Acid-base status determines the renal expression of Ca2+ and Mg2+ transport proteins.

NARCIS (Netherlands)

Nijenhuis, T.; Renkema, K.Y.; Hoenderop, J.G.J.; Bindels, R.J.M.

2006-01-01

Chronic metabolic acidosis results in renal Ca2+ and Mg2+ wasting, whereas chronic metabolic alkalosis is known to exert the reverse effects. It was hypothesized that these adaptations are mediated at least in part by the renal Ca2+ and Mg2+ transport proteins. The aim of this study, therefore, was

Drug-related acute renal failure in hospitalised patients.

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Iavecchia, Lujan; Cereza García, Gloria; Sabaté Gallego, Mònica; Vidal Guitart, Xavier; Ramos Terrades, Natalia; de la Torre, Judith; Segarra Medrano, Alfons; Agustí Escasany, Antònia

2015-01-01

The information available on the incidence and the characteristics of patients with acute renal failure (ARF) related to drugs is scarce. To estimate the incidence of drug-related ARF in hospitalised patients and to compare their characteristics with those of patients with ARF due to other causes. We selected a prospective cohort of patients with ARF during hospital admission (July 2010-July 2011). Information on patients' demographics, medical antecedents, ARF risk factors, ARF severity according to the RIFLE classification and hospital drug administration was collected. We analysed the relationship of drugs with the ARF episodes using Spanish Pharmacovigilance System methods and algorithm. A total of 194 cases had an episode of hospital-acquired ARF. The median age of patients was 72 years [IQR 20]; 60% were men. The ARF incidence during hospitalization was 9.6 per 1,000 admissions. According to the RIFLE classification, a risk of kidney damage or kidney injury was present in 77.8% of cases. In 105 (54.1%) cases, ARF was drug-related; the drugs most frequently involved were diuretics, agents acting on the renin-angiotensin system, immunosuppressants, β-blocking agents, calcium channel blockers, contrast media and non-steroid anti-inflammatory drugs. Patients with drug-related ARF had more multi-morbidity, fewer ARF risk factors and lower mortality. Half of ARF episodes during hospitalisation were drug related. Patients with drug-related ARF had higher cardiovascular morbidity than those with ARF related to other causes, but they had a lower frequency of ARF risk factors and mortality. Copyright © 2015 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.

Interplay of Drug-Metabolizing Enzymes and Transporters in Drug Absorption and Disposition.

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Shi, Shaojun; Li, Yunqiao

2014-01-01

In recent years, the functional interplay between drug-metabolizing enzymes (DMEs) and drug transporters (DTs) in drug absorption and disposition, as well as the complex drug interactions (DIs), has become an intriguing contention, which has also been termed the "transport-metabolism interplay". The current mechanistic understanding for this interplay is first discussed. In the present article, studies investigating the interplay between cytochrome P450 enzymes (CYPs) and efflux transporters have been systematically reviewed in vitro, in situ, in silico, in animals and humans, followed by CYPs-uptake transporters, CYPs-uptake transporters-efflux transporters, and phase II metabolic enzymes-transporters interplay studies. Although several cellular, isolated organ and whole animal studies, in conjunction with simulation and modelling, have addressed the issue that DMEs and DTs can work cooperatively to affect the bioavailability of shared substrate drugs, convincing evidences in human studies are still lacking. Furthermore, the functional interplay between DMEs and DTs will be highly substrate- and dose- dependent. Additionally, we review recent studies to evaluate the influence of genetic variations in the interplay between DMEs and DTs, which might be helpful for the prediction of pharmacokinetics (PK) and possible DIs in human more correctly. There is strong evidence of coordinately regulated DEMs and DTs gene expression and protein activity (e.g. nuclear receptors). Taken together, further investigations and analysis are urgently needed to explore the functional interplay of DMEs and DTs and to delineate the underlying mechanisms.

Evaluation of transporters in drug development: Current status and contemporary issues.

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Lee, Sue-Chih; Arya, Vikram; Yang, Xinning; Volpe, Donna A; Zhang, Lei

2017-07-01

Transporters govern the access of molecules to cells or their exit from cells, thereby controlling the overall distribution of drugs to their intracellular site of action. Clinically relevant drug-drug interactions mediated by transporters are of increasing interest in drug development. Drug transporters, acting alone or in concert with drug metabolizing enzymes, can play an important role in modulating drug absorption, distribution, metabolism and excretion, thus affecting the pharmacokinetics and/or pharmacodynamics of a drug. The drug interaction guidance documents from regulatory agencies include various decision criteria that may be used to predict the need for in vivo assessment of transporter-mediated drug-drug interactions. Regulatory science research continues to assess the prediction performances of various criteria as well as to examine the strength and limitations of each prediction criterion to foster discussions related to harmonized decision criteria that may be used to facilitate global drug development. This review discusses the role of transporters in drug development with a focus on methodologies in assessing transporter-mediated drug-drug interactions, challenges in both in vitro and in vivo assessments of transporters, and emerging transporter research areas including biomarkers, assessment of tissue concentrations, and effect of diseases on transporters. Published by Elsevier B.V.

Renal aquaporins and sodium transporters with special focus on urinary tract obstruction

DEFF Research Database (Denmark)

Frøkiaer, Jørgen; Li, Chunling; Shi, Yimin

2003-01-01

seven aquaporins are expressed at distinct sites in the kidney and 4 members of this family (AQP1-4) have been demonstrated to play pivotal roles in the physiology and pathophysiology for renal regulation of body water balance. Osmotic equilibration via renal aquaporins is maintained by active transport......The discovery of aquaporin-1 (AQP1) by Agre and colleagues explained the long-standing biophysical question of how water specifically crosses biological membranes. These studies led to the discovery and identification of a whole new family of membrane proteins, the aquaporins. At present, at least...

Yohimbine-induced cutaneous drug eruption, progressive renal failure, and lupus-like syndrome.

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Sandler, B; Aronson, P

1993-04-01

Yohimbine is an indole alkaloid obtained from the yohimbe tree, a common tree in West Africa. We describe a forty-two-year black man in whom a generalized erythrodermic skin eruption, progressive renal failure, and lupus-like syndrome developed following treatment with the drug, yohimbine. A literature review failed to reveal any reported association of these side effects. We review current information on yohimbine's use in male impotence, reported side effects, and its role as a drug allergen.

Renal handling of drugs in renal failure. I: Differential effects of uranyl nitrate- and glycerol-induced acute renal failure on renal excretion of TEAB and PAH in rats

International Nuclear Information System (INIS)

Lin, J.H.; Lin, T.H.

1988-01-01

Two etiologically different models of experimental acute renal failure were induced in rats by administration of either glycerol or uranyl nitrate. Both compounds caused a substantial decrease in the glomerular filtration rate (GFR) and the net tubular secretion of tetraethylammonium bromide (TEAB) and para-aminohippuric acid (PAH). The degree of renal impairment induced by uranyl nitrate and glycerol appeared to be dose related. Deprivation of drinking water 24 hr before the administration of glycerol potentiated the renal damage. In uranyl nitrate-induced renal failure, the decline of the net tubular secretion for TEAB and PAH was not proportional to the decrease in GFR; the secretion process deteriorated faster than the GFR. For example, when 0.5 mg/kg uranyl nitrate was administered, GFR fell to approximately 65% of normal, whereas the net tubular secretion was decreased to 30% of normal. These results suggest that the tubular transport was preferentially affected by uranyl nitrate. In contrast, in glycerol-induced renal failure, the decline of TEAB secretion fell in a parallel fashion with the GFR, suggesting that the glomeruli and the proximal tubules were equally damaged by glycerol. However, in this latter model, the decline of PAH secretion did not parallel the decrease in GFR, contradicting the proposal that glycerol affects equally the glomeruli and the proximal tubules. This discrepancy may be due to the selective competitive inhibition of PAH secretion by the accumulation of naturally occurring organic acids

Nephron segment specific microRNA biomarkers of pre-clinical drug-induced renal toxicity: Opportunities and challenges

Energy Technology Data Exchange (ETDEWEB)

Nassirpour, Rounak, E-mail: Rounak.nassirpour@pfizer.com [Drug Safety, Pfizer Worldwide Research and Development, 1 Burtt Rd, Andover, MA 01810 (United States); Ramaiah, Shashi K. [Drug Safety, Pfizer Worldwide Research and Development, 610 Main Street, Cambridge, MA 02139 (United States); Whiteley, Laurence O. [Drug Safety, Pfizer Worldwide Research and Development, 1 Burtt Rd, Andover, MA 01810 (United States)

2016-12-01

Drug-induced nephrotoxicity is a common drug development complication for pharmaceutical companies. Sensitive, specific, translatable and non-invasive biomarkers of renal toxicity are urgently needed to diagnose nephron segment specific injury. The currently available gold standard biomarkers for nephrotoxicity are not kidney-specific, lack sensitivity for early detection, and are not suitable for renal damage localization (glomerular vs tubulointerstitial injury). MicroRNAs (miRNAs) are increasingly gaining momentum as promising biomarkers of various organ toxicities, including drug induced renal injury. This is mostly due to their stability in easily accessible biofluids, ease of developing nucleic acids detection compared to protein detection assays, as well as their interspecies translatability. Increasing concordance of miRNA findings by standardizing methodology most suitable for their detection and quantitation, as well as characterization of their expression pattern in a cell type specific manner, will accelerate progress toward validation of these miRNAs as biomarkers in pre-clinical, and clinical settings. This review aims to highlight the current pre-clinical findings surrounding miRNAs as biomarkers in two important segments of the nephron, the glomerulus and tubules. - Highlights: • miRNAs are promising biomarkers of drug-induced kidney injury. • Summarized pre-clinical miRNA biomarkers of drug-induced nephrotoxicity. • Described the strengths and challenges associated with miRNAs as biomarkers.

Hepatic transporter drug-drug interactions: an evaluation of approaches and methodologies.

Science.gov (United States)

Williamson, Beth; Riley, Robert J

2017-12-01

Drug-drug interactions (DDIs) continue to account for 5% of hospital admissions and therefore remain a major regulatory concern. Effective, quantitative prediction of DDIs will reduce unexpected clinical findings and encourage projects to frontload DDI investigations rather than concentrating on risk management ('manage the baggage') later in drug development. A key challenge in DDI prediction is the discrepancies between reported models. Areas covered: The current synopsis focuses on four recent influential publications on hepatic drug transporter DDIs using static models that tackle interactions with individual transporters and in combination with other drug transporters and metabolising enzymes. These models vary in their assumptions (including input parameters), transparency, reproducibility and complexity. In this review, these facets are compared and contrasted with recommendations made as to their application. Expert opinion: Over the past decade, static models have evolved from simple [I]/k i models to incorporate victim and perpetrator disposition mechanisms including the absorption rate constant, the fraction of the drug metabolised/eliminated and/or clearance concepts. Nonetheless, models that comprise additional parameters and complexity do not necessarily out-perform simpler models with fewer inputs. Further, consideration of the property space to exploit some drug target classes has also highlighted the fine balance required between frontloading and back-loading studies to design out or 'manage the baggage'.

Membrane Transporters: Structure, Function and Targets for Drug Design

Science.gov (United States)

Ravna, Aina W.; Sager, Georg; Dahl, Svein G.; Sylte, Ingebrigt

Current therapeutic drugs act on four main types of molecular targets: enzymes, receptors, ion channels and transporters, among which a major part (60-70%) are membrane proteins. This review discusses the molecular structures and potential impact of membrane transporter proteins on new drug discovery. The three-dimensional (3D) molecular structure of a protein contains information about the active site and possible ligand binding, and about evolutionary relationships within the protein family. Transporters have a recognition site for a particular substrate, which may be used as a target for drugs inhibiting the transporter or acting as a false substrate. Three groups of transporters have particular interest as drug targets: the major facilitator superfamily, which includes almost 4000 different proteins transporting sugars, polyols, drugs, neurotransmitters, metabolites, amino acids, peptides, organic and inorganic anions and many other substrates; the ATP-binding cassette superfamily, which plays an important role in multidrug resistance in cancer chemotherapy; and the neurotransmitter:sodium symporter family, which includes the molecular targets for some of the most widely used psychotropic drugs. Recent technical advances have increased the number of known 3D structures of membrane transporters, and demonstrated that they form a divergent group of proteins with large conformational flexibility which facilitates transport of the substrate.

Interaction and Transport of Methamphetamine and its Primary Metabolites by Organic Cation and Multidrug and Toxin Extrusion Transporters.

Science.gov (United States)

Wagner, David J; Sager, Jennifer E; Duan, Haichuan; Isoherranen, Nina; Wang, Joanne

2017-07-01

Methamphetamine is one of the most abused illicit drugs with roughly 1.2 million users in the United States alone. A large portion of methamphetamine and its metabolites is eliminated by the kidney with renal clearance larger than glomerular filtration clearance. Yet the mechanism of active renal secretion is poorly understood. The goals of this study were to characterize the interaction of methamphetamine and its major metabolites with organic cation transporters (OCTs) and multidrug and toxin extrusion (MATE) transporters and to identify the major transporters involved in the disposition of methamphetamine and its major metabolites, amphetamine and para -hydroxymethamphetamine ( p -OHMA). We used cell lines stably expressing relevant transporters to show that methamphetamine and its metabolites inhibit human OCTs 1-3 (hOCT1-3) and hMATE1/2-K with the greatest potencies against hOCT1 and hOCT2. Methamphetamine and amphetamine are substrates of hOCT2, hMATE1, and hMATE2-K, but not hOCT1 and hOCT3. p -OHMA is transported by hOCT1-3 and hMATE1, but not hMATE2-K. In contrast, organic anion transporters 1 and 3 do not interact with or transport these compounds. Methamphetamine and its metabolites exhibited complex interactions with hOCT1 and hOCT2, suggesting the existence of multiple binding sites. Our studies suggest the involvement of the renal OCT2/MATE pathway in tubular secretion of methamphetamine and its major metabolites and the potential of drug-drug interactions with substrates or inhibitors of the OCTs. This information may be considered when prescribing medications to suspected or known abusers of methamphetamine to mitigate the risk of increased toxicity or reduced therapeutic efficacy. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Maternal use of drug substrates of placental transporters and the effect of transporter-mediated drug interactions on the risk of congenital anomalies.

Directory of Open Access Journals (Sweden)

Aizati N A Daud

Full Text Available A number of transporter proteins are expressed in the placenta, and they facilitate the placental transfer of drugs. The inhibition of P-glycoprotein (P-gp was previously found to be associated with an increase in the risk of congenital anomalies caused by drug substrates of this transporter. We now explore the role of other placental transporter proteins.A population-based case-referent study was performed using cases with congenital anomalies (N = 5,131 from EUROCAT Northern Netherlands, a registry of congenital anomalies. The referent population (N = 31,055 was selected from the pregnancy IADB.nl, a pharmacy prescription database.Ten placental transporters known to have comparable expression levels in the placenta to that of P-gp, were selected in this study. In total, 147 drugs were identified to be substrates, inhibitors or inducers, of these transporters. Fifty-eight of these drugs were used by at least one mother in our cases or referent population, and 28 were used in both. The highest user rate was observed for the substrates of multidrug resistance-associated protein 1, mainly folic acid (6% of cases, 8% of referents, and breast cancer resistance protein, mainly nitrofurantoin (2.3% of cases, 2.9% of referents. In contrast to P-gp, drug interactions involving substrates of these transporters did not have a significant effect on the risk of congenital anomalies.Some of the drugs which are substrates or inhibitors of placental transporters were commonly used during pregnancy. No significant effect of transporter inhibition was found on fetal drug exposure, possibly due to a limited number of exposures.

Renal targeting potential of a polymeric drug carrier, poly-L-glutamic acid, in normal and diabetic rats

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Chai HJ

2017-01-01

Full Text Available Hann-Juang Chai,1 Lik-Voon Kiew,1 Yunni Chin,1 Anwar Norazit,2 Suzita Mohd Noor,2 Yoke-Lin Lo,3,4 Chung-Yeng Looi,1 Yeh-Siang Lau,1 Tuck-Meng Lim,5 Won-Fen Wong,6 Nor Azizan Abdullah,1 Munavvar Zubaid Abdul Sattar,7 Edward J Johns,8 Zamri Chik,1 Lip-Yong Chung3 1Department of Pharmacology, 2Department of Biomedical Science, 3Department of Pharmacy, Faculty of Medicine, University of Malaya, 4School of Pharmacy, International Medical University, Kuala Lumpur, 5Department of Chemical Science, Faculty of Science, Universiti Tunku Abdul Rahman, Kampar, 6Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, 7School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden, Malaysia; 8Department of Physiology, University College Cork, Cork, Republic of Ireland Background and purpose: Poly-L-glutamic acid (PG has been used widely as a carrier to deliver anticancer chemotherapeutics. This study evaluates PG as a selective renal drug carrier.Experimental approach: 3H-deoxycytidine-labeled PGs (17 or 41 kDa and 3H-deoxycytidine were administered intravenously to normal rats and streptozotocin-induced diabetic rats. The biodistribution of these compounds was determined over 24 h. Accumulation of PG in normal kidneys was also tracked using 5-(aminoacetamido fluorescein (fluoresceinyl glycine amide-labeled PG (PG-AF. To evaluate the potential of PGs in ferrying renal protective anti-oxidative stress compounds, the model drug 4-(2-aminoethylbenzenesulfonyl fluoride hydrochloride (AEBSF was conjugated to 41 kDa PG to form PG-AEBSF. PG-AEBSF was then characterized and evaluated for intracellular anti-oxidative stress efficacy (relative to free AEBSF.Results: In the normal rat kidneys, 17 kDa radiolabeled PG (PG-Tr presents a 7-fold higher, while 41 kDa PG-Tr shows a 15-fold higher renal accumulation than the free radiolabel after 24 h post injection. The accumulation of PG-AF was primarily found in the renal tubular �

Luminal uptake and intracellular transport of insulin in renal proximal tubules

International Nuclear Information System (INIS)

Hellfritzsch, M.; Christensen, E.I.; Sonne, O.

1986-01-01

It is generally accepted that proteins taken up from the renal tubular fluid are transported into lysosomes in proximal tubule cells. Recently, however, it has been postulated that insulin in isolated perfused rat kidneys did not accumulate in lysosomes but to a certain degree in the Golgi region. The present study was undertaken to investigate the intracellular handling of biologically unaltered insulin in rat renal proximal tubule cells. Rats were prepared for in vivo micropuncture and either a colloidal gold insulin complex or insulin monoiodinated in the A-14 position ( 125 I-insulin) was microinfused into proximal tubules. After 5, 10, 25 or 60 min the tubules were fixed by microinfusion of glutaraldehyde and processed for electron microscopy or electron microscope autoradiography. A qualitative analysis of tubules infused with colloidal gold insulin or 125 I-insulin showed that insulin was taken up by endocytosis and transported to lysosomes, and a quantitative autoradiographic analysis of the 125 I-insulin microinfused tubules showed that the grain density after five min was significantly increased for endocytic vacuoles and for lysosomes. After 60 min the grain density was still significant over lysosomes. The accumulation of grains was non-significant over all other areas analyzed at any time. This study shows that insulin is taken up from the luminal side of the proximal tubule by endocytosis and transported to the lysosomes. There was no significant transport to the Golgi region

Role of transporters in placental transfer of drugs

International Nuclear Information System (INIS)

Ganapathy, Vadivel; Prasad, Puttur D.

2005-01-01

Human placenta functions as an important transport organ that mediates the exchange of nutrients and metabolites between maternal and fetal circulations. This function is made possible because of the expression of a multitude of transport proteins in the placental syncytiotrophoblast with differential localization in the maternal-facing brush border membrane versus the fetal-facing basal membrane. Even though the physiological role of most of these transport proteins is to handle nutrients, many of them interact with xenobiotics and pharmacological agents. These transport proteins therefore play a critical role in the disposition of drugs across the maternal-fetal interface, with some transporters facilitating the entry of drugs from maternal circulation into fetal circulation whereas others preventing such entry by actively eliminating drugs from the placenta back into maternal circulation. The net result as to whether the placenta enhances the exposure of the developing fetus to drugs and xenobiotics or functions as a barrier to protect the fetus from such agents depends on the types of transporters expressed in the brush border membrane and basal membrane of the syncytiotrophoblast and on the functional mode of these transporters (influx versus efflux)

Placental Drug Transport-on-a-Chip: A Microengineered In Vitro Model of Transporter-Mediated Drug Efflux in the Human Placental Barrier.

Science.gov (United States)

Blundell, Cassidy; Yi, Yoon-Suk; Ma, Lin; Tess, Emily R; Farrell, Megan J; Georgescu, Andrei; Aleksunes, Lauren M; Huh, Dongeun

2018-01-01

The current lack of knowledge about the effect of maternally administered drugs on the developing fetus is a major public health concern worldwide. The first critical step toward predicting the safety of medications in pregnancy is to screen drug compounds for their ability to cross the placenta. However, this type of preclinical study has been hampered by the limited capacity of existing in vitro and ex vivo models to mimic physiological drug transport across the maternal-fetal interface in the human placenta. Here the proof-of-principle for utilizing a microengineered model of the human placental barrier to simulate and investigate drug transfer from the maternal to the fetal circulation is demonstrated. Using the gestational diabetes drug glyburide as a model compound, it is shown that the microphysiological system is capable of reconstituting efflux transporter-mediated active transport function of the human placental barrier to limit fetal exposure to maternally administered drugs. The data provide evidence that the placenta-on-a-chip may serve as a new screening platform to enable more accurate prediction of drug transport in the human placenta. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A Mathematical Analysis of Intravitreal Drug Transport | Avtar ...

African Journals Online (AJOL)

Method: A simple mathematical model for the intravitreal transport of drugs was developed ... of the equation describing the drug transport in the vitreous body was written, in which the ... EMAIL FREE FULL TEXT EMAIL FREE FULL TEXT

The urinary excretion of metformin, ceftizoxime and ofloxacin in high serum creatinine rats: Can creatinine predict renal tubular elimination?

Science.gov (United States)

Ma, Yan-Rong; Zhou, Yan; Huang, Jing; Qin, Hong-Yan; Wang, Pei; Wu, Xin-An

2018-03-01

The renal excretion of creatinine and most drugs are the net result of glomerular filtration and tubular secretion, and their tubular secretions are mediated by individual transporters. Thus, we hypothesized that the increase of serum creatinine (SCr) levels attributing to inhibiting tubular transporters but not glomerular filtration rate (GFR) could be used to evaluate the tubular excretion of drugs mediated by identical or partial overlap transporter with creatinine. In this work, we firstly developed the creatinine excretion inhibition model with normal GFR by competitively inhibiting tubular transporters, and investigated the renal excretion of metformin, ceftizoxime and ofloxacin in vivo and in vitro. The results showed that the 24-hour urinary excretion of metformin and ceftizoxime in model rats were decreased by 25% and 17% compared to that in control rats, respectively. The uptake amount and urinary excretion of metformin and ceftizoxime could be inhibited by creatinine in renal cortical slices and isolated kidney perfusion. However, the urinary excretion of ofloxacin was not affected by high SCr. These results showed that the inhibition of tubular creatinine transporters by high SCr resulted to the decrease of urinary excretion of metformin and ceftizoxime, but not ofloxacin, which implied that the increase of SCr could also be used to evaluate the tubular excretion of drugs mediated by identical or partial overlap transporter with creatinine in normal GFR rats. Copyright © 2018 Elsevier Inc. All rights reserved.

[Drug-Drug Interactions with Consideration of Pharmacogenetics].

Science.gov (United States)

Ozawa, Shogo

2018-01-01

　Elderly patients often suffer from a variety of diseases and therefore may be prescribed several kinds of drugs. Interactions between these drugs may cause problems in some patients. Guidelines for drug interactions were released on July 8, 2014 "Drug Interaction Guideline for Drug Development and Labeling Recommendations (Final Draft)". These guidelines include the theoretical basis for evaluating the mechanisms of drug interaction, the possible extent of drug interactions, and take into consideration special populations (e.g., infants, children, elderly patients, patients with hepatic or renal dysfunction, and subjects with minor deficient alleles for drug metabolizing enzymes and drug transporters). In this symposium article, I discuss this last special population: altered drug metabolism and drug interactions in subjects with minor alleles of genes encoding deficient drug metabolizing enzymes. I further discuss a drug label for eliglustat (Cerdelga) with instructions for patients with ultra-rapid, extensive, intermediate, and poor metabolizer phenotypes that arise from different CYP2D6 gene alleles.

Multidrug and toxin extrusion proteins as transporters of antimicrobial drugs.

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Nies, Anne T; Damme, Katja; Schaeffeler, Elke; Schwab, Matthias

2012-12-01

Antimicrobial drugs are essential in the treatment of infectious diseases. A better understanding of transport processes involved in drug disposition will improve the predictability of drug-drug interactions with consequences for drug response. Multidrug And Toxin Extrusion (MATE; SLC47A) proteins are efflux transporters mediating the excretion of several antimicrobial drugs as well as other organic compounds into bile and urine, thereby contributing to drug disposition. This review summarizes current knowledge of the structural and molecular features of human MATE transporters including their functional role in drug transport with a specific focus on antimicrobial drugs. The PubMed database was searched using the terms "MATE1," "MATE-2K," "MATE2," "SLC47A1," "SLC47A2," and "toxin extrusion protein" (up to June 2012). MATE proteins have been recognized as important transporters mediating the final excretion step of cationic drugs into bile and urine. These include the antiviral drugs acyclovir, amprenavir, and ganciclovir, the antibiotics cephalexin, cephradine and levofloxacin, as well as the antimalarial agents chloroquine and quinine. It is therefore important to enhance our understanding of the role of MATEs in drug extrusion with particular emphasis on the functional consequences of genetic variants on disposition of these antimicrobial drugs.

Atrial Natriuretic Peptide Stimulates Dopamine Tubular Transport by Organic Cation Transporters: A Novel Mechanism to Enhance Renal Sodium Excretion

Science.gov (United States)

Kouyoumdzian, Nicolás M.; Rukavina Mikusic, Natalia L.; Kravetz, María C.; Lee, Brenda M.; Carranza, Andrea; Del Mauro, Julieta S.; Pandolfo, Marcela; Gironacci, Mariela M.; Gorzalczany, Susana; Toblli, Jorge E.; Fernández, Belisario E.

2016-01-01

The aim of this study was to demonstrate the effects of atrial natriuretic peptide (ANP) on organic cation transporters (OCTs) expression and activity, and its consequences on dopamine urinary levels, Na+, K+-ATPase activity and renal function. Male Sprague Dawley rats were infused with isotonic saline solution during 120 minutes and randomized in nine different groups: control, pargyline plus tolcapone (P+T), ANP, dopamine (DA), D-22, DA+D-22, ANP+D-22, ANP+DA and ANP+DA+D-22. Renal functional parameters were determined and urinary dopamine concentration was quantified by HPLC. Expression of OCTs and D1-receptor in membrane preparations from renal cortex tissues were determined by western blot and Na+, K+-ATPase activity was determined using in vitro enzyme assay. 3H-DA renal uptake was determined in vitro. Compared to P+T group, ANP and dopamine infusion increased diuresis, urinary sodium and dopamine excretion significantly. These effects were more pronounced in ANP+DA group and reversed by OCTs blockade by D-22, demonstrating that OCTs are implied in ANP stimulated-DA uptake and transport in renal tissues. The activity of Na+, K+-ATPase exhibited a similar fashion when it was measured in the same experimental groups. Although OCTs and D1-receptor protein expression were not modified by ANP, OCTs-dependent-dopamine tubular uptake was increased by ANP through activation of NPR-A receptor and protein kinase G as signaling pathway. This effect was reflected by an increase in urinary dopamine excretion, natriuresis, diuresis and decreased Na+, K+-ATPase activity. OCTs represent a novel target that links the activity of ANP and dopamine together in a common mechanism to enhance their natriuretic and diuretic effects. PMID:27392042

Simultaneous Assessment of Transporter-Mediated Drug-Drug Interactions Using a Probe Drug Cocktail in Cynomolgus Monkey.

Science.gov (United States)

Kosa, Rachel E; Lazzaro, Sarah; Bi, Yi-An; Tierney, Brendan; Gates, Dana; Modi, Sweta; Costales, Chester; Rodrigues, A David; Tremaine, Larry M; Varma, Manthena V

2018-06-07

We aim to establish an in vivo preclinical model to enable simultaneous assessment of inhibition potential of an investigational drug on clinically relevant drug transporters, organic anion transporting polypeptide (OATP)1B, breast cancer resistance protein (BCRP), P-glycoprotein (P-gp) and organic anion transporter (OAT)3. Pharmacokinetics of substrate cocktail consisting of pitavastatin (OATP1B substrate), rosuvastatin (OATP1B/BCRP/OAT3), sulfasalazine (BCRP) and talinolol (P-gp) were obtained in cynomolgus monkey - alone or in combination with transporter inhibitors. Single dose rifampicin (30 mg/kg) significantly (pdrugs, with a marked effect on pitavastatin and rosuvastatin (AUC ratio ~21-39). Elacridar, BCRP/P-gp inhibitor, increased the AUC of sulfasalazine, talinolol, as well as rosuvastatin and pitavastatin. An OAT1/3 inhibitor (probenecid) significantly (pdrug-drug interaction risk assessment, before advancing a new molecular entity into clinical development, as well as providing mechanistic insights on transporter-mediated interactions. The American Society for Pharmacology and Experimental Therapeutics.

Transporter-mediated natural product–drug interactions for the treatment of cardiovascular diseases

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Weibin Zha

2018-04-01

Full Text Available The growing use of natural products in cardiovascular (CV patients has been greatly raising the concerns about potential natural product–CV drug interactions. Some of these may lead to unexpected cardiovascular adverse effects and it is, therefore, essential to identify or predict potential natural product–CV drug interactions, and to understand the underlying mechanisms. Drug transporters are important determinants for the pharmacokinetics of drugs and alterations of drug transport has been recognized as one of the major causes of natural product–drug interactions. In last two decades, many CV drugs (e.g., angiotensin II receptor blockers, beta-blockers and statins have been identified to be substrates and inhibitors of the solute carrier (SLC transporters and the ATP-binding cassette (ABC transporters, which are two major transporter superfamilies. Meanwhile, in vitro and in vivo studies indicate that a growing number of natural products showed cardioprotective effects (e.g., gingko biloba, danshen and their active ingredients are also substrates and inhibitors of drug transporters. Thus, to understand transporter-mediated natural product–CV drug interactions is important and some transporter-mediated interactions have already shown to have clinical relevance. In this review, we review the current knowledge on the role of ABC and SLC transporters in CV therapy, as well as transporter modulation by natural products used in CV diseases and their induced natural product–CV drug interactions through alterations of drug transport. We hope our review will aid in a comprehensive summary of transporter-mediated natural product–CV drug interactions and help public and physicians understand these type of interactions. Keywords: Cardiovascular drugs, Natural products, Drug transporters, Natural product–drug interaction, Pharmacokinetics

Transportation and retention in outpatient drug abuse treatment programs.

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Friedmann, P D; Lemon, S C; Stein, M D

2001-09-01

To determine whether certain types of transportation assistance improve outpatient treatment retention beyond thresholds shown to have therapeutic benefits, we analyzed data from 1,144 clients in 22 outpatient methadone maintenance (OMM) programs and 2,031 clients in 22 outpatient drug-free (ODF) programs in the Drug Abuse Treatment Outcomes Study (DATOS), a national, 12-month, longitudinal study of drug abuse treatment programs. Directors' surveys provided information about provision of car, van, or contracted transportation services or individual vouchers/payment for public transportation. Chart-abstracted treatment retention was dichotomized at 365 days for OMM and 90 days for ODF. Separate multivariate hierarchical linear models revealed that provision of car, van, or contracted transportation services improved treatment retention beyond these thresholds for both OMM and ODF, but individual vouchers or payment for public transportation did not. Future research should validate whether car, van, or contracted transportation services improve retention and other treatment outcomes in outpatient drug abuse treatment.

Radiation inactivation studies of renal brush border water and urea transport

International Nuclear Information System (INIS)

Verkman, A.S.; Dix, J.A.; Seifter, J.L.; Skorecki, K.L.; Jung, C.Y.; Ausiello, D.A.

1985-01-01

Radiation inactivation was used to determine the nature and molecular weight of water and urea transport pathways in brush border membrane vesicles (BBMV) isolated from rabbit renal cortex. BBMV were frozen to -50 degrees C, irradiated with 1.5 MeV electrons, thawed, and assayed for transport or enzyme activity. The freezing process had no effect on enzyme or transport kinetics. BBMV alkaline phosphatase activity gave linear ln(activity) vs. radiation dose plots with a target size of 68 +/- 3 kDa, similar to previously reported values. Water and solute transport were measured using the stopped-flow light-scattering technique. The rates of acetamide and osmotic water transport did not depend on radiation dose (0-7 Mrad), suggesting that transport of these substances does not require a protein carrier. In contrast, urea and thiourea transport gave linear ln(activity) vs. dose curves with a target size of 125-150 kDa; 400 mM urea inhibited thiourea flux by -50% at 0 and 4.7 Mrad, showing that radiation does not affect inhibitor binding to surviving transporters. These studies suggest that BBMV urea transport requires a membrane protein, whereas osmotic water transport does not

Expression of Genes for Drug Transporters in the Human Female Genital Tract and Modulatory Effect of Antiretroviral Drugs.

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Karolin Hijazi

Full Text Available Anti-retroviral (ARV -based microbicides are one of the strategies pursued to prevent HIV-1 transmission. Delivery of ARV drugs to subepithelial CD4+ T cells at concentrations for protection is likely determined by drug transporters expressed in the cervicovaginal epithelium. To define the role of drug transporters in mucosal disposition of topically applied ARV-based microbicides, these must be tested in epithelial cell line-based biopharmaceutical assays factoring the effect of relevant drug transporters. We have characterised gene expression of influx and efflux drug transporters in a panel of cervicovaginal cell lines and compared this to expression in cervicovaginal tissue. We also investigated the effect of dapivirine, darunavir and tenofovir, currently at advanced stages of microbicides development, on expression of drug transporters in cell lines. Expression of efflux ABC transporters in cervical tissue was best represented in HeLa, Ect1/E6E7 and End1/E6E7 cell lines. Expression of influx OCT and ENT transporters in ectocervix matched expression in Hela while expression of influx SLCO transporters in vagina was best reflected in VK2/E6E7 cell line. Stimulation with darunavir and dapivirine upregulated MRP transporters, including MRP5 involved in transport of tenofovir. Dapivirine also significantly downregulated tenofovir substrate MRP4 in cervical cell lines. Treatment with darunavir and dapivirine showed no significant effect on expression of BCRP, MRP2 and P-glycoprotein implicated in efflux of different ARV drugs. Darunavir strongly induced expression in most cell lines of CNT3 involved in cell uptake of nucleotide/nucleoside analogue reverse transcriptase inhibitors and SLCO drug transporters involved in cell uptake of protease inhibitors. This study provides insight into the suitability of cervicovaginal cell lines for assessment of ARV drugs in transport kinetics studies. The modulatory effect of darunavir and dapivirine on

Expression of Genes for Drug Transporters in the Human Female Genital Tract and Modulatory Effect of Antiretroviral Drugs.

Science.gov (United States)

Hijazi, Karolin; Cuppone, Anna M; Smith, Kieron; Stincarelli, Maria A; Ekeruche-Makinde, Julia; De Falco, Giulia; Hold, Georgina L; Shattock, Robin; Kelly, Charles G; Pozzi, Gianni; Iannelli, Francesco

2015-01-01

Anti-retroviral (ARV) -based microbicides are one of the strategies pursued to prevent HIV-1 transmission. Delivery of ARV drugs to subepithelial CD4+ T cells at concentrations for protection is likely determined by drug transporters expressed in the cervicovaginal epithelium. To define the role of drug transporters in mucosal disposition of topically applied ARV-based microbicides, these must be tested in epithelial cell line-based biopharmaceutical assays factoring the effect of relevant drug transporters. We have characterised gene expression of influx and efflux drug transporters in a panel of cervicovaginal cell lines and compared this to expression in cervicovaginal tissue. We also investigated the effect of dapivirine, darunavir and tenofovir, currently at advanced stages of microbicides development, on expression of drug transporters in cell lines. Expression of efflux ABC transporters in cervical tissue was best represented in HeLa, Ect1/E6E7 and End1/E6E7 cell lines. Expression of influx OCT and ENT transporters in ectocervix matched expression in Hela while expression of influx SLCO transporters in vagina was best reflected in VK2/E6E7 cell line. Stimulation with darunavir and dapivirine upregulated MRP transporters, including MRP5 involved in transport of tenofovir. Dapivirine also significantly downregulated tenofovir substrate MRP4 in cervical cell lines. Treatment with darunavir and dapivirine showed no significant effect on expression of BCRP, MRP2 and P-glycoprotein implicated in efflux of different ARV drugs. Darunavir strongly induced expression in most cell lines of CNT3 involved in cell uptake of nucleotide/nucleoside analogue reverse transcriptase inhibitors and SLCO drug transporters involved in cell uptake of protease inhibitors. This study provides insight into the suitability of cervicovaginal cell lines for assessment of ARV drugs in transport kinetics studies. The modulatory effect of darunavir and dapivirine on expression of drug

Transporter-mediated natural product-drug interactions for the treatment of cardiovascular diseases.

Science.gov (United States)

Zha, Weibin

2018-04-01

The growing use of natural products in cardiovascular (CV) patients has been greatly raising the concerns about potential natural product-CV drug interactions. Some of these may lead to unexpected cardiovascular adverse effects and it is, therefore, essential to identify or predict potential natural product-CV drug interactions, and to understand the underlying mechanisms. Drug transporters are important determinants for the pharmacokinetics of drugs and alterations of drug transport has been recognized as one of the major causes of natural product-drug interactions. In last two decades, many CV drugs (e.g., angiotensin II receptor blockers, beta-blockers and statins) have been identified to be substrates and inhibitors of the solute carrier (SLC) transporters and the ATP-binding cassette (ABC) transporters, which are two major transporter superfamilies. Meanwhile, in vitro and in vivo studies indicate that a growing number of natural products showed cardioprotective effects (e.g., gingko biloba, danshen and their active ingredients) are also substrates and inhibitors of drug transporters. Thus, to understand transporter-mediated natural product-CV drug interactions is important and some transporter-mediated interactions have already shown to have clinical relevance. In this review, we review the current knowledge on the role of ABC and SLC transporters in CV therapy, as well as transporter modulation by natural products used in CV diseases and their induced natural product-CV drug interactions through alterations of drug transport. We hope our review will aid in a comprehensive summary of transporter-mediated natural product-CV drug interactions and help public and physicians understand these type of interactions. Copyright © 2017. Published by Elsevier B.V.

Transportation of drug-gold nanocomposites by actinomyosin motor system

Science.gov (United States)

Kaur, Harsimran; Chaudhary, Archana; Kaur, Inderpreet; Singh, Kashmir; Bharadwaj, Lalit M.

2011-06-01

Nanotechnology is playing an important role in drug delivery to overcome limitations of conventional drug delivery systems in terms of solubility, in vivo stability, pharmacokinetics, and bio-distribution. The controlled transportation of drug into the cell and within the cell is a major challenge to be addressed. Cellular molecular motors have been exploited for their cargo carrying capacity for various applications including engineering and health care. Combination of nanotechnology and biomolecular motors can address some of the challenges in drug delivery. In the present study, transportation of drug nanocomposites has been demonstrated. Nanocomposites of 6-mercaptopurine and levodopa drugs (cancer and Parkinson's disease, respectively) were prepared with gold nanoparticles (GNPs) by covalent attachment and these nanocomposites were attached to actin filaments. These nanocomposites were in-turn transported by actin filaments on myosin tracks. Characterization of drug nanocomposites formation was done by UV-Vis spectroscopy, field emission scanning electron microscopy, transmission electron microscopy, and confocal microscopy. GNP composites of 6-mercaptopurine and levodopa were formed by sulfide and amide bond formation, respectively. Average velocity of actin filament attached to nanocomposites was found to be 3.17 and 3.89 μm/s for levodopa and 6-mercaptopurine, respectively, as compared to actin filaments with velocity of 4.0-6.0 μm/s. Three concepts have been proposed for the study of drug transportation into the cell based on polycationic complex formation, interaction of actin with cellular myosin and Biomolecular Adaptor for Retrograde Transport (BART) technology. The aspects of this study heads toward the development of an approach to utilize molecular motors for nanoscale transportation endogenously.

Transportation of drug-gold nanocomposites by actinomyosin motor system

Energy Technology Data Exchange (ETDEWEB)

Kaur, Harsimran, E-mail: microsimbac@gmail.com; Chaudhary, Archana; Kaur, Inderpreet [Council of Scientific and Industrial Research (CSIR), Biomolecular Electronics and Nanotechnology Division (BEND), Central Scientific Instruments Organization - CSIO (India); Singh, Kashmir [Panjab University, Department of Biotechnology (India); Bharadwaj, Lalit M. [Council of Scientific and Industrial Research (CSIR), Biomolecular Electronics and Nanotechnology Division (BEND), Central Scientific Instruments Organization - CSIO (India)

2011-06-15

Nanotechnology is playing an important role in drug delivery to overcome limitations of conventional drug delivery systems in terms of solubility, in vivo stability, pharmacokinetics, and bio-distribution. The controlled transportation of drug into the cell and within the cell is a major challenge to be addressed. Cellular molecular motors have been exploited for their cargo carrying capacity for various applications including engineering and health care. Combination of nanotechnology and biomolecular motors can address some of the challenges in drug delivery. In the present study, transportation of drug nanocomposites has been demonstrated. Nanocomposites of 6-mercaptopurine and levodopa drugs (cancer and Parkinson's disease, respectively) were prepared with gold nanoparticles (GNPs) by covalent attachment and these nanocomposites were attached to actin filaments. These nanocomposites were in-turn transported by actin filaments on myosin tracks. Characterization of drug nanocomposites formation was done by UV-Vis spectroscopy, field emission scanning electron microscopy, transmission electron microscopy, and confocal microscopy. GNP composites of 6-mercaptopurine and levodopa were formed by sulfide and amide bond formation, respectively. Average velocity of actin filament attached to nanocomposites was found to be 3.17 and 3.89 {mu}m/s for levodopa and 6-mercaptopurine, respectively, as compared to actin filaments with velocity of 4.0-6.0 {mu}m/s. Three concepts have been proposed for the study of drug transportation into the cell based on polycationic complex formation, interaction of actin with cellular myosin and Biomolecular Adaptor for Retrograde Transport (BART) technology. The aspects of this study heads toward the development of an approach to utilize molecular motors for nanoscale transportation endogenously.

Multiple Drug Transport Pathways through Human P-Glycoprotein.

Science.gov (United States)

McCormick, James W; Vogel, Pia D; Wise, John G

2015-07-21

P-Glycoprotein (P-gp) is a plasma membrane efflux pump that is commonly associated with therapy resistances in cancers and infectious diseases. P-gp can lower the intracellular concentrations of many drugs to subtherapeutic levels by translocating them out of the cell. Because of the broad range of substrates transported by P-gp, overexpression of P-gp causes multidrug resistance. We reported previously on dynamic transitions of P-gp as it moved through conformations based on crystal structures of homologous ABCB1 proteins using in silico targeted molecular dynamics techniques. We expanded these studies here by docking transport substrates to drug binding sites of P-gp in conformations open to the cytoplasm, followed by cycling the pump through conformations that opened to the extracellular space. We observed reproducible transport of two substrates, daunorubicin and verapamil, by an average of 11-12 Å through the plane of the membrane as P-gp progressed through a catalytic cycle. Methylpyrophosphate, a ligand that should not be transported by P-gp, did not show this movement through P-gp. Drug binding to either of two subsites on P-gp appeared to determine the initial pathway used for drug movement through the membrane. The specific side-chain interactions with drugs within each pathway seemed to be, at least in part, stochastic. The docking and transport properties of a P-gp inhibitor, tariquidar, were also studied. A mechanism of inhibition by tariquidar that involves stabilization of an outward open conformation with tariquidar bound in intracellular loops or at the drug binding domain of P-gp is presented.

The rise and fall of novel renal magnesium transporters.

Science.gov (United States)

Schäffers, Olivier J M; Hoenderop, Joost G J; Bindels, René J M; de Baaij, Jeroen H F

2018-06-01

Body Mg 2+ balance is finely regulated in the distal convoluted tubule (DCT), where a tight interplay among transcellular reabsorption, mitochondrial exchange, and basolateral extrusion takes place. In the last decades, several research groups have aimed to identify the molecular players in these processes. A multitude of proteins have been proposed to function as Mg 2+ transporter in eukaryotes based on phylogenetic analysis, differential gene expression, and overexpression studies. However, functional evidence for many of these proteins is lacking. The aim of this review is, therefore, to critically reconsider all putative Mg 2+ transporters and put their presumed function in context of the renal handling of Mg 2+ . Sufficient experimental evidence exists to acknowledge transient receptor potential melastatin (TRPM) 6 and TRPM7, solute carrier family 41 (SLC41) A1 and SLC41A3, and mitochondrial RNA splicing 2 (MRS2) as Mg 2+ transporters. TRPM6/7 facilitate Mg 2+ influx, SLC41A1 mediates Mg 2+ extrusion, and MRS2 and SLC41A3 are implicated in mitochondrial Mg 2+ homeostasis. These proteins are highly expressed in the DCT. The function of cyclin M (CNNM) proteins is still under debate. For the other proposed Mg 2+ transporters including Mg 2+ transporter subtype 1 (MagT1), nonimprinted in Prader-Willi/Angelman syndrome (NIPA), membrane Mg 2+ transport (MMgT), Huntingtin-interacting protein 14 (HIP14), and ATP13A4, functional evidence is limited, or functions alternative to Mg 2+ transport have been suggested. Additional characterization of their Mg 2+ transport proficiency should be provided before further claims about their role as Mg 2+ transporter can be made.

Switch-loop flexibility affects transport of large drugs by the promiscuous AcrB multidrug efflux transporter.

Science.gov (United States)

Cha, Hi-jea; Müller, Reinke T; Pos, Klaas M

2014-08-01

Multidrug efflux transporters recognize a variety of structurally unrelated compounds for which the molecular basis is poorly understood. For the resistance nodulation and cell division (RND) inner membrane component AcrB of the AcrAB-TolC multidrug efflux system from Escherichia coli, drug binding occurs at the access and deep binding pockets. These two binding areas are separated by an 11-amino-acid-residue-containing switch loop whose conformational flexibility is speculated to be essential for drug binding and transport. A G616N substitution in the switch loop has a distinct and local effect on the orientation of the loop and on the ability to transport larger drugs. Here, we report a distinct phenotypical pattern of drug recognition and transport for the G616N variant, indicating that drug substrates with minimal projection areas of >70 Å(2) are less well transported than other substrates. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

[The therapeutic drug monitoring network server of tacrolimus for Chinese renal transplant patients].

Science.gov (United States)

Deng, Chen-Hui; Zhang, Guan-Min; Bi, Shan-Shan; Zhou, Tian-Yan; Lu, Wei

2011-07-01

This study is to develop a therapeutic drug monitoring (TDM) network server of tacrolimus for Chinese renal transplant patients, which can facilitate doctor to manage patients' information and provide three levels of predictions. Database management system MySQL was employed to build and manage the database of patients and doctors' information, and hypertext mark-up language (HTML) and Java server pages (JSP) technology were employed to construct network server for database management. Based on the population pharmacokinetic model of tacrolimus for Chinese renal transplant patients, above program languages were used to construct the population prediction and subpopulation prediction modules. Based on Bayesian principle and maximization of the posterior probability function, an objective function was established, and minimized by an optimization algorithm to estimate patient's individual pharmacokinetic parameters. It is proved that the network server has the basic functions for database management and three levels of prediction to aid doctor to optimize the regimen of tacrolimus for Chinese renal transplant patients.

Renal denervation: Results of a single-center cohort study; Renale Denervation. Ergebnisse einer Single-Center Kohortenstudie

Energy Technology Data Exchange (ETDEWEB)

Luetkens, J.A.; Thomas, D.; Doerner, J.; Schild, H.H.; Naehle, C.P. [Bonn Univ. (Germany). Dept. of Radiology; Wilhelm, K. [Johanniter Hospital, Bonn (Germany). Dept. of Radiology; Duesing, R. [Hypertension Center, Bonn (Germany); Woitas, R.P.; Hundt, F. [Bonn Univ. (Germany). Dept. of Internal Medicine I

2015-01-15

To investigate the effect of renal denervation on office-based and 24-h ambulatory blood pressure measurements (ABPM) in a highly selective patient population with drug-resistant hypertension. Patients with drug resistant hypertension eligible for renal denervation were included in the study population. Office blood pressure and ABPM were assessed prior to and after renal denervation. To detect procedure related renal or renal artery damage, magnetic resonance imaging (MRI) and angiography (MRA) were performed pre-interventional, one day post-interventional, and one month after renal denervation. Mean follow-up time between renal denervation and blood pressure re-assessment was 9.5 ± 3.9 months. Between August 2011 and March 2013, 17 patients prospectively underwent renal denervation. Pre-interventional mean office blood pressure and ABPM were 177.3 ± 20.3/103.8 ± 20.4 mmHg and 155.2 ± 20.5/93.7 ± 14.5 mmHg, respectively. Post-interventional, office blood pressure was significantly reduced to 144.7 ± 14.9/89.5 ± 12.1 (p < 0.05). ABPM values remained unchanged (147.9 ± 20.3/90.3 ± 15.6, p > 0.05). The number of prescribed antihypertensive drugs was unchanged after renal denervation (4.7 ± 2.0 vs. 4.2 ± 1.2, p = 0.18). No renovascular complications were detected in follow-up MRI. After renal denervation, no significant decrease in ABPM was observed. These results may indicate a limited impact of renal denervation for drug resistant hypertension.

A new human NHERF1 mutation decreases renal phosphate transporter NPT2a expression by a PTH-independent mechanism.

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Marie Courbebaisse

Full Text Available BACKGROUND: The sodium-hydrogen exchanger regulatory factor 1 (NHERF1 binds to the main renal phosphate transporter NPT2a and to the parathyroid hormone (PTH receptor. We have recently identified mutations in NHERF1 that decrease renal phosphate reabsorption by increasing PTH-induced cAMP production in the renal proximal tubule. METHODS: We compared relevant parameters of phosphate homeostasis in a patient with a previously undescribed mutation in NHERF1 and in control subjects. We expressed the mutant NHERF1 protein in Xenopus Oocytes and in cultured cells to study its effects on phosphate transport and PTH-induced cAMP production. RESULTS: We identified in a patient with inappropriate renal phosphate reabsorption a previously unidentified mutation (E68A located in the PDZ1 domain of NHERF1.We report the consequences of this mutation on NHERF1 function. E68A mutation did not modify cAMP production in the patient. PTH-induced cAMP synthesis and PKC activity were not altered by E68A mutation in renal cells in culture. In contrast to wild-type NHERF1, expression of the E68A mutant in Xenopus oocytes and in human cells failed to increase phosphate transport. Pull down experiments showed that E68A mutant did not interact with NPT2a, which robustly interacted with wild type NHERF1 and previously identified mutants. Biotinylation studies revealed that E68A mutant was unable to increase cell surface expression of NPT2a. CONCLUSIONS: Our results indicate that the PDZ1 domain is critical for NHERF1-NPT2a interaction in humans and for the control of NPT2a expression at the plasma membrane. Thus we have identified a new mechanism of renal phosphate loss and shown that different mutations in NHERF1 can alter renal phosphate reabsorption via distinct mechanisms.

Protein Kinases C-Mediated Regulations of Drug Transporter Activity, Localization and Expression

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Abdullah Mayati

2017-04-01

Full Text Available Drug transporters are now recognized as major actors in pharmacokinetics, involved notably in drug–drug interactions and drug adverse effects. Factors that govern their activity, localization and expression are therefore important to consider. In the present review, the implications of protein kinases C (PKCs in transporter regulations are summarized and discussed. Both solute carrier (SLC and ATP-binding cassette (ABC drug transporters can be regulated by PKCs-related signaling pathways. PKCs thus target activity, membrane localization and/or expression level of major influx and efflux drug transporters, in various normal and pathological types of cells and tissues, often in a PKC isoform-specific manner. PKCs are notably implicated in membrane insertion of bile acid transporters in liver and, in this way, are thought to contribute to cholestatic or choleretic effects of endogenous compounds or drugs. The exact clinical relevance of PKCs-related regulation of drug transporters in terms of drug resistance, pharmacokinetics, drug–drug interactions and drug toxicity remains however to be precisely determined. This issue is likely important to consider in the context of the development of new drugs targeting PKCs-mediated signaling pathways, for treating notably cancers, diabetes or psychiatric disorders.

Anionic and cationic drug secretion in the isolated perfused rat kidney after neonatal surgical induction of ureteric obstruction.

NARCIS (Netherlands)

Gier, R.P.E. de; Feitz, W.F.J.; Masereeuw, R.; Wouterse, A.C.; Smits, D.; Russel, F.G.M.

2003-01-01

OBJECTIVE: To study the pathophysiological changes of renal tubular drug transport mechanisms in congenital renal obstruction, by developing a model for perfusing the isolated kidney (IPK) after neonatal surgical induction of partial ureteric obstruction in Hanover Wistar rats. MATERIAL AND METHODS:

Interaction of coenzyme Q10 with the intestinal drug transporter P-glycoprotein.

Science.gov (United States)

Itagaki, Shirou; Ochiai, Akiko; Kobayashi, Masaki; Sugawara, Mitsuru; Hirano, Takeshi; Iseki, Ken

2008-08-27

In clinical trials, patients usually take many kinds of drugs at the same time. Thus, drug-drug interactions can often directly affect the therapeutic safety and efficacy of many drugs. Oral delivery is the most desirable means of drug administration. Changes in the activity of drug transporters may substantially influence the absorption of administered drugs from the intestine. However, there have been a few studies on food-drug interactions involving transporters. It is important to be aware of the potential of food-drug interactions and to act in order to prevent undesirable and harmful clinical consequences. Coenzyme Q10 (CoQ10) is very widely consumed by humans as a food supplement because of its recognition by the public as an important nutrient in supporting human health. Since intestinal efflux transporter P-glycoprotein (P-gp) is one of the major factors in drug-drug interactions, we focused on this transporter. We report here for the first time that CoQ10, which is widely used as a food supplement, affects the transport activity of P-gp.

Transport mechanisms at the pulmonary mucosa: implications for drug delivery.

Science.gov (United States)

Nickel, Sabrina; Clerkin, Caoimhe G; Selo, Mohammed Ali; Ehrhardt, Carsten

2016-01-01

Over the past years, a significant number of papers have substantiated earlier findings proposing a role for drug transporter proteins in pulmonary drug disposition. Whilst the majority of reports present data from in vitro models, a growing number of publications advance the field by introducing sophisticated ex vivo and in vivo techniques. In a few cases, evidence from clinical studies in human volunteers is complementing the picture. In this review, recent advances in pulmonary drug transporter research are critically evaluated. Transporter expression data in tissues and cell-based in vitro models is summarized and information on transport activity assessed. Novel techniques allowing for better quantification of transporter-related effects following pulmonary delivery are also described. Different tissue and cell populations of the lung have distinct transporter expression patterns. Whether these patterns are affected by disease, gender and smoking habits requires further clarification. Transporters have been found to have an impact on drug absorption processes, at least in vitro. Recent ex vivo experiments using isolated, perfused lung models, however, suggest that mainly efflux pumps have significant effects on absorption into the pulmonary circulation. Whether these rodent-based ex vivo models predict the human situation is basis for further research.

Chemical renal denervation in the rat.

Science.gov (United States)

Consigny, Paul M; Davalian, Dariush; Donn, Rosy; Hu, Jie; Rieser, Matthew; Stolarik, Deanne

2014-02-01

The recent success of renal denervation in lowering blood pressure in drug-resistant hypertensive patients has stimulated interest in developing novel approaches to renal denervation including local drug/chemical delivery. The purpose of this study was to develop a rat model in which depletion of renal norepinephrine (NE) could be used to determine the efficacy of renal denervation after the delivery of a chemical to the periadventitial space of the renal artery. Renal denervation was performed on a single renal artery of 90 rats (n = 6 rats/group). The first study determined the time course of renal denervation after surgical stripping of a renal artery plus the topical application of phenol in alcohol. The second study determined the efficacy of periadventitial delivery of hypertonic saline, guanethidine, and salicylic acid. The final study determined the dose-response relationship for paclitaxel. In all studies, renal NE content was determined by liquid chromatography-mass spectrometry. Renal NE was depleted 3 and 7 days after surgical denervation. Renal NE was also depleted by periadventitial delivery of all agents tested (hypertonic saline, salicylic acid, guanethidine, and paclitaxel). A dose response was observed after the application of 150 μL of 10(-5) M through 10(-2) M paclitaxel. We developed a rat model in which depletion of renal NE was used to determine the efficacy of renal denervation after perivascular renal artery drug/chemical delivery. We validated this model by demonstrating the efficacy of the neurotoxic agents hypertonic saline, salicylic acid, and guanethidine and increasing doses of paclitaxel.

Results of the use of a kinetic model of radiohippuran transport in the human body for quantitative assessment of summary and isolated renal function

International Nuclear Information System (INIS)

Ryabov, S.I.; Degtereva, O.A.; Klemina, I.K.; Degterev, B.V.; Senchik, R.V.

1986-01-01

The results of a method for the interpretation of commonly used methods of the determination of blood clearance and radionephrography with 131 I-hipuran based on a mathematical model of its transport in the human body are presented. Empirical values of model parameters were obtained in 120 patients with chronic glomerulo- and pyelonephritides verified morphologically and roentgenologically. The use of computational-interpretation algorithms made it possible to determine the volume of circulating plasma (blood), values of true summary and isolated effective renal plasma flow (blood flow) by means of a single i.v. hippuran administration. New indicators for assessment of isolated excretory-transport function and renal hemodynamics as well as indicators of the symmetry of renal function were proposed. The results of a statistical analysis made it possible to recommend some of them as criteria of early diagnosis of preuremic disorder of renal function. Radionuclide indicators of renal function showed good correlation with biochemical, morphological and roentgenological characteristics of renal damage in renal

Several hPepT1-transported drugs are substrates of the Escherichia coli proton-coupled oligopeptide transporter YdgR.

Science.gov (United States)

Prabhala, Bala K; Aduri, Nanda G; Iqbal, Mazhar; Rahman, Moazur; Gajhede, Michael; Hansen, Paul R; Mirza, Osman

2017-06-01

Proton-dependent oligopeptide transporters (POTs) are secondary active transporters found in all kingdoms of life. POTs utilize the proton electrochemical gradient for the uptake of nutrient dipeptides and tripeptides. The human POT hPepT1 is known to transport a number of drugs. As part of ongoing studies on substrate specificities of POTs from Escherichia coli, our aim in this study was to investigate whether bacterial POTs could also transport these drugs. For this, we selected the common orally administered drugs sulpiride, bestatin, valacyclovir, ampicillin and oseltamivir, that are all transported by hPepT1. The transport of these drugs was evaluated using the prototypical POT YdgR from E. coli. The transport studies were pursued through combining cell-based assays with liquid chromatography-tandem mass spectrometric (LC-MS/MS) analysis. These investigations revealed that YdgR from E. coli is able to transport five (sulpiride, bestatin, valacyclovir, ampicillin and oseltamivir) drugs. Furthermore, cells not overexpressing YdgR were also able to transport these drugs in a POT-like manner. Orthologues of YdgR are found in several species in the gut microbiome; hence, our findings could have implications for further understanding about the interaction between gut microbes and orally administered drugs. Copyright © 2017 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Application of physiologically-based pharmacokinetic modeling to explore the role of kidney transporters in renal reabsorption of perfluorooctanoic acid in the rat

Energy Technology Data Exchange (ETDEWEB)

Worley, Rachel Rogers, E-mail: idz7@cdc.gov [Agency for Toxic Substances and Disease Registry, Division of Community Health Investigations, 4770 Buford Highway, Atlanta, GA 30341 (United States); Interdisciplinary Toxicology Program, University of Georgia, 341 Pharmacy South, Athens, GA 30602 (United States); Fisher, Jeffrey [Interdisciplinary Toxicology Program, University of Georgia, 341 Pharmacy South, Athens, GA 30602 (United States); Food and Drug Administration, National Center for Toxicological Research, 3900 NCTR Road, Jefferson, AR 72079 (United States)

2015-12-15

ABSTRACT: Renal elimination and the resulting clearance of perfluorooctanoic acid (PFOA) from the serum exhibit pronounced sex differences in the adult rat. The literature suggests that this is largely due to hormonally regulated expression of organic anion transporters (OATs) on the apical and basolateral membranes of the proximal tubule cells that facilitate excretion and reabsorption of PFOA from the filtrate into the blood. Previously developed PBPK models of PFOA exposure in the rat have not been parameterized to specifically account for transporter-mediated renal elimination. We developed a PBPK model for PFOA in male and female rats to explore the role of Oat1, Oat3, and Oatp1a1 in sex-specific renal reabsorption and excretion of PFOA. Descriptions of the kinetic behavior of these transporters were extrapolated from in vitro studies and the model was used to simulate time-course serum, liver, and urine data for intravenous (IV) and oral exposures in both sexes. Model predicted concentrations of PFOA in the liver, serum, and urine showed good agreement with experimental data for both male and female rats indicating that in vitro derived physiological descriptions of transporter-mediated renal reabsorption can successfully predict sex-dependent excretion of PFOA in the rat. This study supports the hypothesis that sex-specific serum half-lives for PFOA are largely driven by expression of transporters in the kidney and contribute to the development of PBPK modeling as a tool for evaluating the role of transporters in renal clearance. - Highlights: • The PBPK model for PFOA in the rat explores the role of OATs in sex-specific clearance. • Descriptions of OAT kinetics were extrapolated from in vitro studies. • Model predictions showed good fit with experimental data for male and female rats.

Application of physiologically-based pharmacokinetic modeling to explore the role of kidney transporters in renal reabsorption of perfluorooctanoic acid in the rat

International Nuclear Information System (INIS)

Worley, Rachel Rogers; Fisher, Jeffrey

2015-01-01

ABSTRACT: Renal elimination and the resulting clearance of perfluorooctanoic acid (PFOA) from the serum exhibit pronounced sex differences in the adult rat. The literature suggests that this is largely due to hormonally regulated expression of organic anion transporters (OATs) on the apical and basolateral membranes of the proximal tubule cells that facilitate excretion and reabsorption of PFOA from the filtrate into the blood. Previously developed PBPK models of PFOA exposure in the rat have not been parameterized to specifically account for transporter-mediated renal elimination. We developed a PBPK model for PFOA in male and female rats to explore the role of Oat1, Oat3, and Oatp1a1 in sex-specific renal reabsorption and excretion of PFOA. Descriptions of the kinetic behavior of these transporters were extrapolated from in vitro studies and the model was used to simulate time-course serum, liver, and urine data for intravenous (IV) and oral exposures in both sexes. Model predicted concentrations of PFOA in the liver, serum, and urine showed good agreement with experimental data for both male and female rats indicating that in vitro derived physiological descriptions of transporter-mediated renal reabsorption can successfully predict sex-dependent excretion of PFOA in the rat. This study supports the hypothesis that sex-specific serum half-lives for PFOA are largely driven by expression of transporters in the kidney and contribute to the development of PBPK modeling as a tool for evaluating the role of transporters in renal clearance. - Highlights: • The PBPK model for PFOA in the rat explores the role of OATs in sex-specific clearance. • Descriptions of OAT kinetics were extrapolated from in vitro studies. • Model predictions showed good fit with experimental data for male and female rats.

Drug Transport and Pharmacokinetics for Chemical Engineers

Science.gov (United States)

Simon, Laurent; Kanneganti, Kumud; Kim, Kwang Seok

2010-01-01

Experiments in continuous-stirred vessels were proposed to introduce methods in pharmacokinetics and drug transport to chemical engineering students. The activities can be incorporated into the curriculum to illustrate fundamentals learned in the classroom. An appreciation for the role of pharmacokinetics in drug discovery will also be gained…

Construction of bioartificial renal tubule assist device in vitro and its function of transporting sodium and glucose.

Science.gov (United States)

Dong, Xinggang; Chen, Jianghua; He, Qiang; Yang, Yi; Zhang, Wei

2009-08-01

To explore a new way of constructing bioartificial renal tubule assist device (RAD) in vitro and its function of transporting sodium (Na(+)) and glucose and to evaluate the application of atomic force microscope in the RAD construction, rat renal tubular epithelial cell line NRK-52E was cultured in vitro, seeded onto the outer surfaces of hollow fibers in a bioreactor, and then cultured for two weeks to construct RAD. Bioreactor hollow fibers without NRK-52E cells were used as control. The morphologies of attached cells were observed with scanning electron microscope, and the junctions of cells and polysulfone membrane were observed with atomic force microscope. Transportation of Na(+) and glucose was measured. Oubaine and phlorizin were used to inhibit the transporting property. The results showed that NRK-52E cells and polysulfone membrane were closely linked, as observed under atomic force microscope. After exposure to oubaine and phlorizin, transporting rates of Na(+) and glucose were decreased significantly in the RAD group as compared with that in the control group (Pconstructed successfully in vitro, and it is able to selectively transport Na(+) and glucose.

Sodium dependent multivitamin transporter (SMVT): a potential target for drug delivery.

Science.gov (United States)

Vadlapudi, Aswani Dutt; Vadlapatla, Ramya Krishna; Mitra, Ashim K

2012-06-01

Sodium dependent multivitamin transporter (SMVT; product of the SLC5A6 gene) is an important transmembrane protein responsible for translocation of vitamins and other essential cofactors such as biotin, pantothenic acid and lipoic acid. Hydropathy plot (Kyte-Dolittle algorithm) revealed that human SMVT protein consists of 635 amino acids and 12 transmembrane domains with both amino and carboxyl termini oriented towards the cytoplasm. SMVT is expressed in various tissues such as placenta, intestine, brain, liver, lung, kidney, cornea, retina and heart. This transporter displays broad substrate specificity and excellent capacity for utilization in drug delivery. Drug absorption is often limited by the presence of physiological (epithelial tight junctions), biochemical (efflux transporters and enzymatic degradation) and chemical (size, lipophilicity, molecular weight, charge etc.) barriers. These barriers may cause many potential therapeutics to be dropped from the preliminary screening portfolio and subsequent entry into the market. Transporter targeted delivery has become a powerful approach to deliver drugs to target tissues because of the ability of the transporter to translocate the drug to intracellular organelles at a higher rate. This review highlights studies employing SMVT transporter as a target for drug delivery to improve bioavailability and investigate the feasibility of developing SMVT targeted drug delivery systems.

Drug Transporter Expression and Activity in Human Hepatoma HuH-7 Cells

Directory of Open Access Journals (Sweden)

Elodie Jouan

2016-12-01

Full Text Available Human hepatoma cells may represent a valuable alternative to the use of human hepatocytes for studying hepatic drug transporters, which is now a regulatory issue during drug development. In the present work, we have characterized hepatic drug transporter expression, activity and regulation in human hepatoma HuH-7 cells, in order to determine the potential relevance of these cells for drug transport assays. HuH-7 cells displayed notable multidrug resistance-associated protein (MRP activity, presumed to reflect expression of various hepatic MRPs, including MRP2. By contrast, they failed to display functional activities of the uptake transporters sodium taurocholate co-transporting polypeptide (NTCP, organic anion-transporting polypeptides (OATPs and organic cation transporter 1 (OCT1, and of the canalicular transporters P-glycoprotein and breast cancer resistance protein (BCRP. Concomitantly, mRNA expressions of various sinusoidal and canalicular hepatic drug transporters were not detected (NTCP, OATP1B1, organic anion transporter 2 (OAT2, OCT1 and bile salt export pump or were found to be lower (OATP1B3, OATP2B1, multidrug and toxin extrusion protein 1, BCRP and MRP3 in hepatoma HuH-7 cells than those found in human hepatocytes, whereas other transporters such as OAT7, MRP4 and MRP5 were up-regulated. HuH-7 cells additionally exhibited farnesoid X receptor (FXR- and nuclear factor erythroid 2-related factor 2 (Nrf2-related up-regulation of some transporters. Such data indicate that HuH-7 cells, although expressing rather poorly some main hepatic drug transporters, may be useful for investigating interactions of drugs with MRPs, notably MRP2, and for studying FXR- or Nrf2-mediated gene regulation.

Chemical Renal Denervation in the Rat

Energy Technology Data Exchange (ETDEWEB)

Consigny, Paul M., E-mail: paul.consigny@av.abbott.com; Davalian, Dariush, E-mail: dariush.davalian@av.abbott.com [Abbott Vascular, Innovation Incubator (United States); Donn, Rosy, E-mail: rosy.donn@av.abbott.com; Hu, Jie, E-mail: jie.hu@av.abbott.com [Abbott Vascular, Bioanalytical and Material Characterization (United States); Rieser, Matthew, E-mail: matthew.j.rieser@abbvie.com; Stolarik, DeAnne, E-mail: deanne.f.stolarik@abbvie.com [Abbvie, Analytical Pharmacology (United States)

2013-12-03

Introduction: The recent success of renal denervation in lowering blood pressure in drug-resistant hypertensive patients has stimulated interest in developing novel approaches to renal denervation including local drug/chemical delivery. The purpose of this study was to develop a rat model in which depletion of renal norepinephrine (NE) could be used to determine the efficacy of renal denervation after the delivery of a chemical to the periadventitial space of the renal artery. Methods: Renal denervation was performed on a single renal artery of 90 rats (n = 6 rats/group). The first study determined the time course of renal denervation after surgical stripping of a renal artery plus the topical application of phenol in alcohol. The second study determined the efficacy of periadventitial delivery of hypertonic saline, guanethidine, and salicylic acid. The final study determined the dose–response relationship for paclitaxel. In all studies, renal NE content was determined by liquid chromatography–mass spectrometry. Results: Renal NE was depleted 3 and 7 days after surgical denervation. Renal NE was also depleted by periadventitial delivery of all agents tested (hypertonic saline, salicylic acid, guanethidine, and paclitaxel). A dose response was observed after the application of 150 μL of 10{sup −5} M through 10{sup −2} M paclitaxel. Conclusion: We developed a rat model in which depletion of renal NE was used to determine the efficacy of renal denervation after perivascular renal artery drug/chemical delivery. We validated this model by demonstrating the efficacy of the neurotoxic agents hypertonic saline, salicylic acid, and guanethidine and increasing doses of paclitaxel.

Chemical Renal Denervation in the Rat

International Nuclear Information System (INIS)

Consigny, Paul M.; Davalian, Dariush; Donn, Rosy; Hu, Jie; Rieser, Matthew; Stolarik, DeAnne

2014-01-01

Introduction: The recent success of renal denervation in lowering blood pressure in drug-resistant hypertensive patients has stimulated interest in developing novel approaches to renal denervation including local drug/chemical delivery. The purpose of this study was to develop a rat model in which depletion of renal norepinephrine (NE) could be used to determine the efficacy of renal denervation after the delivery of a chemical to the periadventitial space of the renal artery. Methods: Renal denervation was performed on a single renal artery of 90 rats (n = 6 rats/group). The first study determined the time course of renal denervation after surgical stripping of a renal artery plus the topical application of phenol in alcohol. The second study determined the efficacy of periadventitial delivery of hypertonic saline, guanethidine, and salicylic acid. The final study determined the dose–response relationship for paclitaxel. In all studies, renal NE content was determined by liquid chromatography–mass spectrometry. Results: Renal NE was depleted 3 and 7 days after surgical denervation. Renal NE was also depleted by periadventitial delivery of all agents tested (hypertonic saline, salicylic acid, guanethidine, and paclitaxel). A dose response was observed after the application of 150 μL of 10 −5  M through 10 −2  M paclitaxel. Conclusion: We developed a rat model in which depletion of renal NE was used to determine the efficacy of renal denervation after perivascular renal artery drug/chemical delivery. We validated this model by demonstrating the efficacy of the neurotoxic agents hypertonic saline, salicylic acid, and guanethidine and increasing doses of paclitaxel

Multiple Drug Transport Pathways through human P-Glycoprotein(†)

Science.gov (United States)

McCormick, James W.; Vogel, Pia D.; Wise, John G.

2015-01-01

P-glycoprotein (P-gp) is a plasma membrane efflux pump that is commonly associated with therapy resistances in cancers and infectious diseases. P-gp can lower the intracellular concentrations of many drugs to subtherapeutic levels by translocating them out of the cell. Because of the broad range of substrates transported by P-gp, overexpression of P-gp causes multidrug resistance. We reported previously on dynamic transitions of P-gp as it moved through conformations based on crystal structures of homologous ABCB1 proteins using in silico targeted molecular dynamics techniques. We expanded these studies here by docking transport substrates to drug binding sites of P-gp in conformations open to the cytoplasm, followed by cycling the pump through conformations that opened to the extracellular space. We observed reproducible transport of two substrates, daunorubicin and verapamil, by an average of 11 to 12 Å through the plane of the membrane as P-gp progressed through a catalytic cycle. Methyl-pyrophosphate, a ligand that should not be transported by P-gp, did not show this movement through P-gp. Drug binding to either of two subsites on P-gp appeared to determine the initial pathway used for drug movement through the membrane. The specific side-chain interactions with drugs within each pathway seemed to be, at least in part, stochastic. The docking and transport properties of a P-gp inhibitor, tariquidar, were also studied. A mechanism of inhibition by tariquidar is presented that involves stabilization of an outward open conformation with tariquidar bound in intracellular loops or at the drug binding domain of P-gp. PMID:26125482

Safety and performance of the second generation EnligHTN™ Renal Denervation System in patients with drug-resistant, uncontrolled hypertension.

Science.gov (United States)

Worthley, Stephen G; Wilkins, Gerard T; Webster, Mark W; Montarello, Joseph K; Delacroix, Sinny; Whitbourn, Robert J; Warren, Roderic J

2017-07-01

Catheter-based renal denervation for the treatment of drug-resistant hypertension has been intensively investigated in recent years. To date, only limited data have been published using multi-electrode radiofrequency ablation systems that can deliver lesions with a pre-determined pattern. This study was designed to evaluate the safety and performance of the second generation EnligHTN™ Renal Denervation System. This first-in-human, prospective, multi-center, non-randomized study included 39 patients (62% male, mean age 63 years, and mean baseline office blood pressure 174/93 mmHg) with drug-resistant hypertension. The primary safety and performance objectives were to characterize, from baseline to 6 months post procedure, the rate of serious procedural and device related adverse events, as adjudicated by an independent Clinical Events Committee, and the reduction of office systolic blood pressure. Renal artery denervation, using the second generation EnligHTN multi-electrode system significantly reduced office blood pressure from baseline to 1, 3, 6, 12, 18 and 24 months by 19/7, 26/9, 25/7, 23/7, 25/8 and 27/9 mmHg, respectively (p ≤ 0.0005). No serious device or procedure related adverse events affecting the renal arteries or renal function occurred through 24 months of follow-up. Renal sympathetic denervation using the second generation EnligHTN Renal Denervation System resulted in safe, rapid, and significant mean office blood pressure reduction that was sustained through 24 months. Future studies will need to address the utility of this system against an appropriate sham based comparator. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

A comparative study of renal care in Brazil and Mexico: hemodialysis treatment from the perspective of ESRD sufferers.

Science.gov (United States)

Mercado-Martinez, Francisco J; da Silva, Denise Guerreiro V; Correa-Mauricio, Mauricio E

2017-04-01

Renal replacement therapy is the indicated treatment for individuals with chronic kidney disease (CKD) to survive. However, not all sick people have access to the same treatment. This study compares renal care in two developing countries with different health systems. Specifically, it explores hemodialysis treatment from the perspective of low-income individuals. A qualitative, comparative study was performed in Brazil and Mexico. Using purposive sampling, the research was based on open-ended interviews with nineteen participants with kidney failure undergoing hemodialysis treatment in public hospitals and ten relatives. According to our results, Brazilian participants perceived hemodialysis care as satisfactory because of health personnel courtesy as well as free access to dialysis treatment, prescription drugs, hospitalization and transportation. However, they reported deficiencies in the care they were receiving due to shortages of specialists, prescription drugs, laboratory tests and transportation. Mexican participants, in contrast, highlighted the catastrophic costs of medical care because they had no free access to renal therapy, nor adequate financial resources. Our findings suggest that low-income Brazilian CKD sufferers experience renal care differently, as they are more satisfied and face less obstacles with hemodialysis compared with those of Mexico. More studies on the topic are needed. © 2016 John Wiley & Sons Ltd.

Flavonoids as modulators of metabolic enzymes and drug transporters.

Science.gov (United States)

Miron, Anca; Aprotosoaie, Ana Clara; Trifan, Adriana; Xiao, Jianbo

2017-06-01

Flavonoids, natural compounds found in plants and in plant-derived foods and beverages, have been extensively studied with regard to their capacity to modulate metabolic enzymes and drug transporters. In vitro, flavonoids predominantly inhibit the major phase I drug-metabolizing enzyme CYP450 3A4 and the enzymes responsible for the bioactivation of procarcinogens (CYP1 enzymes) and upregulate the enzymes involved in carcinogen detoxification (UDP-glucuronosyltransferases, glutathione S-transferases (GSTs)). Flavonoids have been reported to inhibit ATP-binding cassette (ABC) transporters (multidrug resistance (MDR)-associated proteins, breast cancer-resistance protein) that contribute to the development of MDR. P-glycoprotein, an ABC transporter that limits drug bioavailability and also induces MDR, was differently modulated by flavonoids. Flavonoids and their phase II metabolites (sulfates, glucuronides) inhibit organic anion transporters involved in the tubular uptake of nephrotoxic compounds. In vivo studies have partially confirmed in vitro findings, suggesting that the mechanisms underlying the modulatory effects of flavonoids are complex and difficult to predict in vivo. Data summarized in this review strongly support the view that flavonoids are promising candidates for the enhancement of oral drug bioavailability, chemoprevention, and reversal of MDR. © 2017 New York Academy of Sciences.

Hereditary tubular transport disorders: implications for renal handling of Ca2+ and Mg2+.

NARCIS (Netherlands)

Dimke, H.; Hoenderop, J.G.J.; Bindels, R.J.M.

2010-01-01

The kidney plays an important role in maintaining the systemic Ca2+ and Mg2+ balance. Thus the renal reabsorptive capacity of these cations can be amended to adapt to disturbances in plasma Ca2+ and Mg2+ concentrations. The reabsorption of Ca2+ and Mg2+ is driven by transport of other electrolytes,

Epigenetic Modulation of the Biophysical Properties of Drug-Resistant Cell Lipids to Restore Drug Transport and Endocytic Functions

OpenAIRE

Vijayaraghavalu, Sivakumar; Peetla, Chiranjeevi; Lu, Shan; Labhasetwar, Vinod

2012-01-01

In our recent studies exploring the biophysical characteristics of resistant cell lipids, and the role they play in drug transport, we demonstrated the difference of drug-resistant breast cancer cells from drug-sensitive cells in lipid composition and biophysical properties, suggesting that cancer cells acquire a drug-resistant phenotype through the alteration of lipid synthesis to inhibit intracellular drug transport to protect from cytotoxic effect. In cancer cells, epigenetic changes (e.g....

Contribution of the organic anion transporter OAT2 to the renal active tubular secretion of creatinine and mechanism for serum creatinine elevations caused by cobicistat.

Science.gov (United States)

Lepist, Eve-Irene; Zhang, Xuexiang; Hao, Jia; Huang, Jane; Kosaka, Alan; Birkus, Gabriel; Murray, Bernard P; Bannister, Roy; Cihlar, Tomas; Huang, Yong; Ray, Adrian S

2014-08-01

Many xenobiotics including the pharmacoenhancer cobicistat increase serum creatinine by inhibiting its renal active tubular secretion without affecting the glomerular filtration rate. This study aimed to define the transporters involved in creatinine secretion, applying that knowledge to establish the mechanism for xenobiotic-induced effects. The basolateral uptake transporters organic anion transporter OAT2 and organic cation transporters OCT2 and OCT3 were found to transport creatinine. At physiologic creatinine concentrations, the specific activity of OAT2 transport was over twofold higher than OCT2 or OCT3, establishing OAT2 as a likely relevant creatinine transporter and further challenging the traditional view that creatinine is solely transported by a cationic pathway. The apical multidrug and toxin extrusion transporters MATE1 and MATE2-K demonstrated low-affinity and high-capacity transport. All drugs known to affect creatinine inhibited OCT2 and MATE1. Similar to cimetidine and ritonavir, cobicistat had the greatest effect on MATE1 with a 50% inhibition constant of 0.99 μM for creatinine transport. Trimethoprim potently inhibited MATE2-K, whereas dolutegravir preferentially inhibited OCT2. Cimetidine was unique, inhibiting all transporters that interact with creatinine. Thus, the clinical observation of elevated serum creatinine in patients taking cobicistat is likely a result of OCT2 transport, facilitating intracellular accumulation, and MATE1 inhibition.

Contribution of the organic anion transporter OAT2 to the renal active tubular secretion of creatinine and mechanism for serum creatinine elevations caused by cobicistat

Science.gov (United States)

Lepist, Eve-Irene; Zhang, Xuexiang; Hao, Jia; Huang, Jane; Kosaka, Alan; Birkus, Gabriel; Murray, Bernard P; Bannister, Roy; Cihlar, Tomas; Huang, Yong; Ray, Adrian S

2014-01-01

Many xenobiotics including the pharmacoenhancer cobicistat increase serum creatinine by inhibiting its renal active tubular secretion without affecting the glomerular filtration rate. This study aimed to define the transporters involved in creatinine secretion, applying that knowledge to establish the mechanism for xenobiotic-induced effects. The basolateral uptake transporters organic anion transporter OAT2 and organic cation transporters OCT2 and OCT3 were found to transport creatinine. At physiologic creatinine concentrations, the specific activity of OAT2 transport was over twofold higher than OCT2 or OCT3, establishing OAT2 as a likely relevant creatinine transporter and further challenging the traditional view that creatinine is solely transported by a cationic pathway. The apical multidrug and toxin extrusion transporters MATE1 and MATE2-K demonstrated low-affinity and high-capacity transport. All drugs known to affect creatinine inhibited OCT2 and MATE1. Similar to cimetidine and ritonavir, cobicistat had the greatest effect on MATE1 with a 50% inhibition constant of 0.99 μM for creatinine transport. Trimethoprim potently inhibited MATE2-K, whereas dolutegravir preferentially inhibited OCT2. Cimetidine was unique, inhibiting all transporters that interact with creatinine. Thus, the clinical observation of elevated serum creatinine in patients taking cobicistat is likely a result of OCT2 transport, facilitating intracellular accumulation, and MATE1 inhibition. PMID:24646860

In vitro comparison of renal handling and uptake of two somatostatin receptor-specific peptides labeled with indium-111

International Nuclear Information System (INIS)

Trejtnar, F.; Novy, Z.; Petrik, M.; Laznickova, A.; Melicharova, L.; Vankova, M.; Laznicek, M.

2008-01-01

Radiolabeled receptor-specific somatostatin analogs labeled with gamma- or beta-emitting radionuclides are useful for scintigraphic imaging and/or therapy of selected neuroendocrine tumors. However, significant renal uptake may result in radiotoxicological injury of the kidney and can limit clinical application of the agents. The aim of the study was to analyze renal handling, rate, and mechanism of renal accumulation of two somatostatin receptor-targeted peptides, [DOTA 0 , Tyr 3 , Thr 8 ]-octreotide (DOTA-TATE) and [DOTA 0 , 1-Nal 3 ]-octreotide (DOTA-NOC), labeled with indium-111 using in vitro methods. The perfused rat kidney and freshly isolated rat renal cells were used as experimental models. The perfusion was performed in a recirculation regimen at constant pressure with solution containing bovine albumin, erythrocytes, and a mixture of essential substrates. The renal cells were isolated from rat kidneys using two-phase collagenase perfusion. Accumulation studies were used to evaluate the renal uptake of the peptides and to compare their accumulation with that of passively or actively transported model drugs. The influence of selected inhibitors of receptor-mediated endocytosis and the inhibition of energy-dependent transport processes on the uptake were also investigated using isolated renal cells. The renal clearance of 111 In-DOTA-NOC in the perfused rat kidney was significantly lower than that of 111 In-DOTA-TATE. Reverse situation was found in the case of renal retention. Pretreatment of the perfused kidney with maleate markedly decreased the renal retention. 111 In-DOTA-NOC was accumulated in the isolated renal cells at a higher rate than 111 In-DOTA-TATE (ratio 3:1). The uptake of the radiopeptides in renal cells was higher than the uptake of not only the passively transported sucrose but also actively transported and accumulated methylglucose. The rank order of potency to inhibit the uptake by active endocytosis was approximately aprotinin

Mathematical rationalization for the renal tubular transport: revised concepts.

Science.gov (United States)

Mioni, Roberto; Marega, Alessandra; Romano, Giulio; Montanaro, Domenico

2017-09-01

The current emphasis on kinetics and in situ control of molecular exchanges, across the tubular membrane, has not been paralleled by corresponding improvements in our understanding of tubular behaviour at the macroscopic level of classical physiology. In this paper, we propose a mathematical rationalization of macroscopic tubular transport by means of a principal transport equation, originating from the law of mass action between substrate and carrier. The other equations, derived from the main one, demonstrate the possibility of distinguishing between transporters with low affinity and high capacity and transporters with high affinity and low capacity. Moreover, our model formalizes both tubular reabsorption and tubular secretion. Regarding the renal calcium handling, our model confirms the two-compartment system proposed by Mioni in 1971, with some important variants, which are in agreement with the fractional reabsorptions of this cation along the tubule, as verified by micro-puncture technique. To obtain the frequency distribution of saturated tubules, we have utilized the infinitesimal analysis method, starting from the equations proposed by Smith in 1943, concluding that all titration curves result from the combined effect of enzymatic approach and anatomical heterogeneity of the nephrons. The theoretical equations included in our manuscript reflect substantial and palpable physiological mechanisms able to suggest diagnosis and therapy of some electrolyte and hormonal disorders. At the end of this paper, we highlight advantages and disadvantages detectable by comparing our mathematical approach with Marshall's and Bijvoet's methods, proposed, respectively, in 1976 and 1984.

RENAL DAMAGE WITH MALIGNANT NEOPLASMS

Directory of Open Access Journals (Sweden)

I. B. Kolina

2015-01-01

Full Text Available The relationship between renal damage and malignant neoplasms is one of the most actual problems of the medicine of internal diseases. Very often, exactly availability of renal damage determines the forecast of cancer patients. The range of renal pathologies associated with tumors is unusually wide: from the mechanical effect of the tumor or metastases on the kidneys and/or the urinary tract and paraneoplastic manifestations in the form of nephritis or amyloidosis to nephropathies induced with drugs or tumor lysis, etc. Thrombotic complications that develop as a result of exposure to tumor effects, side effects of certain drugs or irradiation also play an important role in the development of the kidney damage. The most frequent variants of renal damage observed in the practice of medical internists (therapists, urologists, surgeons, etc., as well as methods of diagnosis and treatment approaches are described in the article. Timely and successful prevention and treatment of tumor-associated nephropathies give hope for retaining renal functions, therefore, a higher life standard after completion of anti-tumor therapy. Even a shortterm episode of acute renal damage suffered by a cancer patient must be accompanied with relevant examination and treatment. In the caseof transformation of acute renal damage into the chronic kidney disease, such patients need systematic and weighted renoprotective therapy and correct dosing of nephrotoxic drugs.

Nano carriers for drug transport across the blood-brain barrier.

Science.gov (United States)

Li, Xinming; Tsibouklis, John; Weng, Tingting; Zhang, Buning; Yin, Guoqiang; Feng, Guangzhu; Cui, Yingde; Savina, Irina N; Mikhalovska, Lyuba I; Sandeman, Susan R; Howel, Carol A; Mikhalovsky, Sergey V

2017-01-01

Effective therapy lies in achieving a therapeutic amount of drug to the proper site in the body and then maintaining the desired drug concentration for a sufficient time interval to be clinically effective for treatment. The blood-brain barrier (BBB) hinders most drugs from entering the central nervous system (CNS) from the blood stream, leading to the difficulty of delivering drugs to the brain via the circulatory system for the treatment, diagnosis and prevention of brain diseases. Several brain drug delivery approaches have been developed, such as intracerebral and intracerebroventricular administration, intranasal delivery and blood-to-brain delivery, as a result of transient BBB disruption induced by biological, chemical or physical stimuli such as zonula occludens toxin, mannitol, magnetic heating and ultrasound, but these approaches showed disadvantages of being dangerous, high cost and unsuitability for most brain diseases and drugs. The strategy of vector-mediated blood-to-brain delivery, which involves improving BBB permeability of the drug-carrier conjugate, can minimize side effects, such as being submicrometre objects that behave as a whole unit in terms of their transport and properties, nanomaterials, are promising carrier vehicles for direct drug transport across the intact BBB as a result of their potential to enter the brain capillary endothelial cells by means of normal endocytosis and transcytosis due to their small size, as well as their possibility of being functionalized with multiple copies of the drug molecule of interest. This review provids a concise discussion of nano carriers for drug transport across the intact BBB, various forms of nanomaterials including inorganic/solid lipid/polymeric nanoparticles, nanoemulsions, quantum dots, nanogels, liposomes, micelles, dendrimers, polymersomes and exosomes are critically evaluated, their mechanisms for drug transport across the BBB are reviewed, and the future directions of this area are fully

Renal accumulation of [{sup 111}In]DOTATOC in rats: influence of inhibitors of the organic ion transport and diuretics

Energy Technology Data Exchange (ETDEWEB)

Stahl, A.R. [Technische Universitaet Muenchen, Klinikum rechts der Isar, Department of Nuclear Medicine, Munich (Germany); Universitaetsklinikum Essen, Department of Radiology, Essen (Germany); Wagner, B.; Heemann, U.; Lutz, J. [Technische Universitaet Muenchen, Klinikum rechts der Isar, Department of Nephrology, Munich (Germany); Poethko, T.; Perutka, M.; Wester, H.J.; Essler, M.; Schwaiger, M. [Technische Universitaet Muenchen, Klinikum rechts der Isar, Department of Nuclear Medicine, Munich (Germany)

2007-12-15

Radiation exposure to the kidney limits therapy with radiometal labelled DOTATOC. This study evaluates the organic anion and cation transport (inhibitors: probenecid and cimetidine/dexamethason) as well as diuresis (furosemide and mannitol) regarding renal uptake of [{sup 111}In]DOTATOC. One hundred eight male Fisher rats were injected with [{sup 111}In]DOTATOC via the tail vein. Prior to activity injection a total of 84 rats underwent injection with probenecid vs. sodium chloride 0.9% (48 rats), cimetidine vs. dexamethasone vs. sodium chloride 0.9% (18 rats), and furosemide vs. mannitol vs. sodium chloride 0.9% (18 rats). Rats were sacrificed at predetermined time points up to 48 h after activity injection. Kidneys, adrenal glands, pancreas, spleen, blood, liver, and muscle were harvested and injected activity per gram tissue was determined. Autoradiographic images of the kidneys were acquired in a total of 24 rats. Probenecid led to a reduction in renal uptake by up to 30% while not significantly changing the activity accumulation in the other organs investigated. This reduction was attributable to the renal cortex (ratio cortex/medulla 1.72 vs. 1.99; p = 0.006). Cimetidine and dexamethasone had no effect in any of the organs. Furosemide led to a 44% increase in renal activity accumulation attributable to enhanced renal medullary uptake (ratio cortex/medulla 1.44 versus 1.69; p = 0.006). Mannitol had no effect on renal activity uptake. Inhibition of the organic anion transport by probenecid may help reduce renal uptake regarding therapy with radiometal labelled DOTATOC. The enhancing effect of furosemide may be unfavourable for therapy. The results must be confirmed by human studies. (orig.)

Expression of transcellular and paracellular calcium and magnesium transport proteins in renal and intestinal epithelia during lactation.

Science.gov (United States)

Beggs, Megan R; Appel, Ida; Svenningsen, Per; Skjødt, Karsten; Alexander, R Todd; Dimke, Henrik

2017-09-01

Significant alterations in maternal calcium (Ca 2+ ) and magnesium (Mg 2+ ) balance occur during lactation. Ca 2+ is the primary divalent cation mobilized into breast milk by demineralization of the skeleton and alterations in intestinal and renal Ca 2+ transport. Mg 2+ is also concentrated in breast milk, but the underlying mechanisms are not well understood. To determine the molecular alterations in Ca 2+ and Mg 2+ transport in the intestine and kidney during lactation, three groups of female mice consisting of either nonpregnant controls, lactating mice, or mice undergoing involution were examined. The fractional excretion of Ca 2+ , but not Mg 2+ , rose significantly during lactation. Renal 1-α hydroxylase and 24-OHase mRNA levels increased markedly, as did plasma 1,25 dihydroxyvitamin D levels. This was accompanied by significant increases in intestinal expression of Trpv6 and S100g in lactating mice. However, no alterations in the expression of cation-permeable claudin-2, claudin-12, or claudins-15 were found in the intestine. In the kidney, increased expression of Trpv5 and Calb1 was observed during lactation, while no changes in claudins involved in Ca 2+ and Mg 2+ transport (claudin-2, claudin-14, claudin-16, or claudin-19) were found. Consistent with the mRNA expression, expression of both calbindin-D 28K and transient receptor potential vanilloid 5 (TRPV5) proteins increased. Colonic Trpm6 expression increased during lactation, while renal Trpm6 remained unaltered. In conclusion, proteins involved in transcellular Ca 2+ and Mg 2+ transport pathways increase during lactation, while expression of paracellular transport proteins remained unchanged. Increased fractional Ca 2+ excretion can be explained by vitamin D-dependent intestinal hyperabsorption and bone demineralization, despite enhanced transcellular Ca 2+ uptake by the kidney. Copyright © 2017 the American Physiological Society.

Organic solute carrier 22 (SLC22 family: Potential for interactions with food, herbal/dietary supplements, endogenous compounds, and drugs

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Raymond E. Lai

2018-04-01

Full Text Available Many drugs, hormones, components of herbal medicines, environmental pesticides and toxins are Solute Carrier family 22 (SLC22 substrates. The last twenty years has seen great progress in determining SLC22 tissue expression profiles, membrane localization, energetics, substrate profiles and biopharmaceutical significance. However, much still remains to be answered in terms of SLC22 family member's roles in ‘normal’ physiology as compared to pathophysiological states, as well as in drug interactions that impact pharmacokinetics, efficacy and toxicity. This review begins with a brief synopsis of SLC22 family discovery, function and tissue expression. Subsequent sections provide examples establishing a role for SLC22 transporters in food-drug, herbal supplement-drug, endogenous substrate-drug and drug–drug interactions. Keywords: Hepatic transport, Nephrotoxicity, Organic anion transporter, Organic cation transporter, Renal transport

Drug-permeability and transporter assays in Caco-2 and MDCK cell lines.

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Volpe, Donna A

2011-12-01

The human colon adenocarcinoma Caco-2 and Madin-Darby canine kidney epithelial cell lines provide in vitro tools to assess a drug's permeability and transporter interactions during discovery and development. The cells, when cultured on semiporous filters, form confluent monolayers that model the intestinal epithelial barrier for permeability, transporter and drug-interaction assays. The applications of these assays in pharmaceutical research include qualitative prediction and ranking of absorption, determining mechanism(s) of permeability, formulation effects on drug permeability, and the potential for transporter-mediated drug-drug interactions. This review focuses on recent examples of Caco-2 and Madin-Darby canine kidney cells assays for drug permeability including transfected and knock-down cells, miniaturization and automation, and assay combinations to better understand and predict intestinal drug absorption.

Validation of a microdose probe drug cocktail for clinical drug interaction assessments for drug transporters and CYP3A.

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Prueksaritanont, T; Tatosian, D A; Chu, X; Railkar, R; Evers, R; Chavez-Eng, C; Lutz, R; Zeng, W; Yabut, J; Chan, G H; Cai, X; Latham, A H; Hehman, J; Stypinski, D; Brejda, J; Zhou, C; Thornton, B; Bateman, K P; Fraser, I; Stoch, S A

2017-04-01

A microdose cocktail containing midazolam, dabigatran etexilate, pitavastatin, rosuvastatin, and atorvastatin has been established to allow simultaneous assessment of a perpetrator impact on the most common drug metabolizing enzyme, cytochrome P450 (CYP)3A, and the major transporters organic anion-transporting polypeptides (OATP)1B, breast cancer resistance protein (BCRP), and MDR1 P-glycoprotein (P-gp). The clinical utility of these microdose cocktail probe substrates was qualified by conducting clinical drug interaction studies with three inhibitors with different in vitro inhibitory profiles (rifampin, itraconazole, and clarithromycin). Generally, the pharmacokinetic profiles of the probe substrates, in the absence and presence of the inhibitors, were comparable to their reported corresponding pharmacological doses, and/or in agreement with theoretical expectations. The exception was dabigatran, which resulted in an approximately twofold higher magnitude for microdose compared to conventional dosing, and, thus, can be used to flag a worst-case scenario for P-gp. Broader application of the microdose cocktail will facilitate a more comprehensive understanding of the roles of drug transporters in drug disposition and drug interactions. © 2016 American Society for Clinical Pharmacology and Therapeutics.

Excessive fructose intake causes 1,25-(OH)2D3-dependent inhibition of intestinal and renal calcium transport in growing rats

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Douard, Veronique; Sabbagh, Yves; Lee, Jacklyn; Patel, Chirag; Kemp, Francis W.; Bogden, John D.; Lin, Sheldon

2013-01-01

We recently discovered that chronic high fructose intake by lactating rats prevented adaptive increases in rates of active intestinal Ca2+ transport and in levels of 1,25-(OH)2D3, the active form of vitamin D. Since sufficient Ca2+ absorption is essential for skeletal growth, our discovery may explain findings that excessive consumption of sweeteners compromises bone integrity in children. We tested the hypothesis that 1,25-(OH)2D3 mediates the inhibitory effect of excessive fructose intake on active Ca2+ transport. First, compared with those fed glucose or starch, growing rats fed fructose for 4 wk had a marked reduction in intestinal Ca2+ transport rate as well as in expression of intestinal and renal Ca2+ transporters that was tightly associated with decreases in circulating levels of 1,25-(OH)2D3, bone length, and total bone ash weight but not with serum parathyroid hormone (PTH). Dietary fructose increased the expression of 24-hydroxylase (CYP24A1) and decreased that of 1α-hydroxylase (CYP27B1), suggesting that fructose might enhance the renal catabolism and impair the synthesis, respectively, of 1,25-(OH)2D3. Serum FGF23, which is secreted by osteocytes and inhibits CYP27B1 expression, was upregulated, suggesting a potential role of bone in mediating the fructose effects on 1,25-(OH)2D3 synthesis. Second, 1,25-(OH)2D3 treatment rescued the fructose effect and normalized intestinal and renal Ca2+ transporter expression. The mechanism underlying the deleterious effect of excessive fructose intake on intestinal and renal Ca2+ transporters is a reduction in serum levels of 1,25-(OH)2D3. This finding is significant because of the large amounts of fructose now consumed by Americans increasingly vulnerable to Ca2+ and vitamin D deficiency. PMID:23571713

[Carrier-mediated Transport of Cationic Drugs across the Blood-Tissue Barrier].

Science.gov (United States)

Kubo, Yoshiyuki

2015-01-01

Studies of neurological dysfunction have revealed the neuroprotective effect of several cationic drugs, suggesting their usefulness in the treatment of neurological diseases. In the brain and retina, blood-tissue barriers such as blood-brain barrier (BBB) and blood-retinal barrier (BRB) are formed to restrict nonspecific solute transport between the circulating blood and neural tissues. Therefore study of cationic drug transport at these barriers is essential to achieve systemic delivery of neuroprotective agents into the neural tissues. In the retina, severe diseases such as diabetic retinopathy and macular degeneration can cause neurological dysfunction that dramatically affects patients' QOL. The BRB is formed by retinal capillary endothelial cells (inner BRB) and retinal pigment epithelial cells (outer BRB). Blood-to-retina transport of cationic drugs was investigated at the inner BRB, which is known to nourish two thirds of the retina. Blood-to-retinal transport of verapamil suggested that the barrier function of the BRB differs from that of the BBB. Moreover, carrier-mediated transport of verapamil and pyrilamine revealed the involvement of novel organic cation transporters at the inner BRB. The identified transport systems for cationic drugs are sensitive to several cationic neuroprotective and anti-angiogenic agents such as clonidine and propranolol, and the involvement of novel transporters was also suggested in their blood-to-retina transport across the inner BRB.

Transporter-Guided Delivery of Nanoparticles to Improve Drug Permeation across Cellular Barriers and Drug Exposure to Selective Cell Types

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Longfa Kou

2018-01-01

Full Text Available Targeted nano-drug delivery systems conjugated with specific ligands to target selective cell-surface receptors or transporters could enhance the efficacy of drug delivery and therapy. Transporters are expressed differentially on the cell-surface of different cell types, and also specific transporters are expressed at higher than normal levels in selective cell types under pathological conditions. They also play a key role in intestinal absorption, delivery via non-oral routes (e.g., pulmonary route and nasal route, and transfer across biological barriers (e.g., blood–brain barrier and blood–retinal barrier. As such, the cell-surface transporters represent ideal targets for nano-drug delivery systems to facilitate drug delivery to selective cell types under normal or pathological conditions and also to avoid off-target adverse side effects of the drugs. There is increasing evidence in recent years supporting the utility of cell-surface transporters in the field of nano-drug delivery to increase oral bioavailability, to improve transfer across the blood–brain barrier, and to enhance delivery of therapeutics in a cell-type selective manner in disease states. Here we provide a comprehensive review of recent advancements in this interesting and important area. We also highlight certain key aspects that need to be taken into account for optimal development of transporter-assisted nano-drug delivery systems.

The impact of renal protection clinics on prescription of and adherence to cardioprotective drug therapy in chronic kidney disease patients.

Science.gov (United States)

Lepeytre, Fanny; Cardinal, Héloise; Fradette, Lorraine; Verhave, Jacobien; Dorais, Marc; LeLorier, Jacques; Pichette, Vincent; Madore, François

2017-06-01

Background: The aim of this study was to assess the impact of follow-up in renal protection clinics on the prescription of and adherence to cardioprotective drugs in patients with chronic kidney disease (CKD). Methods: We studied stage 4 and 5 CKD patients who initiated follow-up in three renal protection clinics. The prescription pattern of antihypertensive agents (AHA) and lipid-lowering agents (LLAs) was measured as the percentage of patients who are prescribed the agents of interest at a given time. Adherence to drug therapy was defined as the percentage of days, during a pre-defined observation period, in which patients have an on-hand supply of their prescribed medications. Results: A total of 259 CKD patients were enrolled and followed for up to 1 year after referral to renal protection clinics. There was a significant increase in the prescription of angiotensin-converting enzyme inhibitors (34-39%), angiotensin II receptor blockers (11-14%), beta-blockers (40-51%), calcium channel blockers (62-74%), diuretics (66-78%) and LLAs (39-47%) during follow-up in the renal protection clinic compared with baseline (P-values protection clinics. Conclusion: Our results suggest that referral and follow-up in a renal protection clinic may increase the prescription of cardioprotective agents in CKD patients, but does not appear to improve adherence to these medications.

Extra-Renal Elimination of Uric Acid via Intestinal Efflux Transporter BCRP/ABCG2

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Hosomi, Atsushi; Nakanishi, Takeo; Fujita, Takuya; Tamai, Ikumi

2012-01-01

Urinary excretion accounts for two-thirds of total elimination of uric acid and the remainder is excreted in feces. However, the mechanism of extra-renal elimination is poorly understood. In the present study, we aimed to clarify the mechanism and the extent of elimination of uric acid through liver and intestine using oxonate-treated rats and Caco-2 cells as a model of human intestinal epithelium. In oxonate-treated rats, significant amounts of externally administered and endogenous uric acid were recovered in the intestinal lumen, while biliary excretion was minimal. Accordingly, direct intestinal secretion was thought to be a substantial contributor to extra-renal elimination of uric acid. Since human efflux transporter BCRP/ABCG2 accepts uric acid as a substrate and genetic polymorphism causing a decrease of BCRP activity is known to be associated with hyperuricemia and gout, the contribution of rBcrp to intestinal secretion was examined. rBcrp was confirmed to transport uric acid in a membrane vesicle study, and intestinal regional differences of expression of rBcrp mRNA were well correlated with uric acid secretory activity into the intestinal lumen. Bcrp1 knockout mice exhibited significantly decreased intestinal secretion and an increased plasma concentration of uric acid. Furthermore, a Bcrp inhibitor, elacridar, caused a decrease of intestinal secretion of uric acid. In Caco-2 cells, uric acid showed a polarized flux from the basolateral to apical side, and this flux was almost abolished in the presence of elacridar. These results demonstrate that BCRP contributes at least in part to the intestinal excretion of uric acid as extra-renal elimination pathway in humans and rats. PMID:22348008

Effect of magnesium deficiency on renal magnesium and calcium transport in the rat.

OpenAIRE

Carney, S L; Wong, N L; Quamme, G A; Dirks, J H

1980-01-01

Recollection of micropuncture experiments were performed on acutely thyroparathyroidectomized rats rendered magnesium deficient by dietary deprivation. Urinary magnesium excretion fell from a control of 15 to 3% of the filtered load after magnesium restriction. The loop of Henle, presumably the thick ascending limb, was the major modulator for renal magnesium homeostasis. The transport capacity for magnesium, however, was less in deficient rats than control animals. Absolute magnesium reabsor...

Acid-base transport by the renal proximal tubule.

Science.gov (United States)

Skelton, Lara A; Boron, Walter F; Zhou, Yuehan

2010-01-01

Each day, the kidneys filter 180 L of blood plasma, equating to some 4,300 mmol of the major blood buffer, bicarbonate (HCO3-). The glomerular filtrate enters the lumen of the proximal tubule (PT), and the majority of filtered HCO3- is reclaimed along the early (S1) and convoluted (S2) portions of the PT in a manner coupled to the secretion of H+ into the lumen. The PT also uses the secreted H+ to titrate non-HCO3- buffers in the lumen, in the process creating "new HCO3-" for transport into the blood. Thus, the PT - along with more distal renal segments - is largely responsible for regulating plasma [HCO3-]. In this review we first focus on the milestone discoveries over the past 50+ years that define the mechanism and regulation of acid-base transport by the proximal tubule. Further on in the review, we will summarize research still in progress from our laboratory, work that addresses the problem of how the PT is able to finely adapt to acid-base disturbances by rapidly sensing changes in basolateral levels of HCO3- and CO2 (but not pH), and thereby to exert tight control over the acid-base composition of the blood plasma.

75 FR 59105 - Procedures for Transportation Workplace Drug and Alcohol Testing Programs: Federal Drug Testing...

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2010-09-27

... 2105-AE03 Procedures for Transportation Workplace Drug and Alcohol Testing Programs: Federal Drug... the Federal workplace drug testing program but also pointed out that ``* * * the Department of.... Executive Order 12866 and Regulatory Flexibility Act This Interim Final Rule is not significant for purposes...

Albumin-based drug delivery

DEFF Research Database (Denmark)

Larsen, Maja Thim; Kuhlmann, Matthias; Hvam, Michael Lykke

2016-01-01

The effectiveness of a drug is dependent on accumulation at the site of action at therapeutic levels, however, challenges such as rapid renal clearance, degradation or non-specific accumulation requires drug delivery enabling technologies. Albumin is a natural transport protein with multiple ligand...... binding sites, cellular receptor engagement, and a long circulatory half-life due to interaction with the recycling neonatal Fc receptor. Exploitation of these properties promotes albumin as an attractive candidate for half-life extension and targeted intracellular delivery of drugs attached by covalent...... conjugation, genetic fusions, association or ligand-mediated association. This review will give an overview of albumin-based products with focus on the natural biological properties and molecular interactions that can be harnessed for the design of a next-generation drug delivery platform....

Renal denervation: Results of a single-center cohort study

International Nuclear Information System (INIS)

Luetkens, J.A.; Thomas, D.; Doerner, J.; Schild, H.H.; Naehle, C.P.; Woitas, R.P.; Hundt, F.

2015-01-01

To investigate the effect of renal denervation on office-based and 24-h ambulatory blood pressure measurements (ABPM) in a highly selective patient population with drug-resistant hypertension. Patients with drug resistant hypertension eligible for renal denervation were included in the study population. Office blood pressure and ABPM were assessed prior to and after renal denervation. To detect procedure related renal or renal artery damage, magnetic resonance imaging (MRI) and angiography (MRA) were performed pre-interventional, one day post-interventional, and one month after renal denervation. Mean follow-up time between renal denervation and blood pressure re-assessment was 9.5 ± 3.9 months. Between August 2011 and March 2013, 17 patients prospectively underwent renal denervation. Pre-interventional mean office blood pressure and ABPM were 177.3 ± 20.3/103.8 ± 20.4 mmHg and 155.2 ± 20.5/93.7 ± 14.5 mmHg, respectively. Post-interventional, office blood pressure was significantly reduced to 144.7 ± 14.9/89.5 ± 12.1 (p 0.05). The number of prescribed antihypertensive drugs was unchanged after renal denervation (4.7 ± 2.0 vs. 4.2 ± 1.2, p = 0.18). No renovascular complications were detected in follow-up MRI. After renal denervation, no significant decrease in ABPM was observed. These results may indicate a limited impact of renal denervation for drug resistant hypertension.

Glomerular Filtration Rate Estimation in Renal and Non-Renal Solid Organ Transplantation

DEFF Research Database (Denmark)

Hornum, Mads; Feldt-Rasmussen, Bo

2017-01-01

Following transplantation (TX) of both renal and non-renal organs, a large proportion of patients have renal dysfunction. There are multiple causes for this. Chronic nephrotoxicity and high doses of calcineurin inhibitors are important factors. Preoperative and perioperative factors like hyperten......Following transplantation (TX) of both renal and non-renal organs, a large proportion of patients have renal dysfunction. There are multiple causes for this. Chronic nephrotoxicity and high doses of calcineurin inhibitors are important factors. Preoperative and perioperative factors like...... hypertension, hypotension, drugs and infections may play a causative role as well. Organ-specific causes include hepatorenal syndrome, cirrhosis, low cardiac function, low respiratory function and diabetes developed both before and after TX. It is important to be able to perform precise and valid measurements...... rate methods for use in renal and non-renal TX....

Effects of a series of acidic drugs on L-lactic acid transport by the monocarboxylate transporters MCT1 and MCT4.

Science.gov (United States)

Leung, Yat Hei; Belanger, Francois; Lu, Jennifer; Turgeon, Jacques; Michaud, Veronique

2018-03-07

Drug-induced myopathy is a serious side effect that often requires removal of a medication from a drug regimen. For most drugs, the underlying mechanism of drug-induced myopathy remains unclear. Monocarboxylate transporters (MCTs) mediate L-lactic acid transport, and inhibition of MCTs may potentially lead to perturbation of L-lactic acid accumulation and muscular disorders. Therefore, we hypothesized that L-lactic acid transport may be involved in the development of drug-induced myopathy. The aim of this study was to assess the inhibitory potential of 24 acidic drugs on L-lactic acid transport using breast cancer cell lines Hs578T and MDA-MB-231, which selectively express MCT1 and MCT4, respectively. The influx transport of L-lactic acid was minimally inhibited by all drugs tested. The efflux transport was next examined: loratadine (IC50: 10 and 61 µM) and atorvastatin (IC50: 78 and 41 µM) demonstrated the greatest potency for inhibition of L-lactic acid efflux by MCT1 and MCT4, respectively. Acidic drugs including fluvastatin, cerivastatin, simvastatin acid, lovastatin acid, irbesartan and losartan exhibited weak inhibitory potency on L-lactic acid efflux. Our results suggest that some acidic drugs, such as loratadine and atorvastatin, can inhibit the efflux transport of L-lactic acid. This inhibition may cause an accumulation of intracellular L-lactic acid leading to acidification and muscular disorders. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Electrogenic Na+-independent Pi transport in canine renal basolateral membrane vesicles

International Nuclear Information System (INIS)

Schwab, S.J.; Hammerman, M.R.

1986-01-01

To define the mechanism by which Pi exists from the renal proximal tubular cell across the basolateral membrane, we measured 32Pi uptake in basolateral membrane vesicles from dog kidney in the absence of Na+. Preloading of basolateral vesicles with 2 mM Pi transstimulated 32Pi uptake, which is consistent with counterflow. We used measurements of transstimulation to quantitate the transport component of 32Pi uptake. Transstimulation of 32Pi uptake was inhibited less than 30% by concentrations of probenecid as high as 50 mM. In contrast, transstimulation of 35SO4(2-) uptake by intravesicular SO4(2-) was inhibited 92% by 5 mM probenecid. Preloading basolateral vesicles with SO4(2-) did not result in transstimulation of 32Pi uptake. Accumulation of 32Pi in basolateral vesicles above steady state was driven by a membrane potential (intravesicular positive), consistent with Na+-independent Pi transport being accompanied by the net transfer of negative charge across the membrane. We conclude that carrier-mediated, electrogenic Na+-independent 32Pi transport can be demonstrated in basolateral vesicles from dog kidney. This process appears to be mediated, at least in part, via a mechanism different from that by which SO4(2-) is transported. Electrogenic Na+-independent Pi transport may reflect one means by which Pi reabsorbed across the luminal membrane exists from the proximal tubular cell down an electrochemical gradient

C-A4-01: Computerized Clinical Decision Support During Drug Ordering for Long-term Care Residents With Renal Insufficiency

Science.gov (United States)

Field, Terry S; Rochon, Paula; Lee, Monica; Gavendo, Linda; Baril, Joann L; Gurwitz, Jerry H

2010-01-01

Objective: To determine whether a computerized clinical decision support system (CDSS) providing patient specific recommendations in real- time improves the quality of prescribing for long-term care residents with renal insufficiency. Design: A randomized trial within the long-stay units of a large long-term care facility. Randomization was within blocks by unit type. Alerts related to medication prescribing for residents with renal insufficiency were displayed to prescribers in the intervention units and hidden but tracked in control units. Measurement: The proportions of final drug orders that were appropriate were compared between intervention and control units within alert categories: recommended medication doses; recommended administration frequencies; recommendations to avoid the drug; 4) warnings of missing information. Results: The rates of alerts were nearly equal in the intervention and control units: 2.5 per 1000 resident days in the intervention units and 2.4 in the control units. The proportions of dose alerts for which the final drug orders were appropriate were similar between the intervention and control units (relative risk 0.95, 95% confidence interval 0.83, 1.1). For the remaining alert categories significantly higher proportions of final drug orders were appropriate in the intervention units: relative risk 2.4 for maximum frequency (1.4, 4.4); 2.6 for drugs that should be avoided (1.4, 5.0); and 1.8 for alerts to acquire missing information (1.1, 3.4). Overall, final drug orders were appropriate significantly more often than a relative risk 1.2 (1.0, 1.4). By tracking personnel time and expenditures, we estimated the cost of developing the CDSS as $48,668.57. Drug costs saved during the 12 months of the trial are estimated at $2,137. Conclusion: Clinical decision support for physicians prescribing medications for long-term care residents with renal insufficiency can improve the quality of prescribing decisions. However, patient well-being and

Neuronal and non-neuronal GABA transporters as targets for antiepileptic drugs

DEFF Research Database (Denmark)

Madsen, Karsten K; White, H Steve; Schousboe, Arne

2010-01-01

of transmembrane transport and enzymatic degradation. The development of tiagabine selectively inhibiting the GABA transporter GAT1 constitutes a proof of concept that the GABA transporters are interesting drug targets in the context of antiepileptic drugs. The review provides a detailed analysis of the role......,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol) has been shown to possess a novel anticonvulsant profile in animal models of epilepsy, involving the ability to inhibit GABA transport mediated by GAT1 and BGT1 at the same time....

Tri-partite complex for axonal transport drug delivery achieves pharmacological effect

Directory of Open Access Journals (Sweden)

Frederickson Martyn

2010-01-01

Full Text Available Abstract Background Targeted delivery of pharmaceutical agents into selected populations of CNS (Central Nervous System neurons is an extremely compelling goal. Currently, systemic methods are generally used for delivery of pain medications, anti-virals for treatment of dermatomal infections, anti-spasmodics, and neuroprotectants. Systemic side effects or undesirable effects on parts of the CNS that are not involved in the pathology limit efficacy and limit clinical utility for many classes of pharmaceuticals. Axonal transport from the periphery offers a possible selective route, but there has been little progress towards design of agents that can accomplish targeted delivery via this intraneural route. To achieve this goal, we developed a tripartite molecular construction concept involving an axonal transport facilitator molecule, a polymer linker, and a large number of drug molecules conjugated to the linker, then sought to evaluate its neurobiology and pharmacological behavior. Results We developed chemical synthesis methodologies for assembling these tripartite complexes using a variety of axonal transport facilitators including nerve growth factor, wheat germ agglutinin, and synthetic facilitators derived from phage display work. Loading of up to 100 drug molecules per complex was achieved. Conjugation methods were used that allowed the drugs to be released in active form inside the cell body after transport. Intramuscular and intradermal injection proved effective for introducing pharmacologically effective doses into selected populations of CNS neurons. Pharmacological efficacy with gabapentin in a paw withdrawal latency model revealed a ten fold increase in half life and a 300 fold decrease in necessary dose relative to systemic administration for gabapentin when the drug was delivered by axonal transport using the tripartite vehicle. Conclusion Specific targeting of selected subpopulations of CNS neurons for drug delivery by axonal

Mathematical Modeling and Experimental Validation of Nanoemulsion-Based Drug Transport across Cellular Barriers.

Science.gov (United States)

Kadakia, Ekta; Shah, Lipa; Amiji, Mansoor M

2017-07-01

Nanoemulsions have shown potential in delivering drug across epithelial and endothelial cell barriers, which express efflux transporters. However, their transport mechanisms are not entirely understood. Our goal was to investigate the cellular permeability of nanoemulsion-encapsulated drugs and apply mathematical modeling to elucidate transport mechanisms and sensitive nanoemulsion attributes. Transport studies were performed in Caco-2 cells, using fish oil nanoemulsions and a model substrate, rhodamine-123. Permeability data was modeled using a semi-mechanistic approach, capturing the following cellular processes: endocytotic uptake of the nanoemulsion, release of rhodamine-123 from the nanoemulsion, efflux and passive permeability of rhodamine-123 in aqueous solution. Nanoemulsions not only improved the permeability of rhodamine-123, but were also less sensitive to efflux transporters. The model captured bidirectional permeability results and identified sensitive processes, such as the release of the nanoemulsion-encapsulated drug and cellular uptake of the nanoemulsion. Mathematical description of cellular processes, improved our understanding of transport mechanisms, such as nanoemulsions don't inhibit efflux to improve drug permeability. Instead, their endocytotic uptake, results in higher intracellular drug concentrations, thereby increasing the concentration gradient and transcellular permeability across biological barriers. Modeling results indicated optimizing nanoemulsion attributes like the droplet size and intracellular drug release rate, may further improve drug permeability.

High Phenobarbital Clearance During Continuous Renal Replacement Therapy

Science.gov (United States)

Rosenborg, Staffan; Saraste, Lars; Wide, Katarina

2014-01-01

Abstract Phenobarbital is an old antiepileptic drug used in severe epilepsy. Despite this, little is written about the need for dose adjustments in renal replacement therapy. Most sources recommend a moderately increased dose guided by therapeutic drug monitoring. A 14 year old boy with nonketotic hyperglycinemia, a rare inborn error of metabolism, characterized by high levels of glycine, epilepsy, spasticity, and cognitive impairment, was admitted to the emergency department with respiratory failure after a few days of fever and cough. The boy was unconscious at admittance and had acute renal and hepatic failure. Due to the acute respiratory infection, hypoxic hepatic and renal failure occurred and the patient had a status epilepticus. The patient was intubated and mechanically ventilated. Continuous renal replacement therapy was initiated. Despite increased phenobarbital doses, therapeutic levels were not reached until the dose was increased to 500 mg twice daily. Therapeutic drug monitoring was performed in plasma and dialysate. Calculations revealed that phenobarbital was almost freely dialyzed. Correct dosing of drugs in patients on renal replacement therapy may need a multidisciplinary approach and guidance by therapeutic drug monitoring. PMID:25101986

Expression and Regulation of Drug Transporters and Metabolizing Enzymes in the Human Gastrointestinal Tract.

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Drozdzik, M; Oswald, S

2016-01-01

Orally administered drugs must pass through the intestinal wall and then through the liver before reaching systemic circulation. During this process drugs are subjected to different processes that may determine the therapeutic value. The intestinal barrier with active drug metabolizing enzymes and drug transporters in enterocytes plays an important role in the determination of drug bioavailability. Accumulating information demonstrates variable distribution of drug metabolizing enzymes and transporters along the human gastrointestinal tract (GI), that creates specific barrier characteristics in different segments of the GI. In this review, expression of drug metabolizing enzymes and transporters in the healthy and diseased human GI as well as their regulatory aspects: genetic, miRNA, DNA methylation are outlined. The knowledge of unique interplay between drug metabolizing enzymes and transporters in specific segments of the GI tract allows more precise definition of drug release sites within the GI in order to assure more complete bioavailability and prediction of drug interactions.

Impacts of nitric oxide and superoxide on renal medullary oxygen transport and urine concentration

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Edwards, Aurélie; Layton, Anita T.

2015-01-01

The goal of this study was to investigate the reciprocal interactions among oxygen (O2), nitric oxide (NO), and superoxide (O2−) and their effects on medullary oxygenation and urinary output. To accomplish that goal, we developed a detailed mathematical model of solute transport in the renal medulla of the rat kidney. The model represents the radial organization of the renal tubules and vessels, which centers around the vascular bundles in the outer medulla and around clusters of collecting ducts in the inner medulla. Model simulations yield significant radial gradients in interstitial fluid oxygen tension (Po2) and NO and O2− concentration in the OM and upper IM. In the deep inner medulla, interstitial fluid concentrations become much more homogeneous, as the radial organization of tubules and vessels is not distinguishable. The model further predicts that due to the nonlinear interactions among O2, NO, and O2−, the effects of NO and O2− on sodium transport, osmolality, and medullary oxygenation cannot be gleaned by considering each solute's effect in isolation. An additional simulation suggests that a sufficiently large reduction in tubular transport efficiency may be the key contributing factor, more so than oxidative stress alone, to hypertension-induced medullary hypoxia. Moreover, model predictions suggest that urine Po2 could serve as a biomarker for medullary hypoxia and a predictor of the risk for hospital-acquired acute kidney injury. PMID:25651567

An Active Learning Exercise to Facilitate Understanding of Nephron Function: Anatomy and Physiology of Renal Transporters

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Dirks-Naylor, Amie J.

2016-01-01

Renal transport is a central mechanism underlying electrolyte homeostasis, acid base balance and other essential functions of the kidneys in human physiology. Thus, knowledge of the anatomy and physiology of the nephron is essential for the understanding of kidney function in health and disease. However, students find this content difficult to…

Schisandra chinensis regulates drug metabolizing enzymes and drug transporters via activation of Nrf2-mediated signaling pathway

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He JL

2014-12-01

Full Text Available Jin-Lian He,1 Zhi-Wei Zhou,2,3 Juan-Juan Yin,2 Chang-Qiang He,1 Shu-Feng Zhou,2,3 Yang Yu1 1College of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China; 2Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA; 3Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou, People’s Republic of China Abstract: Drug metabolizing enzymes (DMEs and drug transporters are regulated via epigenetic, transcriptional, posttranscriptional, and translational and posttranslational modifications. Phase I and II DMEs and drug transporters play an important role in the disposition and detoxification of a large number of endogenous and exogenous compounds. The nuclear factor (erythroid-derived 2-like 2 (Nrf2 is a critical regulator of a variety of important cytoprotective genes that are involved in disposition and detoxification of xenobiotics. Schisandra chinensis (SC is a commonly used traditional Chinese herbal medicine that has been primarily used to protect the liver because of its potent antioxidative and anti-inflammatory activities. SC can modulate some DMEs and drug transporters, but the underlying mechanisms are unclear. In this study, we aimed to explore the role of Nrf2 in the regulatory effect of SC extract (SCE on selected DMEs and drug transporters in human hepatocellular liver carcinoma cell line (HepG2 cells. The results showed that SCE, schisandrin A, and schisandrin B significantly increased the expression of NAD(PH: Nicotinamide Adenine Dinucleotide Phosphate-oxidase or:quinone oxidoreductase 1, heme oxygenase-1, glutamate–cysteine ligase, and glutathione S-transferase A4 at both transcriptional and posttranscriptional levels. Incubation of HepG2 cells with SCE resulted in a significant

Epigenetic modulation of the biophysical properties of drug-resistant cell lipids to restore drug transport and endocytic functions.

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Vijayaraghavalu, Sivakumar; Peetla, Chiranjeevi; Lu, Shan; Labhasetwar, Vinod

2012-09-04

In our recent studies exploring the biophysical characteristics of resistant cell lipids, and the role they play in drug transport, we demonstrated the difference of drug-resistant breast cancer cells from drug-sensitive cells in lipid composition and biophysical properties, suggesting that cancer cells acquire a drug-resistant phenotype through the alteration of lipid synthesis to inhibit intracellular drug transport to protect from cytotoxic effect. In cancer cells, epigenetic changes (e.g., DNA hypermethylation) are essential to maintain this drug-resistant phenotype. Thus, altered lipid synthesis may be linked to epigenetic mechanisms of drug resistance. We hypothesize that reversing DNA hypermethylation in resistant cells with an epigenetic drug could alter lipid synthesis, changing the cell membrane's biophysical properties to facilitate drug delivery to overcome drug resistance. Herein we show that treating drug-resistant breast cancer cells (MCF-7/ADR) with the epigenetic drug 5-aza-2'-deoxycytidine (decitabine) significantly alters cell lipid composition and biophysical properties, causing the resistant cells to acquire biophysical characteristics similar to those of sensitive cell (MCF-7) lipids. Following decitabine treatment, resistant cells demonstrated increased sphingomyelinase activity, resulting in a decreased sphingomyelin level that influenced lipid domain structures, increased membrane fluidity, and reduced P-glycoprotein expression. Changes in the biophysical characteristics of resistant cell lipids facilitated doxorubicin transport and restored endocytic function for drug delivery with a lipid-encapsulated form of doxorubicin, enhancing the drug efficacy. In conclusion, we have established a new mechanism for efficacy of an epigenetic drug, mediated through changes in lipid composition and biophysical properties, in reversing cancer drug resistance.

Phytotherapeutics: The Emerging Role of Intestinal and Hepatocellular Transporters in Drug Interactions with Botanical Supplements.

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Murtaza, Ghulam; Ullah, Naveed; Mukhtar, Farah; Nawazish, Shamyla; Muneer, Saiqa

2017-10-21

In herbalism, botanical supplements are commonly believed to be safe remedies, however, botanical supplements and dietary ingredients interact with transport and metabolic processes, affecting drug disposition. Although a large number of studies have described that botanical supplements interfere with drug metabolism, the mode of their interaction with drug transport processes is not well described. Such interactions may result in serious undesired effects and changed drug efficacy, therefore, some studies on interaction between botanical supplement ingredients and drug transporters such as P-gp and OATPs are described here, suggesting that the interaction between botanical supplements and the drug transporters is clinically significant.

Transport mechanism of lipid covered saquinavir pure drug nanoparticles in intestinal epithelium

DEFF Research Database (Denmark)

Xia, Dengning; He, Yuan; Li, Qiuxia

2018-01-01

are transported. To improve cellular uptake and transport of pure nanodrug in cells, here, a lipid covered saquinavir (SQV) pure drug NP (Lipo@nanodrug) was designed by modifying a pure SQV NP (nanodrug) with a phospholipid bilayer. We studied their endocytosis, intracellular trafficking mechanism using Caco-2...... their intracellular processing, helping to improve drug transport across intestinal epithelium. To our knowledge, this is the first presentation of the novel phospholipid bilayer covered SQV pure drug NP design, and a mechanistic study on intracellular trafficking in in vitro cell models has been described......Pure drug nanoparticles (NPs) represent a promising formulation for improved drug solubility and controlled dissolution velocity. However, limited absorption by the intestinal epithelium remains challenge to their clinical application, and little is known about how these NPs within the cells...

The Role of Hydrogen Sulfide in Renal System.

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Cao, Xu; Bian, Jin-Song

2016-01-01

Hydrogen sulfide has gained recognition as the third gaseous signaling molecule after nitric oxide and carbon monoxide. This review surveys the emerging role of H 2 S in mammalian renal system, with emphasis on both renal physiology and diseases. H 2 S is produced redundantly by four pathways in kidney, indicating the abundance of this gaseous molecule in the organ. In physiological conditions, H 2 S was found to regulate the excretory function of the kidney possibly by the inhibitory effect on sodium transporters on renal tubular cells. Likewise, it also influences the release of renin from juxtaglomerular cells and thereby modulates blood pressure. A possible role of H 2 S as an oxygen sensor has also been discussed, especially at renal medulla. Alternation of H 2 S level has been implicated in various pathological conditions such as renal ischemia/reperfusion, obstructive nephropathy, diabetic nephropathy, and hypertensive nephropathy. Moreover, H 2 S donors exhibit broad beneficial effects in renal diseases although a few conflicts need to be resolved. Further research reveals that multiple mechanisms are underlying the protective effects of H 2 S, including anti-inflammation, anti-oxidation, and anti-apoptosis. In the review, several research directions are also proposed including the role of mitochondrial H 2 S in renal diseases, H 2 S delivery to kidney by targeting D-amino acid oxidase/3-mercaptopyruvate sulfurtransferase (DAO/3-MST) pathway, effect of drug-like H 2 S donors in kidney diseases and understanding the molecular mechanism of H 2 S. The completion of the studies in these directions will not only improves our understanding of renal H 2 S functions but may also be critical to translate H 2 S to be a new therapy for renal diseases.

Cell kinetics of differentiation of Na+-dependent hexose transport in a cultured renal epithelial cell line

International Nuclear Information System (INIS)

Cook, J.S.; Weiss, E.R.

1985-01-01

Fully differentiated cells of the renal proximal tubule have the capability of taking up hexoses across their apical borders by transport coupled to the Na + -electrochemical gradient. This property is also found in postconfluent cultures of the cloned cell line LLC-PK 1 , a morphologically polarized line of renal cells. Postconfluent cells develop the Na + -dependent capacity to transport hexoses at their apical surface. This function is not observable during the growth phase of the cultures. To analyze the developmental process at the cellular level a method has been derived to separate transporting cells, expressing the differentiated function, from nontransporting cells. The method is based on the swelling of the cells accompanying the uptake of the nonmetabolizable glucose analog alpha methylglucoside. The swollen cells have a lower buoyant density than the undifferentiated cells and may be separated from them on density gradients. Analysis of the distribution of cells on such gradients shows that after the cells reach confluence the undifferentiated subpopulation is recruited onto the differentiation pathway with a rate constant of 0.2 per day, that 5 to 7 days are required for a cell to traverse this pathway to the fully differentiated state, and that once the maximum uptake capacity is achieved the cells do not develop further

Pharmacogenetic screening for polymorphisms in drug-metabolizing enzymes and drug transporters in a Dutch population.

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Bosch, T M; Doodeman, V D; Smits, P H M; Meijerman, I; Schellens, J H M; Beijnen, J H

2006-01-01

A possible explanation for the wide interindividual variability in toxicity and efficacy of drug therapy is variation in genes encoding drug-metabolizing enzymes and drug transporters. The allelic frequency of these genetic variants, linkage disequilibrium (LD), and haplotype of these polymorphisms are important parameters in determining the genetic differences between patients. The aim of this study was to explore the frequencies of polymorphisms in drug-metabolizing enzymes (CYP1A1, CYP2C9, CYP2C19, CYP3A4, CYP2D6, CYP3A5, DPYD, UGT1A1, GSTM1, GSTP1, GSTT1) and drug transporters (ABCB1[MDR1] and ABCC2[MRP2]), and to investigate the LD and perform haplotype analysis of these polymorphisms in a Dutch population. Blood samples were obtained from 100 healthy volunteers and genomic DNA was isolated and amplified by PCR. The amplification products were sequenced and analyzed for the presence of polymorphisms by sequence alignment. In the study population, we identified 13 new single nucleotide polymorphisms (SNPs) in Caucasians and three new SNPs in non-Caucasians, in addition to previously recognized SNPs. Three of the new SNPs were found within exons, of which two resulted in amino acid changes (A428T in CYP2C9 resulting in the amino acid substitution D143V; and C4461T in ABCC2 in a non-Caucasian producing the amino acid change T1476M). Several LDs and haplotypes were found in the Caucasian individuals. In this Dutch population, the frequencies of 16 new SNPs and those of previously recognized SNPs were determined in genes coding for drug-metabolizing enzymes and drug transporters. Several LDs and haplotypes were also inferred. These data are important for further research to help explain the interindividual pharmacokinetic and pharmacodynamic variability in response to drug therapy.

Clinical impact of genetic variants of drug transporters in different ethnic groups within and across regions.

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Ono, Chiho; Kikkawa, Hironori; Suzuki, Akiyuki; Suzuki, Misaki; Yamamoto, Yuichi; Ichikawa, Katsuomi; Fukae, Masato; Ieiri, Ichiro

2013-11-01

Drug transporters, together with drug metabolic enzymes, are major determinants of drug disposition and are known to alter the response to many commonly used drugs. Substantial frequency differences for known variants exist across geographic regions for certain drug transporters. To deliver efficacious medicine with the right dose for each patient, it is important to understand the contribution of genetic variants for drug transporters. Recently, mutual pharmacokinetic data usage among Asian regions, which are thought to be relatively similar in their own genetic background, is expected to accelerate new drug applications and reduce developmental costs. Polymorphisms of drug transporters could be key factors to be considered in implementing multiethnic global clinical trials. This review addresses the current knowledge on genetic variations of major drug transporters affecting drug disposition, efficacy and toxicity, focusing on the east Asian populations, and provides insights into future directions for precision medicine and drug development in east Asia.

Renal hemodynamic response to L-dopa during acute renal failure in man

Energy Technology Data Exchange (ETDEWEB)

Zech, P; Collard, M; Guey, A; Plantier, J; Bernard, M; Berthoux, F; Pinet, A; Traeger, J [Hopital Edouard-Herriot, 69 - Lyon (France)

1975-12-20

Twelve patients with acute renal failure underwent L-dopa infusion into a renal artery and /sup 133/Xenon wash-out recordings before and during the infusion. Urine volume and sodium output were also compared during two 24 hours periods, before and after the procedure. Hemodynamic data were compared with data obtained from a matched group of patients receiving Furosemide (8 patients) in place of L-dopa. Only L-dopa infusion significantly increased outer cortical distribution. No blood flow change could be demonstrated in any component nor did the drug improve unitary excretion or the general course of the disease. Control data shows that reduced cortical distribution is the most consistent feature of acute renal failure, so that L-dopa does partially improve intrarenal hemodynamics in this condition. The failure of the drug to restore kidney function may be explained by the following reasons: inability of the agent to restore a normal wash-out pattern: involvment of non-hemodynamic factors, as suggested by comparing similar wash-out improvements after L-dopa in acute glomerulonephritis and in reversible acute renal failure.

Renal hemodynamic response to L-dopa during acute renal failure in man

International Nuclear Information System (INIS)

Zech, P.; Collard, M.; Guey, A.; Plantier, J.; Bernard, M.; Berthoux, F.; Pinet, A.; Traeger, J.

1975-01-01

Twelve patients with acute renal failure underwent L.dopa infusion into a renal artery and 133 Xenon wash-out recordings before and during the infusion. Urine volume and sodium output were also compared during two 24 hours periods, before and after the procedure. Hemodynamic data were compared with data obtained from a matched group of patients receiving Furosemide (8 patients) in place of L.dopa. Only L.dopa infusion significantly increased outer cortical distribution. No blood flow change could be demonstrated in any component nor did the drug improve unitary excretion or the general course of the disease. Control data shows that reduced cortical distribution is the most consistent feature of acute renal failure, so that L.dopa does partially improve intrarenal hemodynamics in this condition. The failure of the drug to restore kidney function may be explained by the following reasons: inability of the agent to restore a normal wash-out pattern: involvment of non-hemodynamic factors, as suggested by comparing similar wash-out improvements after L.dopa in acute glomerulonephritis and in reversible acute renal failure [fr

75 FR 38422 - Procedures for Transportation Workplace Drug and Alcohol Testing Programs

Science.gov (United States)

2010-07-02

... 2105-AD84 Procedures for Transportation Workplace Drug and Alcohol Testing Programs AGENCY: Office of..., 2011. DATES: This rule is effective July 2, 2010. FOR FURTHER INFORMATION CONTACT: For program issues... Federal Regulations, as follows: PART 40--PROCEDURES FOR TRANSPORTATION WORKPLACE DRUG AND ALCOHOL TESTING...

Analysis of adverse events of renal impairment related to platinum-based compounds using the Japanese Adverse Drug Event Report database.

Science.gov (United States)

Naganuma, Misa; Motooka, Yumi; Sasaoka, Sayaka; Hatahira, Haruna; Hasegawa, Shiori; Fukuda, Akiho; Nakao, Satoshi; Shimada, Kazuyo; Hirade, Koseki; Mori, Takayuki; Yoshimura, Tomoaki; Kato, Takeshi; Nakamura, Mitsuhiro

2018-01-01

Platinum compounds cause several adverse events, such as nephrotoxicity, gastrointestinal toxicity, myelosuppression, ototoxicity, and neurotoxicity. We evaluated the incidence of renal impairment as adverse events are related to the administration of platinum compounds using the Japanese Adverse Drug Event Report database. We analyzed adverse events associated with the use of platinum compounds reported from April 2004 to November 2016. The reporting odds ratio at 95% confidence interval was used to detect the signal for each renal impairment incidence. We evaluated the time-to-onset profile of renal impairment and assessed the hazard type using Weibull shape parameter and used the applied association rule mining technique to discover undetected relationships such as possible risk factor. In total, 430,587 reports in the Japanese Adverse Drug Event Report database were analyzed. The reporting odds ratios (95% confidence interval) for renal impairment resulting from the use of cisplatin, oxaliplatin, carboplatin, and nedaplatin were 2.7 (2.5-3.0), 0.6 (0.5-0.7), 0.8 (0.7-1.0), and 1.3 (0.8-2.1), respectively. The lower limit of the reporting odds ratio (95% confidence interval) for cisplatin was >1. The median (lower-upper quartile) onset time of renal impairment following the use of platinum-based compounds was 6.0-8.0 days. The Weibull shape parameter β and 95% confidence interval upper limit of oxaliplatin were impairment during cisplatin use in real-world setting. The present findings demonstrate that the incidence of renal impairment following cisplatin use should be closely monitored when patients are hypertensive or diabetic, or when they are co-administered furosemide, loxoprofen, or pemetrexed. In addition, healthcare professionals should closely assess a patient's background prior to treatment.

Polymorphisms in CTLA4 influence incidence of drug-induced liver injury after renal transplantation in Chinese recipients.

Directory of Open Access Journals (Sweden)

Yifeng Guo

Full Text Available Genetic polymorphisms in cytotoxic T lymphocyte-associated antigen 4 (CTLA4 play an influential role in graft rejection and the long-term clinical outcome of organ transplantation. We investigated the association of 5 CTLA4 single-nucleotide polymorphisms (SNPs (rs733618 C/T, rs4553808 A/G, rs5742909 C/T, rs231775 A/G, and rs3087243 G/A with drug-induced liver injury (DILI in Chinese renal transplantation (RT recipients. Each recipient underwent a 24-month follow-up observation for drug-induced liver damage. The CTLA4 SNPs were genotyped in 864 renal transplantation recipients. A significant association was found between the rs231775 genotype and an early onset of DILI in the recipients. Multivariate analyses revealed that a risk factor, recipient rs231775 genotype (p = 0.040, was associated with DILI. Five haplotypes were estimated for 4 SNPs (excluding rs733618; the frequency of haplotype ACGG was significantly higher in the DILI group (68.9% than in the non-DILI group (61.1% (p = 0.041. In conclusion, CTLA4 haplotype ACGG was partially associated with the development of DILI in Chinese kidney transplant recipients. The rs231775 GG genotype may be a risk factor for immunosuppressive drug-induced liver damage.

Expression of Trans- and Paracellular Calcium and Magnesium Transport Proteins in Renal and Intestinal Epithelia During Lactation

DEFF Research Database (Denmark)

Beggs, Megan R; Appel, Ida; Svenningsen, Per

2017-01-01

Significant alterations in maternal calcium (Ca2+) and magnesium (Mg2+) balance occur during lactation. Ca2+ is the primary divalent cation mobilized into breast milk by demineralization of the skeleton and alterations in intestinal and renal Ca2+ transport. Mg2+ is also concentrated in breast milk...

Glucose Transporters at the Blood-Brain Barrier: Function, Regulation and Gateways for Drug Delivery.

Science.gov (United States)

Patching, Simon G

2017-03-01

Glucose transporters (GLUTs) at the blood-brain barrier maintain the continuous high glucose and energy demands of the brain. They also act as therapeutic targets and provide routes of entry for drug delivery to the brain and central nervous system for treatment of neurological and neurovascular conditions and brain tumours. This article first describes the distribution, function and regulation of glucose transporters at the blood-brain barrier, the major ones being the sodium-independent facilitative transporters GLUT1 and GLUT3. Other GLUTs and sodium-dependent transporters (SGLTs) have also been identified at lower levels and under various physiological conditions. It then considers the effects on glucose transporter expression and distribution of hypoglycemia and hyperglycemia associated with diabetes and oxygen/glucose deprivation associated with cerebral ischemia. A reduction in glucose transporters at the blood-brain barrier that occurs before the onset of the main pathophysiological changes and symptoms of Alzheimer's disease is a potential causative effect in the vascular hypothesis of the disease. Mutations in glucose transporters, notably those identified in GLUT1 deficiency syndrome, and some recreational drug compounds also alter the expression and/or activity of glucose transporters at the blood-brain barrier. Approaches for drug delivery across the blood-brain barrier include the pro-drug strategy whereby drug molecules are conjugated to glucose transporter substrates or encapsulated in nano-enabled delivery systems (e.g. liposomes, micelles, nanoparticles) that are functionalised to target glucose transporters. Finally, the continuous development of blood-brain barrier in vitro models is important for studying glucose transporter function, effects of disease conditions and interactions with drugs and xenobiotics.

Next generation renal denervation: chemical “perivascular” renal denervation with alcohol using a novel drug infusion catheter

Energy Technology Data Exchange (ETDEWEB)

Fischell, Tim A. [Borgess Heart Institute, 1521 Gull Road, Kalamazoo, MI, 49008 (United States); Ablative Solutions, 801 Hermosa Way, Menlo Park, CA, 94025 (United States); Fischell, David R.; Ghazarossian, Vartan E. [Ablative Solutions, 801 Hermosa Way, Menlo Park, CA, 94025 (United States); Vega, Félix [Preclinical Consultation, San Francisco, CA (United States); Ebner, Adrian [Clinics, Ascension (Paraguay)

2015-06-15

Background/Purpose: We update the pre-clinical and early clinical results using a novel endovascular approach, to perform chemical renal denervation, via peri-adventitial injection of micro-doses of dehydrated alcohol (ethanol–EtOH). Methods/Materials: A novel, three-needle delivery device (Peregrine™) was used to denervate the renal arteries of adult swine (n = 17) and in a first-in-man feasibility study (n = 18). In the pre-clinical testing EtOH was infused bilaterally with one infusion per renal artery into to the perivascular space, using EtOH doses of 0.3 ml/artery (n = 8), and 0.6 ml/artery (n = 9), and with saline sham control (0.4 ml/artery n = 3). Renal parenchymal norepinephrine (NE) concentration (performed blindly), and safety were the primary endpoints. Data from the first-in-man study (n = 18) to evaluate device performance, safety and peri-procedural pain are reported. Results: In the pre-clinical testing renal function was unchanged at 3-month follow-up. Angiography at 90 days (n = 34 arteries) demonstrated normal appearing renal arteries, unchanged from baseline, and without stenosis or other abnormalities. The reductions in mean renal parenchymal NE reductions at 3 months were 68% and 88% at doses of 0.3 and 0.6 ml, respectively (p < 0.001 vs. controls). In the first-in-man study, there was 100% device success, no complications, a mean treatment time of 4.3 ± 3 minutes/artery, and minimal or no patient discomfort during treatment. Angiography at 6-months showed no evidence of renal artery stenosis, and evidence of a reduction of blood pressure from baseline. Conclusion: Perivascular RDN using micro-doses of alcohol is a promising alternative to energy-based systems to achieve dose-dependent, predictable, safe and essentially painless renal denervation. Further clinical evaluation is warranted. Summary: (For annotated table of contents) This paper describes the preclinical results, in a porcine model, and the early first-in-man results, using

Sodium glucose co-transporter 2 (SGLT2) inhibitors: new among antidiabetic drugs.

Science.gov (United States)

Opie, L H

2014-08-01

Type 2 diabetes is characterized by decreased insulin secretion and sensitivity. The available oral anti-diabetic drugs act on many different molecular sites. The most used of oral anti-diabetic agents is metformin that activates glucose transport vesicles to the cell surface. Others are: the sulphonylureas; agents acting on the incretin system; GLP-1 agonists; dipetidylpeptidase-4 inhibitors; meglinitide analogues; and the thiazolidinediones. Despite these many drugs acting by different mechanisms, glycaemic control often remains elusive. None of these drugs have a primary renal mechanism of action on the kidneys, where almost all glucose excreted is normally reabsorbed. That is where the inhibitors of glucose reuptake (sodium-glucose cotransporter 2, SGLT2) have a unique site of action. Promotion of urinary loss of glucose by SGLT2 inhibitors embodies a new principle of control in type 2 diabetes that has several advantages with some urogenital side-effects, both of which are evaluated in this review. Specific approvals include use as monotherapy, when diet and exercise alone do not provide adequate glycaemic control in patients for whom the use of metformin is considered inappropriate due to intolerance or contraindications, or as add-on therapy with other anti-hyperglycaemic medicinal products including insulin, when these together with diet and exercise, do not provide adequate glycemic control. The basic mechanisms are improved β-cell function and insulin sensitivity. When compared with sulphonylureas or other oral antidiabetic agents, SGLT2 inhibitors provide greater HbA1c reduction. Urogenital side-effects related to the enhanced glycosuria can be troublesome, yet seldom lead to discontinuation. On this background, studies are analysed that compare SGLT2 inhibitors with other oral antidiabetic agents. Their unique mode of action, unloading the excess glycaemic load, contrasts with other oral agents that all act to counter the effects of diabetic

Studies on diagnosis and treatment of renal artery stenosis

NARCIS (Netherlands)

P. Krijnen (Pieta)

2004-01-01

textabstractThis thesis describes studies on ~onosis and treatment of renal artery stenosis in patients with drug-resistant hypertension. In Chapter 1, the clinical problem of renal artery stenosis is discussed. Renal artery stenosis, a narrowing of the renal artery, is a potential cause of

Designing Novel Nanoformulations Targeting Glutamate Transporter Excitatory Amino Acid Transporter 2: Implications in Treating Drug Addiction.

Science.gov (United States)

Rao, Pss; Yallapu, Murali M; Sari, Youssef; Fisher, Paul B; Kumar, Santosh

Chronic drug abuse is associated with elevated extracellular glutamate concentration in the brain reward regions. Deficit of glutamate clearance has been identified as a contributing factor that leads to enhanced glutamate concentration following extended drug abuse. Importantly, normalization of glutamate level through induction of glutamate transporter 1 (GLT1)/ excitatory amino acid transporter 2 (EAAT2) expression has been described in several in vivo studies. GLT1 upregulators including ceftriaxone, a beta-lactam antibiotic, have been effective in attenuating drug-seeking and drug-consumption behavior in rodent models. However, potential obstacles toward clinical translation of GLT1 (EAAT2) upregulators as treatment for drug addiction might include poor gastrointestinal absorption, serious peripheral adverse effects, and/or suboptimal CNS concentrations. Given the growing success of nanotechnology in targeting CNS ailments, nanoformulating known GLT1 (EAAT2) upregulators for selective uptake across the blood brain barrier presents an ideal therapeutic approach for treating drug addiction. In this review, we summarize the results obtained with promising GLT1 (EAAT2) inducing compounds in animal models recapitulating drug addiction. Additionally, the various nanoformulations that can be employed for selectively increasing the CNS bioavailability of GLT1 (EAAT2) upregulators are discussed. Finally, the applicability of GLT1 (EAAT2) induction via central delivery of drug-loaded nanoformulations is described.

Impact of Drug Therapy, Radiation Dose, and Dose Rate on Renal Toxicity Following Bone Marrow Transplantation

International Nuclear Information System (INIS)

Cheng, Jonathan C.; Schultheiss, Timothy E.; Wong, Jeffrey Y.C.

2008-01-01

Purpose: To demonstrate a radiation dose response and to determine the dosimetric and chemotherapeutic factors that influence the incidence of late renal toxicity following total body irradiation (TBI). Methods and Materials: A comprehensive retrospective review was performed of articles reporting late renal toxicity, along with renal dose, fractionation, dose rate, chemotherapy regimens, and potential nephrotoxic agents. In the final analysis, 12 articles (n = 1,108 patients), consisting of 24 distinct TBI/chemotherapy conditioning regimens were included. Regimens were divided into three subgroups: adults (age ≥18 years), children (age <18 years), and mixed population (both adults and children). Multivariate logistic regression was performed to identify dosimetric and chemotherapeutic factors significantly associated with late renal complications. Results: Individual analysis was performed on each population subgroup. For the purely adult population, the only significant variable was total dose. For the mixed population, the significant variables included total dose, dose rate, and the use of fludarabine. For the pediatric population, only the use of cyclosporin or teniposide was significant; no dose response was noted. A logistic model was generated with the exclusion of the pediatric population because of its lack of dose response. This model yielded the following significant variables: total dose, dose rate, and number of fractions. Conclusion: A dose response for renal damage after TBI was identified. Fractionation and low dose rates are factors to consider when delivering TBI to patients undergoing bone marrow transplantation. Drug therapy also has a major impact on kidney function and can modify the dose-response function

Antineoplastic treatment of patients with renal insufficiency

International Nuclear Information System (INIS)

Rajec, J.; Mego, M.; Rajec, J.

2011-01-01

Kidneys are the main route of elimination for many antineoplastic drugs and their metabolites. The kidney dysfunction may lead to the drug cumulation in organism with the resulting increased systemic toxicity. A lot of used cytostatics requires a dose modification at different levels of renal insufficiency. Due to the lack of data from clinical trials, the limiting of systemic toxicity is difficult especially in patients with severe renal impairment or patients undergoing chronic hemodialysis. The following article is focused on the preventive strategies dealing with recommended dosing modification of various antineoplastic agents in patients with renal insufficiency. (author)

RENAL DENERVATION IN RESISTANT ARTERIAL HYPERTENSION

OpenAIRE

V. A. Sulimov; A. V. Rodionov; A. A. Svetankova; I. E. Deneka

2015-01-01

A new method of non-drug treatment of resistant hypertension – renal denervation is considered. General information about resistant hypertension, method of renal denervation, the results of clinical studies on efficacy and safety, as well as own clinical case are presented.

Altered regulation of renal sodium transporters in salt-sensitive hypertensive rats induced by uninephrectomy.

Science.gov (United States)

Jung, Ji Yong; Lee, Jay Wook; Kim, Sejoong; Jung, Eun Sook; Jang, Hye Ryoun; Han, Jin Suk; Joo, Kwon Wook

2009-12-01

Uninephrectomy (uNx) in young rats causes salt-sensitive hypertension (SSH). Alterations of sodium handling in residual nephrons may play a role in the pathogenesis. Therefore, we evaluated the adaptive alterations of renal sodium transporters according to salt intake in uNx-SSH rats. uNx or sham operations were performed in male Sprague-Dawley rats, and normal-salt diet was fed for 4 weeks. Four experimental groups were used: sham-operated rats raised on a high-salt diet for 2 weeks (CHH) or on a low-salt diet for 1 week after 1 week's high-salt diet (CHL) and uNx rats fed on the same diet (NHH, NHL) as the sham-operated rats were fed. Expression of major renal sodium transporters were determined by semiquantitative immunoblotting. Systolic blood pressure was increased in NHH and NHL groups, compared with CHH and CHL, respectively. Protein abundances of Na(+)/K(+)/2Cl(-) cotransporter (NKCC2) and Na(+)/Cl(-) cotransporter (NCC) in the CHH group were lower than the CHL group. Expression of epithelial sodium channel (ENaC)-γ increased in the CHH group. In contrast, expressions of NKCC2 and NCC in the NHH group didn't show any significant alterations, compared to the NHL group. Expressions of ENaC-α and ENaC-β in the NHH group were higher than the CHH group. Adaptive alterations of NKCC2 and NCC to changes of salt intake were different in the uNx group, and changes in ENaC-α and ENaC-β were also different. These altered regulations of sodium transporters may be involved in the pathogenesis of SSH in the uNx rat model.

Drug transport mechanism of the AcrB efflux pump.

Science.gov (United States)

Pos, Klaas M

2009-05-01

In Gram-negative bacteria such as Escherichia coli and Pseudomonas aeruginosa, tripartite multidrug efflux systems extrude cytotoxic substances from the cell directly into the medium bypassing periplasm and the outer membrane. In E. coli, the tripartite efflux system AcrA/AcrB/TolC is the pump that extrudes multiple antibiotics, dyes, bile salts and detergents. The inner membrane component AcrB, a member of the Resistance Nodulation cell Division (RND) family, is the major site for substrate recognition and energy transduction of the entire tripartite system. The drug/proton antiport processes in this secondary transporter are suggested to be spatially separated, a feature frequently observed for primary transporters like membrane-bound ATPases. The recently elucidated asymmetric structure of the AcrB trimer reveals three different monomer conformations proposed to represent consecutive states in a directional transport cycle. Each monomer shows a distinct tunnel system with entrances located at the boundary of the outer leaflet of the inner membrane and the periplasm through the periplasmic porter (pore) domain towards the funnel of the trimer and TolC. In one monomer a hydrophobic pocket is present which has been shown to bind the AcrB substrates minocyclin and doxorubicin. The energy conversion from the proton motive force into drug efflux includes proton binding in (and release from) the transmembrane part. The conformational changes observed within a triad of essential, titratable residues (D407/D408/K940) residing in the hydrophobic transmembrane domain appear to be transduced by transmembrane helix 8 and associated with the conformational changes seen in the periplasmic domain. From the asymmetric structure a possible peristaltic pump transport mechanism based on a functional rotation of the AcrB trimer has been postulated. The novel drug transport model combines the alternate access pump mechanism with the rotating site catalysis of F(1)F(o) ATPase as

Identification of genomic biomarkers for concurrent diagnosis of drug-induced renal tubular injury using a large-scale toxicogenomics database

International Nuclear Information System (INIS)

Kondo, Chiaki; Minowa, Yohsuke; Uehara, Takeki; Okuno, Yasushi; Nakatsu, Noriyuki; Ono, Atsushi; Maruyama, Toshiyuki; Kato, Ikuo; Yamate, Jyoji; Yamada, Hiroshi; Ohno, Yasuo; Urushidani, Tetsuro

2009-01-01

Drug-induced renal tubular injury is one of the major concerns in preclinical safety evaluations. Toxicogenomics is becoming a generally accepted approach for identifying chemicals with potential safety problems. In the present study, we analyzed 33 nephrotoxicants and 8 non-nephrotoxic hepatotoxicants to elucidate time- and dose-dependent global gene expression changes associated with proximal tubular toxicity. The compounds were administered orally or intravenously once daily to male Sprague-Dawley rats. The animals were exposed to four different doses of the compounds, and kidney tissues were collected on days 4, 8, 15, and 29. Gene expression profiles were generated from kidney RNA by using Affymetrix GeneChips and analyzed in conjunction with the histopathological changes. We used the filter-type gene selection algorithm based on t-statistics conjugated with the SVM classifier, and achieved a sensitivity of 90% with a selectivity of 90%. Then, 92 genes were extracted as the genomic biomarker candidates that were used to construct the classifier. The gene list contains well-known biomarkers, such as Kidney injury molecule 1, Ceruloplasmin, Clusterin, Tissue inhibitor of metallopeptidase 1, and also novel biomarker candidates. Most of the genes involved in tissue remodeling, the immune/inflammatory response, cell adhesion/proliferation/migration, and metabolism were predominantly up-regulated. Down-regulated genes participated in cell adhesion/proliferation/migration, membrane transport, and signal transduction. Our classifier has better prediction accuracy than any of the well-known biomarkers. Therefore, the toxicogenomics approach would be useful for concurrent diagnosis of renal tubular injury.

Role of the Intestinal Bile Acid Transporters in Bile Acid and Drug Disposition

Science.gov (United States)

Dawson, Paul A.

2011-01-01

Membrane transporters expressed by the hepatocyte and enterocyte play critical roles in maintaining the enterohepatic circulation of bile acids, an effective recycling and conservation mechanism that largely restricts these potentially cytotoxic detergents to the intestinal and hepatobiliary compartments. In doing so, the hepatic and enterocyte transport systems ensure a continuous supply of bile acids to be used repeatedly during the digestion of multiple meals throughout the day. Absorption of bile acids from the intestinal lumen and export into the portal circulation is mediated by a series of transporters expressed on the enterocyte apical and basolateral membranes. The ileal apical sodium-dependent bile acid cotransporter (abbreviated ASBT; gene symbol, SLC10A2) is responsible for the initial uptake of bile acids across the enterocyte brush border membrane. The bile acids are then efficiently shuttled across the cell and exported across the basolateral membrane by the heteromeric Organic Solute Transporter, OSTα-OSTβ. This chapter briefly reviews the tissue expression, physiology, genetics, pathophysiology, and transport properties of the ASBT and OSTα-OSTα. In addition, the chapter discusses the relationship between the intestinal bile acid transporters and drug metabolism, including development of ASBT inhibitors as novel hypocholesterolemic or hepatoprotective agents, prodrug targeting of the ASBT to increase oral bioavailability, and involvement of the intestinal bile acid transporters in drug absorption and drug-drug interactions. PMID:21103970

Combined approach with therapeutic drug monitoring and pharmacogenomics in renal transplant recipients

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S Manvizhi

2013-01-01

Full Text Available In patients undergoing renal transplantation, dose individualization for tacrolimus is routinely achieved with therapeutic drug monitoring (TDM. The patient started on 5.5 mg/day of tacrolimus had a significantly elevated tacrolimus trough concentration. The tacrolimus dose was regularly reduced following TDM at many time periods in the post transplant period but the tacrolimus concentration was consistently elevated. Genomic analysis done after four years revealed mutations in the genes encoding for CYP3A5 and MDR1 (2677G > T. Pharmacogenomics alongside TDM, will soon emerge as the backbone of dose individualization. But for genomics to be beneficial, it should be advocated in the pre-transplant or early post transplant period.

Drug transporters in breast cancer

DEFF Research Database (Denmark)

Kümler, Iben; Stenvang, Jan; Moreira, José

2015-01-01

Despite the advances that have taken place in the past decade, including the development of novel molecular targeted agents, cytotoxic chemotherapy remains the mainstay of cancer treatment. In breast cancer, anthracyclines and taxanes are the two main chemotherapeutic options used on a routine...... basis. Although effective, their usefulness is limited by the inevitable development of resistance, a lack of response to drug-induced cancer cell death. A large body of research has resulted in the characterization of a plethora of mechanisms involved in resistance; ATP-binding cassette transporter...

RENAL DENERVATION IN RESISTANT ARTERIAL HYPERTENSION

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V. A. Sulimov

2013-01-01

Full Text Available A new method of non-drug treatment of resistant hypertension – renal denervation is considered. General information about resistant hypertension, method of renal denervation, the results of clinical studies on efficacy and safety, as well as own clinical case are presented.

RENAL DENERVATION IN RESISTANT ARTERIAL HYPERTENSION

Directory of Open Access Journals (Sweden)

V. A. Sulimov

2015-09-01

Full Text Available A new method of non-drug treatment of resistant hypertension – renal denervation is considered. General information about resistant hypertension, method of renal denervation, the results of clinical studies on efficacy and safety, as well as own clinical case are presented.

Drug Holiday in Metastatic Renal-Cell Carcinoma Patients Treated With Vascular Endothelial Growth Factor Receptor Inhibitors.

Science.gov (United States)

Mittal, Kriti; Derosa, Lisa; Albiges, Laurence; Wood, Laura; Elson, Paul; Gilligan, Timothy; Garcia, Jorge; Dreicer, Robert; Escudier, Bernard; Rini, Brian

2018-01-04

Tyrosine kinase inhibitor (TKI) therapy in metastatic renal-cell carcinoma (mRCC) is noncurative and may be associated with significant toxicities. Some patients may receive treatment breaks as a result of TKI-related adverse effects or planned drug holidays. In this retrospective study, mRCC patients who underwent drug holidays during TKI therapy at 2 different institutions were analyzed. A drug holiday was defined as a period of drug cessation for ≥ 3 months for reasons other than progressive disease. Of the 112 patients, the median duration of the first drug holiday for the overall cohort was 16.8 months (95% confidence interval, 12.5-26.4), and 40 patients (36%) remain on the first drug holiday. Overall, patients received a median of 2 lines of treatment. Complete response before the initial drug holiday (n = 14) was associated with a longer surveillance period (P = .0004). The observed median survival of this cohort was 71.7 months (range, 1.3 to 93+ months). Some selected mRCC patients with a favorable response to TKIs may be eligible for drug holidays. The cohort evaluated in this retrospective study represents a highly selected group of patients with indolent disease biology. Copyright © 2018 Elsevier Inc. All rights reserved.

Perioperative acute renal failure.

LENUS (Irish Health Repository)

Mahon, Padraig

2012-02-03

PURPOSE OF REVIEW: Recent biochemical evidence increasingly implicates inflammatory mechanisms as precipitants of acute renal failure. In this review, we detail some of these pathways together with potential new therapeutic targets. RECENT FINDINGS: Neutrophil gelatinase-associated lipocalin appears to be a sensitive, specific and reliable biomarker of renal injury, which may be predictive of renal outcome in the perioperative setting. For estimation of glomerular filtration rate, cystatin C is superior to creatinine. No drug is definitively effective at preventing postoperative renal failure. Clinical trials of fenoldopam and atrial natriuretic peptide are, at best, equivocal. As with pharmacological preconditioning of the heart, volatile anaesthetic agents appear to offer a protective effect to the subsequently ischaemic kidney. SUMMARY: Although a greatly improved understanding of the pathophysiology of acute renal failure has offered even more therapeutic targets, the maintenance of intravascular euvolaemia and perfusion pressure is most effective at preventing new postoperative acute renal failure. In the future, strategies targeting renal regeneration after injury will use bone marrow-derived stem cells and growth factors such as insulin-like growth factor-1.

Blood-brain barrier in vitro models as tools in drug discovery: assessment of the transport ranking of antihistaminic drugs.

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Neuhaus, W; Mandikova, J; Pawlowitsch, R; Linz, B; Bennani-Baiti, B; Lauer, R; Lachmann, B; Noe, C R

2012-05-01

In the course of our validation program testing blood-brain barrier (BBB) in vitro models for their usability as tools in drug discovery it was evaluated whether an established Transwell model based on porcine cell line PBMEC/C1-2 was able to differentiate between the transport properties of first and second generation antihistaminic drugs. First generation antihistamines can permeate the BBB and act in the central nervous system (CNS), whereas entry to the CNS of second generation antihistamines is restricted by efflux pumps such as P-glycoprotein (P-gP) located in brain endothelial cells. P-gP functionality of PBMEC/C1-2 cells grown on Transwell filter inserts was proven by transport studies with P-gP substrate rhodamine 123 and P-gP blocker verapamil. Subsequent drug transport studies with the first generation antihistamines promethazine, diphenhydramine and pheniramine and the second generation antihistamines astemizole, ceterizine, fexofenadine and loratadine were accomplished in single substance as well as in group studies. Results were normalised to diazepam, an internal standard for the transcellular transport route. Moreover, effects after addition of P-gP inhibitor verapamil were investigated. First generation antihistamine pheniramine permeated as fastest followed by diphenhydramine, diazepam, promethazine and second generation antihistaminic drugs ceterizine, fexofenadine, astemizole and loratadine reflecting the BBB in vivo permeability ranking well. Verapamil increased the transport rates of all second generation antihistamines, which suggested involvement of P-gP during their permeation across the BBB model. The ranking after addition of verapamil was significantly changed, only fexofenadine and ceterizine penetrated slower than internal standard diazepam in the presence of verapamil. In summary, permeability data showed that the BBB model based on porcine cell line PBMEC/C1-2 was able to reflect the BBB in vivo situation for the transport of

Cationic uremic toxins affect human renal proximal tubule cell functioning through interaction with the organic cation transporter.

Science.gov (United States)

Schophuizen, Carolien M S; Wilmer, Martijn J; Jansen, Jitske; Gustavsson, Lena; Hilgendorf, Constanze; Hoenderop, Joost G J; van den Heuvel, Lambert P; Masereeuw, Rosalinde

2013-12-01

Several organic cations, such as guanidino compounds and polyamines, have been found to accumulate in plasma of patients with kidney failure due to inadequate renal clearance. Here, we studied the interaction of cationic uremic toxins with renal organic cation transport in a conditionally immortalized human proximal tubule epithelial cell line (ciPTEC). Transporter activity was measured and validated in cell suspensions by studying uptake of the fluorescent substrate 4-(4-(dimethylamino)styryl)-N-methylpyridinium-iodide (ASP(+)). Subsequently, the inhibitory potencies of the cationic uremic toxins, cadaverine, putrescine, spermine and spermidine (polyamines), acrolein (polyamine breakdown product), guanidine, and methylguanidine (guanidino compounds) were determined. Concentration-dependent inhibition of ASP(+) uptake by TPA, cimetidine, quinidine, and metformin confirmed functional endogenous organic cation transporter 2 (OCT2) expression in ciPTEC. All uremic toxins tested inhibited ASP(+) uptake, of which acrolein required the lowest concentration to provoke a half-maximal inhibition (IC50 = 44 ± 2 μM). A Dixon plot was constructed for acrolein using three independent inhibition curves with 10, 20, or 30 μM ASP(+), which demonstrated competitive or mixed type of interaction (K i = 93 ± 16 μM). Exposing the cells to a mixture of cationic uremic toxins resulted in a more potent and biphasic inhibitory response curve, indicating complex interactions between the toxins and ASP(+) uptake. In conclusion, ciPTEC proves a suitable model to study cationic xenobiotic interactions. Inhibition of cellular uptake transport was demonstrated for several uremic toxins, which might indicate a possible role in kidney disease progression during uremia.

Acute renal failure after rifampicin

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Adriana Weinberg

1984-12-01

Full Text Available A patient with miliary tuberculosis and a chronic urogenital focus is described, who had a borderline renal function at diagnosis and developed overt renal failure upon daily treatment with rifampin (RMP, isoniazid (INH and ethambutol (EMB. This is the first Brazilian report of BMP induced renal damage. A renal biopsy taken on the third day of oliguria showed recent tubular necrosis with acute interstitial inflammation and granuloma formation. The aspect of the granulomatous lesion hightly suggested drug etiology because of the lack of palisading, high incidence of neutrophils and absence of facid-fast bacilli. This is the first presentation of an acute granulomatous interstitial nephritis probably due to RMP. Furthermore the pathogenesis of the renal damage caused by tuberculosis and RMP are discussed.

Norepinephrine transporter function and desipramine: residual drug effects versus short-term regulation.

Science.gov (United States)

Ordway, Gregory A; Jia, Weihong; Li, Jing; Zhu, Meng-Yang; Mandela, Prashant; Pan, Jun

2005-04-30

Previous research has shown that exposure of norepinephrine transporter (NET)-expressing cells to desipramine (DMI) downregulates the norepinephrine transporter, although changes in the several transporter parameters do not demonstrate the same time course. Exposures to desipramine for effects of residual desipramine on norepinephrine transporter binding and uptake were re-evaluated following exposures of PC12 cells to desipramine using different methods to remove residual drug. Using a method that minimizes residual drug, exposure of intact PC12 cells to desipramine for 4h had no effect on uptake capacity or [(3)H]nisoxetine binding to the norepinephrine transporter, while exposures for > or =16 h reduced uptake capacity. Desipramine-induced reductions in binding to the transporter required >24 h or greater periods of desipramine exposure. This study confirms that uptake capacity of the norepinephrine transporter is reduced earlier than changes in radioligand binding, but with a different time course than originally shown. Special pre-incubation procedures are required to abolish effects of residual transporter inhibitor when studying inhibitor-induced transporter regulation.

Possibility of Predicting Serotonin Transporter Occupancy From the In Vitro Inhibition Constant for Serotonin Transporter, the Clinically Relevant Plasma Concentration of Unbound Drugs, and Their Profiles for Substrates of Transporters.

Science.gov (United States)

Yahata, Masahiro; Chiba, Koji; Watanabe, Takao; Sugiyama, Yuichi

2017-09-01

Accurate prediction of target occupancy facilitates central nervous system drug development. In this review, we discuss the predictability of serotonin transporter (SERT) occupancy in human brain estimated from in vitro K i values for human SERT and plasma concentrations of unbound drug (C u,plasma ), as well as the impact of drug transporters in the blood-brain barrier. First, the geometric means of in vitro K i values were compared with the means of in vivo K i values (K i,u,plasma ) which were calculated as C u,plasma values at 50% occupancy of SERT obtained from previous clinical positron emission tomography/single photon emission computed tomography imaging studies for 6 selective serotonin transporter reuptake inhibitors and 3 serotonin norepinephrine reuptake inhibitors. The in vitro K i values for 7 drugs were comparable to their in vivo K i,u,plasma values within 3-fold difference. SERT occupancy was overestimated for 5 drugs (P-glycoprotein substrates) and underestimated for 2 drugs (presumably uptake transporter substrates, although no evidence exists as yet). In conclusion, prediction of human SERT occupancy from in vitro K i values and C u,plasma was successful for drugs that are not transporter substrates and will become possible in future even for transporter substrates, once the transporter activities will be accurately estimated from in vitro experiments. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Regulation of Expression of Renal Organic Anion Transporters OAT1 and OAT3 in a Model of Ischemia/Reperfusion Injury

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Christina Preising

2015-08-01

Full Text Available Background: Recently, we gained evidence that impairment of rOat1 and rOat3 expression induced by ischemic acute kidney injury (AKI is mediated by COX metabolites and this suppression might be critically involved in renal damage. Methods: (i Basolateral organic anion uptake into proximal tubular cells after model ischemia and reperfusion (I/R was investigated by fluorescein uptake. The putative promoter sequences from hOAT1 (SLC22A6 and hOAT3 (SCL22A8 were cloned into a reporter plasmid, transfected into HEK cells and (ii transcriptional activity was determined after model ischemia and reperfusion as a SEAP reporter gen assay. Inhibitors or antagonists were applied with the beginning of reperfusion. Results: By using inhibitors of PKA (H89 and PLC (U73122, antagonists of E prostanoid receptor type 2 (AH6809 and type 4 (L161,982, we gained evidence that I/R induced down regulation of organic anion transport is mediated by COX1 metabolites via E prostanoid receptor type 4. The latter signaling was confirmed by application of butaprost (EP2 agonist or TCS2510 (EP4 agonist to control cells. In brief, the latter signaling was verified for the transcriptional activity in the reporter gen assay established. Therein, selective inhibitors for COX1 (SC58125 and COX2 (SC560 were also applied. Conclusion: Our data show (a that COX1 metabolites are involved in the regulation of renal organic anion transport(ers after I/R via the EP4 receptor and (b that this is due to transcriptional regulation of the respective transporters. As the promoter sequences cloned were of human origin and expressed in a human renal epithelial cell line we (c hypothesize that the regulatory mechanisms described after I/R is meaningful for humans as well.

A microfluidic renal proximal tubule with active reabsorptive function.

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Else M Vedula

Full Text Available In the kidney, the renal proximal tubule (PT reabsorbs solutes into the peritubular capillaries through active transport. Here, we replicate this reabsorptive function in vitro by engineering a microfluidic PT. The microfluidic PT architecture comprises a porous membrane with user-defined submicron surface topography separating two microchannels representing a PT filtrate lumen and a peritubular capillary lumen. Human PT epithelial cells and microvascular endothelial cells in respective microchannels created a PT-like reabsorptive barrier. Co-culturing epithelial and endothelial cells in the microfluidic architecture enhanced viability, metabolic activity, and compactness of the epithelial layer. The resulting tissue expressed tight junctions, kidney-specific morphology, and polarized expression of kidney markers. The microfluidic PT actively performed sodium-coupled glucose transport, which could be modulated by administration of a sodium-transport inhibiting drug. The microfluidic PT reproduces human physiology at the cellular and tissue levels, and measurable tissue function which can quantify kidney pharmaceutical efficacy and toxicity.

A mechanistic framework for in vitro-in vivo extrapolation of liver membrane transporters: prediction of drug-drug interaction between rosuvastatin and cyclosporine.

Science.gov (United States)

Jamei, M; Bajot, F; Neuhoff, S; Barter, Z; Yang, J; Rostami-Hodjegan, A; Rowland-Yeo, K

2014-01-01

The interplay between liver metabolising enzymes and transporters is a complex process involving system-related parameters such as liver blood perfusion as well as drug attributes including protein and lipid binding, ionisation, relative magnitude of passive and active permeation. Metabolism- and/or transporter-mediated drug-drug interactions (mDDIs and tDDIs) add to the complexity of this interplay. Thus, gaining meaningful insight into the impact of each element on the disposition of a drug and accurately predicting drug-drug interactions becomes very challenging. To address this, an in vitro-in vivo extrapolation (IVIVE)-linked mechanistic physiologically based pharmacokinetic (PBPK) framework for modelling liver transporters and their interplay with liver metabolising enzymes has been developed and implemented within the Simcyp Simulator(®). In this article an IVIVE technique for liver transporters is described and a full-body PBPK model is developed. Passive and active (saturable) transport at both liver sinusoidal and canalicular membranes are accounted for and the impact of binding and ionisation processes is considered. The model also accommodates tDDIs involving inhibition of multiple transporters. Integrating prior in vitro information on the metabolism and transporter kinetics of rosuvastatin (organic-anion transporting polypeptides OATP1B1, OAT1B3 and OATP2B1, sodium-dependent taurocholate co-transporting polypeptide [NTCP] and breast cancer resistance protein [BCRP]) with one clinical dataset, the PBPK model was used to simulate the drug disposition of rosuvastatin for 11 reported studies that had not been used for development of the rosuvastatin model. The simulated area under the plasma concentration-time curve (AUC), maximum concentration (C max) and the time to reach C max (t max) values of rosuvastatin over the dose range of 10-80 mg, were within 2-fold of the observed data. Subsequently, the validated model was used to investigate the impact of

Glucuronidation as a mechanism of intrinsic drug resistance in colon cancer cells: contribution of drug transport proteins

NARCIS (Netherlands)

Cummings, Jeffrey; Zelcer, Noam; Allen, John D.; Yao, Denggao; Boyd, Gary; Maliepaard, Mark; Friedberg, Thomas H.; Smyth, John F.; Jodrell, Duncan I.

2004-01-01

We have recently shown that drug conjugation catalysed by UDP-glucuronosyltransferases (UGTs) functions as an intrinsic mechanism of resistance to the topoisomerase I inhibitors 7-ethyl-10-hydroxycamptothecin and NU/ICRF 505 in human colon cancer cells and now report on the role of drug transport in

Therapeutic embolization of renal artery to control severe hypertension due to renal trauma

Energy Technology Data Exchange (ETDEWEB)

Cotroneo, A R; Patane, D; De Cinque, M; Falappa, P; Doglietto, G

1987-05-01

In a young patient with a post-traumatic renal hematoma, severe systemic hypertension, secondary to the activation of the renin-angiotensin axis, developed. Because of persistent hypertension, after 3 months of drug therapy, selective percutaneous embolization of the damaged vessels was performed. One year after procedure, the patient is normotensive without drugs.

Therapeutic embolization of renal artery to control severe hypertension due to renal trauma

International Nuclear Information System (INIS)

Cotroneo, A.R.; Patane, D.; De Cinque, M.; Falappa, P.; Doglietto, G.

1987-01-01

In a young patient with a post-traumatic renal hematoma, severe systemic hypertension, secondary to the activation of the renin-angiotensin axis, developed. Because of persistent hypertension, after 3 months of drug therapy, selective percutaneous embolization of the damaged vessels was performed. One year after procedure, the patient is normotensive without drugs. (orig.)

The Role of Non-Steroidal Anti-Inflammatory Drugs in Renal Colic

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Elizabeth Waine

2010-04-01

Full Text Available NSAIDs provide optimal analgesia in renal colic due to the reduction in glomerular filtration and renal pelvic pressure, ureteric peristalsis and ureteric oedema. Prevention of glomerular afferent arteriolar vasodilatation renders these patients at risk of renal impairment. NSAIDs have the additional benefit of reducing the number of new colic episodes and preventing subsequent readmission to hospital. Despite recent work promoting the use of pharmacological agents to improve stone passage rates, NSAIDs do not appear to reduce the time to stone passage or increase the likelihood of stone passage in renal colic.

Automated applications of sandwich-cultured hepatocytes in the evaluation of hepatic drug transport.

Science.gov (United States)

Perry, Cassandra H; Smith, William R; St Claire, Robert L; Brouwer, Kenneth R

2011-04-01

Predictions of the absorption, distribution, metabolism, excretion, and toxicity of compounds in pharmaceutical development are essential aspects of the drug discovery process. B-CLEAR is an in vitro system that uses sandwich-cultured hepatocytes to evaluate and predict in vivo hepatobiliary disposition (hepatic uptake, biliary excretion, and biliary clearance), transporter-based hepatic drug-drug interactions, and potential drug-induced hepatotoxicity. Automation of predictive technologies is an advantageous and preferred format in drug discovery. In this study, manual and automated studies are investigated and equivalence is demonstrated. In addition, automated applications using model probe substrates and inhibitors to assess the cholestatic potential of drugs and evaluate hepatic drug transport are examined. The successful automation of this technology provides a more reproducible and less labor-intensive approach, reducing potential operator error in complex studies and facilitating technology transfer.

Pharmacogenomics of the human ABC transporter ABCG2: from functional evaluation to drug molecular design

Science.gov (United States)

Ishikawa, Toshihisa; Tamura, Ai; Saito, Hikaru; Wakabayashi, Kanako; Nakagawa, Hiroshi

2005-10-01

In the post-genome-sequencing era, emerging genomic technologies are shifting the paradigm for drug discovery and development. Nevertheless, drug discovery and development still remain high-risk and high-stakes ventures with long and costly timelines. Indeed, the attrition of drug candidates in preclinical and development stages is a major problem in drug design. For at least 30% of the candidates, this attrition is due to poor pharmacokinetics and toxicity. Thus, pharmaceutical companies have begun to seriously re-evaluate their current strategies of drug discovery and development. In that light, we propose that a transport mechanism-based design might help to create new, pharmacokinetically advantageous drugs, and as such should be considered an important component of drug design strategy. Performing enzyme- and/or cell-based drug transporter, interaction tests may greatly facilitate drug development and allow the prediction of drug-drug interactions. We recently developed methods for high-speed functional screening and quantitative structure-activity relationship analysis to study the substrate specificity of ABC transporters and to evaluate the effect of genetic polymorphisms on their function. These methods would provide a practical tool to screen synthetic and natural compounds, and these data can be applied to the molecular design of new drugs. In this review article, we present an overview on the genetic polymorphisms of human ABC transporter ABCG2 and new camptothecin analogues that can circumvent AGCG2-associated multidrug resistance of cancer.

Polyester-Based, Biodegradable Core-Multishell Nanocarriers for the Transport of Hydrophobic Drugs

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Karolina A. Walker

2016-05-01

Full Text Available A water-soluble, core-multishell (CMS nanocarrier based on a new hyperbranched polyester core building block was synthesized and characterized towards drug transport and degradation of the nanocarrier. The hydrophobic drug dexamethasone was encapsulated and the enzyme-mediated biodegradability was investigated by NMR spectroscopy. The new CMS nanocarrier can transport one molecule of dexamethasone and degrades within five days at a skin temperature of 32 °C to biocompatible fragments.

Percutaneous renal sympathetic nerve ablation for loin pain haematuria syndrome.

Science.gov (United States)

Gambaro, Giovanni; Fulignati, Pierluigi; Spinelli, Alessio; Rovella, Valentina; Di Daniele, Nicola

2013-09-01

Loin pain haematuria syndrome (LPHS) is a severe renal pain condition of uncertain origin and often resistant to treatment. Nephrectomy and renal autotrasplantation have occasionally been performed in very severe cases. Its pathogenesis is controversial. A 40-year-old hypertensive lady was diagnosed with LPHS after repeated diagnostic imaging procedures had ruled out any renal, abdominal or spinal conditions to justify pain. Notwithstanding treatment with three drugs, she had frequent hypertensive crises during which the loin pain was dramatically exacerbated. Vascular causes of the pain and hypertension were investigated and excluded. Her renal function was normal. The patient was referred to a multidisciplinary pain clinic, but had no significant improvement in her pain symptoms despite the use of non-steroidal anti-inflammatory drugs, adjuvant antidepressants and opioid-like agents. The pain and the discomfort were so severe that her quality of life was very poor, and her social and professional activities were compromised. Nephrectomy and renal autotransplantation have occasionally been performed in these cases. Since visceral pain signals flow through afferent sympathetic fibres, we felt that percutaneous catheter-based radiofrequency ablation of the renal sympathetic nerve fibres (recently introduced for the treatment of drug-resistant hypertension) could be valuable for pain relief. We treated the patient with radiofrequency ablation (Medtronic Symplicity Catheter) applied only to the right renal artery. After a 6-month follow-up, the patient is pain free and normotensive with all drugs withdrawn. She has experienced no hypertensive crises in the meantime. This observation suggests that percutaneous sympathetic denervation could prove to be an effective mini-invasive strategy for the treatment of chronic renal pain, and LPHS in particular.

Pharmacogenetics of taxanes: impact of gene polymorphisms of drug transporters on pharmacokinetics and toxicity.

Science.gov (United States)

Jabir, Rafid Salim; Naidu, Rakesh; Annuar, Muhammad Azrif Bin Ahmad; Ho, Gwo Fuang; Munisamy, Murali; Stanslas, Johnson

2012-12-01

Interindividual variability in drug response and the emergence of adverse drug effects are the main causes of treatment failure in cancer therapy. Functional membrane drug transporters play important roles in altering pharmacokinetic profile, resistance to treatment, toxicity and patient survival. Pharmacogenetic studies of these transporters are expected to provide new approaches for optimizing therapy. Taxanes are approved for the treatment of various cancers. Circulating taxanes are taken up by SLCO1B3 into hepatocytes. The CYP450 enzymes CYP3A4, CYP3A5 and CYP2C8 are responsible for the conversion of taxanes into their metabolites. Ultimately, ABCB1 and ABCC2 will dispose the metabolites into bile canaliculi. Polymorphisms of genes encoding for proteins involved in the transport and clearance of taxanes reduce excretion of the drugs, leading to development of toxicity in patients. This review addresses current knowledge on genetic variations of transporters affecting taxanes pharmacokinetics and toxicity, and provides insights into future direction for personalized medicine.

Computational Studies of Drug Release, Transport and Absorption in the Human Intestines

Science.gov (United States)

Behafarid, Farhad; Brasseur, J. G.; Vijayakumar, G.; Jayaraman, B.; Wang, Y.

2016-11-01

Following disintegration of a drug tablet, a cloud of particles 10-200 μm in diameter enters the small intestine where drug molecules are absorbed into the blood. Drug release rate depends on particle size, solubility and hydrodynamic enhancements driven by gut motility. To quantify the interrelationships among dissolution, transport and wall permeability, we apply lattice Boltzmann method to simulate the drug concentration field in the 3D gut released from polydisperse distributions of drug particles in the "fasting" vs. "fed" motility states. Generalized boundary conditions allow for both solubility and gut wall permeability to be systematically varied. We apply a local 'quasi-steady state' approximation for drug dissolution using a mathematical model generalized for hydrodynamic enhancements and heterogeneity in drug release rate. We observe fundamental differences resulting from the interplay among release, transport and absorption in relationship to particle size distribution, luminal volume, motility, solubility and permeability. For example, whereas smaller volume encourages higher bulk concentrations and reduced release rate, it also encourages higher absorption rate, making it difficult to generalize predictions. Supported by FDA.

A health record integrated clinical decision support system to support prescriptions of pharmaceutical drugs in patients with reduced renal function: design, development and proof of concept.

Science.gov (United States)

Shemeikka, Tero; Bastholm-Rahmner, Pia; Elinder, Carl-Gustaf; Vég, Anikó; Törnqvist, Elisabeth; Cornelius, Birgitta; Korkmaz, Seher

2015-06-01

To develop and verify proof of concept for a clinical decision support system (CDSS) to support prescriptions of pharmaceutical drugs in patients with reduced renal function, integrated in an electronic health record system (EHR) used in both hospitals and primary care. A pilot study in one geriatric clinic, one internal medicine admission ward and two outpatient healthcare centers was evaluated with a questionnaire focusing on the usefulness of the CDSS. The usage of the system was followed in a log. The CDSS is considered to increase the attention on patients with impaired renal function, provides a better understanding of dosing and is time saving. The calculated glomerular filtration rate (eGFR) and the dosing recommendation classification were perceived useful while the recommendation texts and background had been used to a lesser extent. Few previous systems are used in primary care and cover this number of drugs. The global assessment of the CDSS scored high but some elements were used to a limited extent possibly due to accessibility or that texts were considered difficult to absorb. Choosing a formula for the calculation of eGFR in a CDSS may be problematic. A real-time CDSS to support kidney-related drug prescribing in both hospital and outpatient settings is valuable to the physicians. It has the potential to improve quality of drug prescribing by increasing the attention on patients with renal insufficiency and the knowledge of their drug dosing. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Non-steroidal anti-inflammatory drugs and renal response to exercise

DEFF Research Database (Denmark)

Olsen, Niels Vidiendal; Jensen, N G; Hansen, J M

1999-01-01

baseline values or exercise-induced decreases in renal plasma flow or glomerular filtration rate. Indomethacin, but not nabumetone, decreased sodium excretion, urine flow rate and free water clearance. The renal response to exercise, however, remained unchanged. In contrast with nabumatone, indomethacin...

From nose to brain: understanding transport capacity and transport rate of drugs.

Science.gov (United States)

Wu, Hongbing; Hu, Kaili; Jiang, Xinguo

2008-10-01

The unique relationship between nasal cavity and cranial cavity tissues in anatomy and physiology makes intranasal delivery to the brain feasible. An intranasal delivery provides some drugs with short channels to bypass the blood-brain barrier (BBB), especially for those with fairly low brain concentrations after a routine delivery, thus greatly enhancing the therapeutic effect on brain diseases. In the past two decades, a good number of encouraging outcomes have been reported in the treatment of diseases of the brain or central nervous system (CNS) through nasal administration. In spite of the significant merit of bypassing the BBB, direct nose-to-brain delivery still bears the problems of low efficiency and volume for capacity due to the limited volume of the nasal cavity, the small area ratio of olfactory mucosa to nasal mucosa and the limitations of low dose and short retention time of drug absorption. It is crucial that selective distribution and retention time of drugs or preparations on olfactory mucosa should be enhanced so as to increase the direct delivery efficiency. In this article, we first briefly review the nose-to-brain transport pathways, before detailing the impacts on them, followed by a comprehensive summary of effective methods, including formulation modification, agglutinant-mediated transport and a brain-homing, peptide-mediated delivery based on phage display screening technique, with a view to providing a theoretic reference for elevating the therapeutic effects on brain diseases.

Comparison of equations for dosing of medications in renal impairment.

Science.gov (United States)

Khanal, Aarati; Peterson, Gregory M; Jose, Matthew D; Castelino, Ronald L

2017-06-01

The aim of this study is to determine the concordance among the Cockcroft-Gault, the Modification of Diet in Renal Disease and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations in hypothetical dosing of renally cleared medications. A total of 2163 patients prescribed at least one of the 31 renally cleared drugs under review were included in the study. Kidney function was estimated using the three equations. We compared actual prescribed dosages of the same drug with recommended dosages based on the kidney function as calculated by each of the equations and applying dosing recommendations in the Australian Medicines Handbook. There was a significant difference in the kidney function values estimated from the three equations (P < 0.001). Despite the good overall agreement in renal drug dosing, we found selected but potentially important discrepancies among the doses rendered from the equations. The CKD-EPI equation non-normalized for body surface area had a greater rate of concordance with the Cockcroft-Gault equation than the Modification of Diet in Renal Disease equation for renal drug dosing. There is need for a long-term multi-centre study in a diverse population to define the clinical effects of the discrepancies among the equations for drug dosing. Given the greater concordance of the non-normalized CKD-EPI equation with the Cockcroft-Gault equation for dosing, the recommendation by Kidney Health Australia and the United States National Kidney Disease Education Program that 'dosing based on either eCrCl or an eGFR with body surface area normalization removed are acceptable' seems suitable and practicable for the purpose of dosing of non-critical drugs in the primary care setting. © 2016 Asian Pacific Society of Nephrology.

Review of the State of Renal Nerve Ablation for Patients with Severe and Resistant Hypertension

Science.gov (United States)

Gulati, Vinay; White, William B.

2013-01-01

Through modulation of renin secretion, glomerular filtration rate and renal absorption of sodium, the sympathetic innervation of the kidneys plays an important role in the pathogenesis of hypertension. Renal nerve ablation technology is being developed for treatment of drug-treatment resistant hypertension worldwide. Preliminary research with the use of radiofrequency based renal denervation systems have demonstrated encouraging results with significant reduction of blood pressure in patients inadequately controlled despite nearly maximal drug therapy regimens. From work done thus far, the renal denervation procedure has not been associated with serious adverse effects. Long term efficacy and safety still needs to be established for renal nerve ablation. This review focuses on the impact of the renal sympathetic system on blood pressure regulation, the clinical rationale for renal nerve ablation in severe and drug-treatment resistant hypertension and current evidence from the more advanced renal denervation devices. PMID:23953998

Urea and Ammonia Metabolism and the Control of Renal Nitrogen Excretion

Science.gov (United States)

Mitch, William E.; Sands, Jeff M.

2015-01-01

Renal nitrogen metabolism primarily involves urea and ammonia metabolism, and is essential to normal health. Urea is the largest circulating pool of nitrogen, excluding nitrogen in circulating proteins, and its production changes in parallel to the degradation of dietary and endogenous proteins. In addition to serving as a way to excrete nitrogen, urea transport, mediated through specific urea transport proteins, mediates a central role in the urine concentrating mechanism. Renal ammonia excretion, although often considered only in the context of acid-base homeostasis, accounts for approximately 10% of total renal nitrogen excretion under basal conditions, but can increase substantially in a variety of clinical conditions. Because renal ammonia metabolism requires intrarenal ammoniagenesis from glutamine, changes in factors regulating renal ammonia metabolism can have important effects on glutamine in addition to nitrogen balance. This review covers aspects of protein metabolism and the control of the two major molecules involved in renal nitrogen excretion: urea and ammonia. Both urea and ammonia transport can be altered by glucocorticoids and hypokalemia, two conditions that also affect protein metabolism. Clinical conditions associated with altered urine concentrating ability or water homeostasis can result in changes in urea excretion and urea transporters. Clinical conditions associated with altered ammonia excretion can have important effects on nitrogen balance. PMID:25078422

Renal sympathetic nervous system and the effects of denervation on renal arteries.

Science.gov (United States)

Kannan, Arun; Medina, Raul Ivan; Nagajothi, Nagapradeep; Balamuthusamy, Saravanan

2014-08-26

Resistant hypertension is associated with chronic activation of the sympathetic nervous system resulting in various comorbidities. The prevalence of resistant hypertension is often under estimated due to various reasons. Activation of sympathetic nervous system at the renal- as well as systemic- level contributes to the increased level of catecholamines and resulting increase in the blood pressure. This increased activity was demonstrated by increased muscle sympathetic nerve activity and renal and total body noradrenaline spillover. Apart from the hypertension, it is hypothesized to be associated with insulin resistance, congestive heart failure and obstructive sleep apnea. Renal denervation is a novel procedure where the sympathetic afferent and efferent activity is reduced by various techniques and has been used successfully to treat drug-resistant hypertension improvement of various metabolic derangements. Renal denervation has the unique advantage of offering the denervation at the renal level, thus mitigating the systemic side effects. Renal denervation can be done by various techniques including radiofrequency ablation, ultrasound guided ablation and chemical ablation. Various trials evaluated the role of renal denervation in the management of resistant hypertension and have found promising results. More studies are underway to evaluate the role of renal denervation in patients presenting with resistant hypertension in different scenarios. Appropriate patient selection might be the key in determining the effectiveness of the procedure.

Functional Expression of P-glycoprotein and Organic Anion Transporting Polypeptides at the Blood-Brain Barrier: Understanding Transport Mechanisms for Improved CNS Drug Delivery?

Science.gov (United States)

Abdullahi, Wazir; Davis, Thomas P; Ronaldson, Patrick T

2017-07-01

Drug delivery to the central nervous system (CNS) is greatly limited by the blood-brain barrier (BBB). Physical and biochemical properties of the BBB have rendered treatment of CNS diseases, including those with a hypoxia/reoxygenation (H/R) component, extremely difficult. Targeting endogenous BBB transporters from the ATP-binding cassette (ABC) superfamily (i.e., P-glycoprotein (P-gp)) or from the solute carrier (SLC) family (i.e., organic anion transporting polypeptides (OATPs in humans; Oatps in rodents)) has been suggested as a strategy that can improve delivery of drugs to the brain. With respect to P-gp, direct pharmacological inhibition using small molecules or selective regulation by targeting intracellular signaling pathways has been explored. These approaches have been largely unsuccessful due to toxicity issues and unpredictable pharmacokinetics. Therefore, our laboratory has proposed that optimization of CNS drug delivery, particularly for treatment of diseases with an H/R component, can be achieved by targeting Oatp isoforms at the BBB. As the major drug transporting Oatp isoform, Oatp1a4 has demonstrated blood-to-brain transport of substrate drugs with neuroprotective properties. Furthermore, our laboratory has shown that targeting Oatp1a4 regulation (i.e., TGF-β signaling mediated via the ALK-1 and ALK-5 transmembrane receptors) represents an opportunity to control Oatp1a4 functional expression for the purpose of delivering therapeutics to the CNS. In this review, we will discuss limitations of targeting P-gp-mediated transport activity and the advantages of targeting Oatp-mediated transport. Through this discussion, we will also provide critical information on novel approaches to improve CNS drug delivery by targeting endogenous uptake transporters expressed at the BBB.

P-gp, MRP2 and OAT1/OAT3 mediate the drug-drug interaction between resveratrol and methotrexate

Energy Technology Data Exchange (ETDEWEB)

Jia, Yongming [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044 (China); Liu, Zhihao; Wang, Changyuan; Meng, Qiang; Huo, Xiaokui; Liu, Qi; Sun, Huijun [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044 (China); Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian 116044 (China); Sun, Pengyuan; Yang, Xiaobo; Ma, Xiaodong [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044 (China); Liu, Kexin, E-mail: kexinliu@dlmedu.edu.cn [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044 (China); Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian 116044 (China)

2016-09-01

The purpose of present study was to investigate the effect of resveratrol (Res) on altering methotrexate (MTX) pharmacokinetics and clarify the related molecular mechanism. Res significantly increased rat intestinal absorption of MTX in vivo and in vitro. Simultaneously, Res inhibited MTX efflux transport in MDR1-MDCK and MRP2-MDCK cell monolayers, suggesting that the target of drug interaction was MDR1 and MRP2 in the intestine during the absorption process. Furthermore, there was a significant decrease in renal clearance of MTX after simultaneous intravenous administration. Similarly, MTX uptake was markedly inhibited by Res in rat kidney slices and hOAT1/3-HEK293 cell, indicating that OAT1 and OAT3 were involved in the drug interaction in the kidney. Additionally, concomitant administration of Res decreased cytotoxic effects of MTX in hOAT1/3-HEK293 cells, and ameliorated nephrotoxicity caused by MTX in rats. Conversely, intestinal damage caused by MTX was not exacerbated after Res treatment. In conclusion, Res enhanced MTX absorption in intestine and decreased MTX renal elimination by inhibiting P-gp, MRP2, OAT1 and OAT3 in vivo and in vitro. Res improved MTX-induced renal damage without increasing intestinal toxicity. - Highlights: • DDI between MTX and Res will occur when they are co-administered. • The first targets of the DDI are P-gp and MRP2 located in intestine. • The second targets of the DDI are OAT1 and OAT3 in kidney. • Res improved MTX-induced renal damage without increasing intestinal toxicity.

Several hPepT1-transported drugs are substrates of the Escherichia coli proton-coupled oligopeptide transporter YdgR

DEFF Research Database (Denmark)

Prabhala, Bala K; Aduri, Nanda G; Iqbal, Mazhar

2017-01-01

transported by hPepT1. The transport of these drugs was evaluated using the prototypical POT YdgR from E. coli. The transport studies were pursued through combining cell-based assays with liquid chromatography-tandem mass spectrometric (LC-MS/MS) analysis. These investigations revealed that YdgR from E. coli...

Mouse ATP-Binding Cassette (ABC) Transporters Conferring Multi-Drug Resistance

Science.gov (United States)

Shuaizhang, L I; Zhang, Wen; Yin, Xuejiao; Xing, Shilai; Xie, Qunhui; Cao, Zhengyu; Zhao, Bin

2015-04-28

The ABC (ATP-binding cassette) transporter is one of the largest and most ancient protein families with members functioning from protozoa to human. The resistance of cancer and tumor cells to anticancer drugs is due to the over-expression of some ABC transporters, which may finally lead to chemotherapy failure. The mouse ABC transporters are classified into seven subfamilies by phylogenetic analysis. The mouse ABC transporter gene, alias, chromosomal location and function have been determined. Within the ABC super-family, the MDR transporters (Abcb1, Abcc1, Abcg2) in mouse models have been proved to be valuable to investigate the biochemistry and physiological functions. This review concentrates on the multidrug resistance of mouse ABC transporters in cancer and tumor cells.

Contributions of nuclear magnetic resonance to renal biochemistry

International Nuclear Information System (INIS)

Ross, B.; Freeman, D.; Chan, L.

1986-01-01

31 P NMR as a descriptive technique is of interest to nephrologists. Particular contributions of 31 P NMR to our understanding of renal function may be enumerated.: Free metabolite levels are different from those classically accepted; in particular, ADP and Pi are low with implications for the control of renal metabolism and Pi transport, and, via the phosphorylation potential, for Na+ transport. Renal pH is heterogeneous; between cortex, outer medulla, and papilla, and between cell and lumen, a large pH gradient exists. Also, quantitation between cytosol and mitochondrion of the pH gradient is now feasible. In acute renal failure of either ischemic or nonischemic origin, both ATP depletion and acidification of the renal cell result in damage, with increasing evidence for the importance of the latter. Measurements of renal metabolic rate in vivo suggest the existence of a prodromal phase of acute renal failure, which could lead to its detection at an earlier and possibly reversible stage. Human renal cancers show a unique 31 P NMR spectrum and a very acidic environment. Cancer chemotherapy may alter this and detection of such changes with NMR offers a method of therapeutic monitoring with significance beyond nephrology. Renal cortex and medulla have a different T1 relaxation time, possibly due to differences in lipid composition. It seems that NMR spectroscopy has much to offer to the future understanding of the relationship between renal biochemistry and function. 56 references

Intrarenal purinergic signaling in the control of renal tubular transport

DEFF Research Database (Denmark)

Prætorius, Helle; Leipziger, Jens Georg

2010-01-01

Renal tubular epithelial cells receive hormonal input that regulates volume and electrolyte homeostasis. In addition, numerous intrarenal, local signaling agonists have appeared on the stage of renal physiology. One such system is that of intrarenal purinergic signaling. This system involves all......-reaching advances indicate that ATP is often used as a local transmitter for classical sensory transduction. This transmission apparently also applies to sensory functions in the kidney. Locally released ATP is involved in sensing of renal tubular flow or in detecting the distal tubular load of NaCl at the macula...

Interactions of [14C]phosphonoformic acid with renal cortical brush-border membranes. Relationship to the Na+-phosphate co-transporter

International Nuclear Information System (INIS)

Szczepanska-Konkel, M.; Yusufi, A.N.; Dousa, T.P.

1987-01-01

Since phosphonoformic acid (PFA) acts as a specific competitive inhibitor of Na+-Pi co-transport across renal brush-border membrane (BBM), we employed the [ 14 C]PFA as a probe to determine the mechanism of its interaction with rat renal BBM. The binding of [ 14 C]PFA to BBM vesicles (BBMV), with Na+ present in extravesicular medium (Na+o), was time- and temperature-dependent. The replacement of Na+o with other monovalent cations reduced the PFA binding by -80%. Cl- was the most effective accompanying monovalent anion as NaCl for maximum PFA binding. The Na+o increased the apparent affinity of BBMV for [ 14 C]PFA binding, but it did not change the maximum binding capacity. The maximum [ 14 C]PFA binding was achieved at Na+o approximately equal to 50 mM. The extent of Na+-dependent [ 14 C]PFA binding correlated with percent inhibition by an equimolar dose of PFA of the dependent BBMV uptake of 32Pi. Intravesicular Na+ (Na+i) decreased [ 14 C]PFA binding, on BBMV, and this inhibition by Na+i was dependent on the presence of Na+o. The increase in Na+i, at constant [Na+]o, decreased the Vmax, but not the Km, for [ 14 C]PFA binding on BBMV. Bound [ 14 C]PFA was displaced from BBMV by phosphonocarboxylic acids proportionally to their ability to inhibit gradient-dependent Pi transport, whereas other monophosphonates, diphosphonates, L-proline, or D-glucose did not influence the [ 14 C]PFA binding. The Na+-dependent binding of [ 14 C]PFA and of [ 3 H]phlorizin by BBMV was 10 times higher than binding of these ligands to renal basolateral membranes and to mitochondria. [ 14 C]PFA probably binds onto the same locus on the luminal surface of BBM, where Pi and Na+ form a ternary complex with the Na+-Pi co-transporter

Mobilization and removing of cadmium from kidney by GMDTC utilizing renal glucose reabsorption pathway

International Nuclear Information System (INIS)

Tang, Xiaojiang; Zhu, Jinqiu; Zhong, Zhiyong; Luo, Minhui; Li, Guangxian; Gong, Zhihong; Zhang, Chenzi; Fei, Fan; Ruan, Xiaolin; Zhou, Jinlin; Liu, Gaofeng; Li, Guoding; Olson, James; Ren, Xuefeng

2016-01-01

Chronic exposure to cadmium compounds (Cd 2+ ) is one of the major public health problems facing humans in the 21st century. Cd 2+ in the human body accumulates primarily in the kidneys which leads to renal dysfunction and other adverse health effects. Efforts to find a safe and effective drug for removing Cd 2+ from the kidneys have largely failed. We developed and synthesized a new chemical, sodium (S)-2-(dithiocarboxylato((2S,3R,4R,5R)-2,3,4,5,6 pentahydroxyhexyl)amino)-4-(methylthio) butanoate (GMDTC). Here we report that GMDTC has a very low toxicity with an acute lethal dose (LD50) of more than 10,000 mg/kg or 5000 mg/kg body weight, respectively, via oral or intraperitoneal injection in mice and rats. In in vivo settings, up to 94% of Cd 2+ deposited in the kidneys of Cd 2+ -laden rabbits was removed and excreted via urine following a safe dose of GMDTC treatment for four weeks, and renal Cd 2+ level was reduced from 12.9 μg/g to 1.3 μg/g kidney weight. We observed similar results in the mouse and rat studies. Further, we demonstrated both in in vitro and in animal studies that the mechanism of transporting GMDTC and GMDTC-Cd complex into and out of renal tubular cells is likely assisted by two glucose transporters, sodium glucose cotransporter 2 (SGLT2) and glucose transporter 2 (GLUT2). Collectively, our study reports that GMDTC is safe and highly efficient in removing deposited Cd 2+ from kidneys assisted by renal glucose reabsorption system, suggesting that GMDTC may be the long-pursued agent used for preventive and therapeutic purposes for both acute and chronic Cd 2+ exposure.

Mobilization and removing of cadmium from kidney by GMDTC utilizing renal glucose reabsorption pathway

Energy Technology Data Exchange (ETDEWEB)

Tang, Xiaojiang, E-mail: river-t@126.com [Guangdong Medical Laboratory Animal Center (China); Zhu, Jinqiu [Department of Epidemiology and Environmental Health, The State University of New York, Buffalo, NY (United States); Zhong, Zhiyong; Luo, Minhui; Li, Guangxian [Guangdong Medical Laboratory Animal Center (China); Gong, Zhihong [Department of Epidemiology and Environmental Health, The State University of New York, Buffalo, NY (United States); Zhang, Chenzi; Fei, Fan [Guangdong Medical Laboratory Animal Center (China); Ruan, Xiaolin [Guangdong Poison Control Center (China); Zhou, Jinlin [Golden Health (Foshan) Technology Co., Ltd (China); Liu, Gaofeng [School of Chemistry and Chemical Engineering, Sun Yat-Sen University (China); Li, Guoding [Guangdong Medical Laboratory Animal Center (China); Olson, James [Department of Epidemiology and Environmental Health, The State University of New York, Buffalo, NY (United States); Department of Pharmacology and Toxicology, The State University of New York, Buffalo, NY (United States); Ren, Xuefeng, E-mail: xuefengr@buffalo.edu [Guangdong Medical Laboratory Animal Center (China); Department of Epidemiology and Environmental Health, The State University of New York, Buffalo, NY (United States); Department of Pharmacology and Toxicology, The State University of New York, Buffalo, NY (United States)

2016-08-15

Chronic exposure to cadmium compounds (Cd{sup 2+}) is one of the major public health problems facing humans in the 21st century. Cd{sup 2+} in the human body accumulates primarily in the kidneys which leads to renal dysfunction and other adverse health effects. Efforts to find a safe and effective drug for removing Cd{sup 2+} from the kidneys have largely failed. We developed and synthesized a new chemical, sodium (S)-2-(dithiocarboxylato((2S,3R,4R,5R)-2,3,4,5,6 pentahydroxyhexyl)amino)-4-(methylthio) butanoate (GMDTC). Here we report that GMDTC has a very low toxicity with an acute lethal dose (LD50) of more than 10,000 mg/kg or 5000 mg/kg body weight, respectively, via oral or intraperitoneal injection in mice and rats. In in vivo settings, up to 94% of Cd{sup 2+} deposited in the kidneys of Cd{sup 2+}-laden rabbits was removed and excreted via urine following a safe dose of GMDTC treatment for four weeks, and renal Cd{sup 2+} level was reduced from 12.9 μg/g to 1.3 μg/g kidney weight. We observed similar results in the mouse and rat studies. Further, we demonstrated both in in vitro and in animal studies that the mechanism of transporting GMDTC and GMDTC-Cd complex into and out of renal tubular cells is likely assisted by two glucose transporters, sodium glucose cotransporter 2 (SGLT2) and glucose transporter 2 (GLUT2). Collectively, our study reports that GMDTC is safe and highly efficient in removing deposited Cd{sup 2+} from kidneys assisted by renal glucose reabsorption system, suggesting that GMDTC may be the long-pursued agent used for preventive and therapeutic purposes for both acute and chronic Cd{sup 2+} exposure.

Computational modeling of drug transport across the in vitro cornea.

Science.gov (United States)

Pak, Joseph; Chen, Z J; Sun, Kay; Przekwas, Andrzej; Walenga, Ross; Fan, Jianghong

2018-01-01

A novel quasi-3D (Q3D) modeling approach was developed to model networks of one dimensional structures like tubes and vessels common in human anatomy such as vascular and lymphatic systems, neural networks, and respiratory airways. Instead of a branching network of the same tissue type, this approach was extended to model an interconnected stack of different corneal tissue layers with membrane junction conditions assigned between the tissues. The multi-laminate structure of the cornea presents a unique barrier design and opportunity for investigation using Q3D modeling. A Q3D model of an in vitro rabbit cornea was created to simulate the drug transport across the cornea, accounting for transcellular and paracellular pathways of passive and convective drug transport as well as physicochemistry of lipophilic partitioning and protein binding. Lipophilic Rhodamine B and hydrophilic fluorescein were used as drug analogs. The model predictions for both hydrophilic and lipophilic tracers were able to match the experimental measurements along with the sharp discontinuities at the epithelium-stroma and stroma-endothelium interfaces. This new modeling approach was successfully applied towards pharmacokinetic modeling for use in topical ophthalmic drug design. Copyright © 2017 Elsevier Ltd. All rights reserved.

Anticancer Drugs Targeting the Mitochondrial Electron Transport Chain

Czech Academy of Sciences Publication Activity Database

Rohlena, Jakub; Dong, L.-F.; Ralph, S.J.; Neužil, Jiří

2011-01-01

Roč. 15, č. 12 (2011), s. 2951-2974 ISSN 1523-0864 R&D Projects: GA AV ČR(CZ) KAN200520703 Institutional research plan: CEZ:AV0Z50520701 Keywords : Targets for anticancer drugs * mitochondrial electron transport chain * mitocans Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 8.456, year: 2011

Human skeletal muscle drug transporters determine local exposure and toxicity of statins.

Science.gov (United States)

Knauer, Michael J; Urquhart, Bradley L; Meyer zu Schwabedissen, Henriette E; Schwarz, Ute I; Lemke, Christopher J; Leake, Brenda F; Kim, Richard B; Tirona, Rommel G

2010-02-05

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, are important drugs used in the treatment and prevention of cardiovascular disease. Although statins are well tolerated, many patients develop myopathy manifesting as muscle aches and pain. Rhabdomyolysis is a rare but severe toxicity of statins. Interindividual differences in the activities of hepatic membrane drug transporters and metabolic enzymes are known to influence statin plasma pharmacokinetics and risk for myopathy. Interestingly, little is known regarding the molecular determinants of statin distribution into skeletal muscle and its relevance to toxicity. We sought to identify statin transporters in human skeletal muscle and determine their impact on statin toxicity in vitro. We demonstrate that the uptake transporter OATP2B1 (human organic anion transporting polypeptide 2B1) and the efflux transporters, multidrug resistance-associated protein (MRP)1, MRP4, and MRP5 are expressed on the sarcolemmal membrane of human skeletal muscle fibers and that atorvastatin and rosuvastatin are substrates of these transporters when assessed using a heterologous expression system. In an in vitro model of differentiated, primary human skeletal muscle myoblast cells, we demonstrate basal membrane expression and drug efflux activity of MRP1, which contributes to reducing intracellular statin accumulation. Furthermore, we show that expression of human OATP2B1 in human skeletal muscle myoblast cells by adenoviral vectors increases intracellular accumulation and toxicity of statins and such effects were abrogated when cells overexpressed MRP1. These results identify key membrane transporters as modulators of skeletal muscle statin exposure and toxicity.

Enhanced cellular transport and drug targeting using dendritic nanostructures

Science.gov (United States)

Kannan, R. M.; Kolhe, Parag; Kannan, Sujatha; Lieh-Lai, Mary

2003-03-01

Dendrimers and hyperbranched polymers possess highly branched architectures, with a large number of controllable, tailorable, peripheral' functionalities. Since the surface chemistry of these materials can be modified with relative ease, these materials have tremendous potential in targeted drug delivery. The large density of end groups can also be tailored to create enhanced affinity to targeted cells, and can also encapsulate drugs and deliver them in a controlled manner. We are developing tailor-modified dendritic systems for drug delivery. Synthesis, drug/ligand conjugation, in vitro cellular and in vivo drug delivery, and the targeting efficiency to the cell are being studied systematically using a wide variety of experimental tools. Results on PAMAM dendrimers and polyol hyperbranched polymers suggest that: (1) These materials complex/encapsulate a large number of drug molecules and release them at tailorable rates; (2) The drug-dendrimer complex is transported very rapidly through a A549 lung epithelial cancel cell line, compared to free drug, perhaps by endocytosis. The ability of the drug-dendrimer-ligand complexes to target specific asthma and cancer cells is currently being explored using in vitro and in vivo animal models.

Dosing of cytotoxic chemotherapy: impact of renal function estimates on dose.

Science.gov (United States)

Dooley, M J; Poole, S G; Rischin, D

2013-11-01

Oncology clinicians are now routinely provided with an estimated glomerular filtration rate on pathology reports whenever serum creatinine is requested. The utility of using this for the dose determination of renally excreted drugs compared with other existing methods is needed to inform practice. Renal function was determined by [Tc(99m)]DTPA clearance in adult patients presenting for chemotherapy. Renal function was calculated using the 4-variable Modification of Diet in Renal Disease (4v-MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Cockcroft and Gault (CG), Wright and Martin formulae. Doses for renal excreted cytotoxic drugs, including carboplatin, were calculated. The concordance of the renal function estimates according to the CKD classification with measured Tc(99m)DPTA clearance in 455 adults (median age 64.0 years: range 17-87 years) for the 4v-MDRD, CKD-EPI, CG, Martin and Wright formulae was 47.7%, 56.3%, 46.2%, 56.5% and 60.2%, respectively. Concordance for chemotherapy dose for these formulae was 89.0%, 89.5%, 85.1%, 89.9% and 89.9%, respectively. Concordance for carboplatin dose specifically was 66.4%, 71.4%, 64.0%, 73.8% and 73.2%. All bedside formulae provide similar levels of concordance in dosage selection for the renal excreted chemotherapy drugs when compared with the use of a direct measure of renal function.

75 FR 26183 - Procedures for Transportation Workplace Drug and Alcohol Testing Programs

Science.gov (United States)

2010-05-11

... 2105-AE01 Procedures for Transportation Workplace Drug and Alcohol Testing Programs AGENCY: Office of...: For program issues, Bohdan Baczara, Office of Drug and Alcohol Policy and Compliance, 1200 New Jersey... of Federal Regulations, as follows: [[Page 26184

Albumin-based drug delivery: harnessing nature to cure disease.

Science.gov (United States)

Larsen, Maja Thim; Kuhlmann, Matthias; Hvam, Michael Lykke; Howard, Kenneth A

2016-01-01

The effectiveness of a drug is dependent on accumulation at the site of action at therapeutic levels, however, challenges such as rapid renal clearance, degradation or non-specific accumulation requires drug delivery enabling technologies. Albumin is a natural transport protein with multiple ligand binding sites, cellular receptor engagement, and a long circulatory half-life due to interaction with the recycling neonatal Fc receptor. Exploitation of these properties promotes albumin as an attractive candidate for half-life extension and targeted intracellular delivery of drugs attached by covalent conjugation, genetic fusions, association or ligand-mediated association. This review will give an overview of albumin-based products with focus on the natural biological properties and molecular interactions that can be harnessed for the design of a next-generation drug delivery platform.

Several issues regarding evaluation of renal injury and renal insufficiency in patients with liver disease

Directory of Open Access Journals (Sweden)

HAO Kunyan

2016-07-01

Full Text Available In patients with liver disease such as viral hepatitis and liver cirrhosis, renal injury and renal insufficiency can be generally classified as acute kidney injury (AKI, chronic kidney disease, and acute-on-chronic nephropathy. AKI can be classified as stage 1 (risk stage, stage 2 (injury stage, and stage 3 (failure stage. Traditionally hepatorenal syndrome is classified as types Ⅰ and Ⅱ, and in recent years, type Ⅲ hepatorenal syndrome with organic renal injury has been proposed. Hepatorenal disorder(HRD is used to describe any renal disease which occurs in patients with liver cirrhosis. At present, sensitive and accurate biochemical parameters used to evaluate renal function in patients with liver disease in clinical practice include estimated glomerular filtration rate, increase in serum creatinine within unit time, and serum cystatin C level, and urinary microalbumin level also plays an important role in the early diagnosis of nephropathy. Causes of liver disease, severity, complications including infection, nutritional status, therapeutic drugs, and underlying nephropathy may be associated with renal injury and renal insufficiency in patients with liver disease and should be differentiated.

Essentials of equine renal and urinary tract physiology.

Science.gov (United States)

Toribio, Ramiro E

2007-12-01

Knowledge of urinary tract anatomy and the numerous functions of the kidney in regulating fluids, electrolytes, acid-base balance, and waste products improves the ability of the clinician to diagnose, treat, and make appropriate recommendations for the management of the horse with renal disease. Several conditions can directly or indirectly affect renal function on a temporary or permanent basis. Endogenous and exogenous compounds (eg, drugs, toxins, hemoglobin) alone or in combination with inappropriate renal blood flow can promote or exacerbate renal disease.

Purinergic Signalling in Inflammatory Renal Disease

Directory of Open Access Journals (Sweden)

Nishkantha eArulkumaran

2013-07-01

Full Text Available Extracellular purines have a role in renal physiology and adaption to inflammation. However, inflammatory renal disease may be mediated by extracellular purines, resulting in renal injury. The role of purinergic signalling is dependent on the concentrations of extracellular purines. Low basal levels of purines are important in normal homeostasis and growth. Concentrations of extracellular purines are significantly elevated during inflammation and mediate either an adaptive role or propagate local inflammation. Adenosine signalling mediates alterations in regional renal blood flow by regulation of the renal microcirculation, tubulo-glomerular feedback, and tubular transport of sodium and water. Increased extracellular ATP and renal P2 receptor-mediated inflammation are associated with various renal diseases, including hypertension, diabetic nephropathy, and glomerulonephritis. Experimental data suggests P2 receptor deficiency or receptor antagonism is associated with amelioration of antibody-mediated nephritis, suggesting a pathogenic (rather than adaptive role of purinergic signalling. We discuss the role of extracellular nucleotides in adaptation to ischaemic renal injury and in the pathogenesis of inflammatory renal disease.

Ammonia transport in the kidney by Rhesus glycoproteins

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Verlander, Jill W.

2014-01-01

Renal ammonia metabolism is a fundamental element of acid-base homeostasis, comprising a major component of both basal and physiologically altered renal net acid excretion. Over the past several years, a fundamental change in our understanding of the mechanisms of renal epithelial cell ammonia transport has occurred, replacing the previous model which was based upon diffusion equilibrium for NH3 and trapping of NH4+ with a new model in which specific and regulated transport of both NH3 and NH4+ across renal epithelial cell membranes via specific membrane proteins is required for normal ammonia metabolism. A major advance has been the recognition that members of a recently recognized transporter family, the Rhesus glycoprotein family, mediate critical roles in renal and extrarenal ammonia transport. The erythroid-specific Rhesus glycoprotein, Rh A Glycoprotein (Rhag), was the first Rhesus glycoprotein recognized as an ammonia-specific transporter. Subsequently, the nonerythroid Rh glycoproteins, Rh B Glycoprotein (Rhbg) and Rh C Glycoprotein (Rhcg), were cloned and identified as ammonia transporters. They are expressed in specific cell populations and membrane domains in distal renal epithelial cells, where they facilitate ammonia secretion. In this review, we discuss the distribution of Rhbg and Rhcg in the kidney, the regulation of their expression and activity in physiological disturbances, the effects of genetic deletion on renal ammonia metabolism, and the molecular mechanisms of Rh glycoprotein-mediated ammonia transport. PMID:24647713

High phenobarbital clearance during continuous renal replacement therapy: a case report and pharmacokinetic analysis.

Science.gov (United States)

Rosenborg, Staffan; Saraste, Lars; Wide, Katarina

2014-08-01

Phenobarbital is an old antiepileptic drug used in severe epilepsy. Despite this, little is written about the need for dose adjustments in renal replacement therapy. Most sources recommend a moderately increased dose guided by therapeutic drug monitoring.A 14 year old boy with nonketotic hyperglycinemia, a rare inborn error of metabolism, characterized by high levels of glycine, epilepsy, spasticity, and cognitive impairment, was admitted to the emergency department with respiratory failure after a few days of fever and cough. The boy was unconscious at admittance and had acute renal and hepatic failure.Due to the acute respiratory infection, hypoxic hepatic and renal failure occurred and the patient had a status epilepticus.The patient was intubated and mechanically ventilated. Continuous renal replacement therapy was initiated. Despite increased phenobarbital doses, therapeutic levels were not reached until the dose was increased to 500 mg twice daily. Therapeutic drug monitoring was performed in plasma and dialysate. Calculations revealed that phenobarbital was almost freely dialyzed.Correct dosing of drugs in patients on renal replacement therapy may need a multidisciplinary approach and guidance by therapeutic drug monitoring.

Effect of indomethacin and salt depletion on renal proton MR imaging

International Nuclear Information System (INIS)

Heyman, S.N.; Mammen, M.

1991-01-01

Blockade of the synthesis of vasodilating prostaglandins with non-steroidal anti-inflammatory drugs (NSAID) renders the renal medulla susceptible to hypoxic injury with reduced renal function, especially in clinical conditions characterized by volume depletion. Alterations in renal hemodynamics and urine production may effect renal MR imaging under these circumstances. We injected salt-depleted and control rats undergoing proton MR imaging with indomethacin 10 mg/kg. Indomethacin abolished the cortico-medullary T2-gradient and markedly diminished the overall renal signal in salt-depleted rats only. These changes, which progressed over a period of 40 min after indomethacin was injected, probably result from renal oligemia and decreased urine production, with an associated decrease in T2-values. We suggest that a history of consumption of non-steroidal anti-inflammatory drugs should be obtained and taken into account in the evaluation of renal proton MR imaging, especially in the presence of salt and volume depletion. (orig.)

Perinatal Na+ Overload Programs Raised Renal Proximal Na+ Transport and Enalapril-Sensitive Alterations of Ang II Signaling Pathways during Adulthood

Science.gov (United States)

Cabral, Edjair V.; Vieira-Filho, Leucio D.; Silva, Paulo A.; Nascimento, Williams S.; Aires, Regina S.; Oliveira, Fabiana S. T.; Luzardo, Ricardo; Vieyra, Adalberto; Paixão, Ana D. O.

2012-01-01

Background High Na+ intake is a reality in nowadays and is frequently accompanied by renal and cardiovascular alterations. In this study, renal mechanisms underlying perinatal Na+ overload-programmed alterations in Na+ transporters and the renin/angiotensin system (RAS) were investigated, together with effects of short-term treatment with enalapril in terms of reprogramming molecular alterations in kidney. Methodology/Principal Findings Male adult Wistar rats were obtained from dams maintained throughout pregnancy and lactation on a standard diet and drinking water (control) or 0.17 M NaCl (saline group). Enalapril (100 mg/l), an angiotensin converting enzyme inhibitor, was administered for three weeks after weaning. Ninety day old offspring from dams that drank saline presented with proximal tubules exhibiting increased (Na++K+)ATPase expression and activity. Ouabain-insensitive Na+-ATPase activity remained unchanged but its response to angiotensin II (Ang II) was lost. PKC, PKA, renal thiobarbituric acid reactive substances (TBARS), macrophage infiltration and collagen deposition markedly increased, and AT2 receptor expression decreased while AT1 expression was unaltered. Early treatment with enalapril reduced expression and activity of (Na++K+)ATPase, partially recovered the response of Na+-ATPase to Ang II, and reduced PKC and PKA activities independently of whether offspring were exposed to high perinatal Na+ or not. In addition, treatment with enalapril per se reduced AT2 receptor expression, and increased TBARS, macrophage infiltration and collagen deposition. The perinatally Na+-overloaded offspring presented high numbers of Ang II-positive cortical cells, and significantly lower circulating Ang I, indicating that programming/reprogramming impacted systemic and local RAS. Conclusions/Significance Maternal Na+ overload programmed alterations in renal Na+ transporters and in its regulation, as well as severe structural lesions in adult offspring. Enalapril

Glycolysis inhibition inactivates ABC transporters to restore drug sensitivity in malignant cells.

Directory of Open Access Journals (Sweden)

Ayako Nakano

Full Text Available Cancer cells eventually acquire drug resistance largely via the aberrant expression of ATP-binding cassette (ABC transporters, ATP-dependent efflux pumps. Because cancer cells produce ATP mostly through glycolysis, in the present study we explored the effects of inhibiting glycolysis on the ABC transporter function and drug sensitivity of malignant cells. Inhibition of glycolysis by 3-bromopyruvate (3BrPA suppressed ATP production in malignant cells, and restored the retention of daunorubicin or mitoxantrone in ABC transporter-expressing, RPMI8226 (ABCG2, KG-1 (ABCB1 and HepG2 cells (ABCB1 and ABCG2. Interestingly, although side population (SP cells isolated from RPMI8226 cells exhibited higher levels of glycolysis with an increased expression of genes involved in the glycolytic pathway, 3BrPA abolished Hoechst 33342 exclusion in SP cells. 3BrPA also disrupted clonogenic capacity in malignant cell lines including RPMI8226, KG-1, and HepG2. Furthermore, 3BrPA restored cytotoxic effects of daunorubicin and doxorubicin on KG-1 and RPMI8226 cells, and markedly suppressed subcutaneous tumor growth in combination with doxorubicin in RPMI8226-implanted mice. These results collectively suggest that the inhibition of glycolysis is able to overcome drug resistance in ABC transporter-expressing malignant cells through the inactivation of ABC transporters and impairment of SP cells with enhanced glycolysis as well as clonogenic cells.

Transepithelial transport and toxicity of PAMAM dendrimers: implications for oral drug delivery.

Science.gov (United States)

Sadekar, S; Ghandehari, H

2012-05-01

This article summarizes efforts to evaluate poly(amido amine) (PAMAM) dendrimers as carriers for oral drug delivery. Specifically, the effect of PAMAM generation, surface charge and surface modification on toxicity, cellular uptake and transepithelial transport is discussed. Studies on Caco-2 monolayers, as models of intestinal epithelial barrier, show that by engineering surface chemistry of PAMAM dendrimers, it is possible to minimize toxicity while maximizing transepithelial transport. It has been demonstrated that PAMAM dendrimers are transported by a combination of paracellular and transcellular routes. Depending on surface chemistry, PAMAM dendrimers can open the tight junctions of epithelial barriers. This tight junction opening is in part mediated by internalization of the dendrimers. Transcellular transport of PAMAM dendrimers is mediated by a variety of endocytic mechanisms. Attachment or complexation of cytotoxic agents to PAMAM dendrimers enhances the transport of such drugs across epithelial barriers. A remaining challenge is the design and development of linker chemistries that are stable in the gastrointestinal tract (GIT) and the blood stream, but amenable to cleavage at the target site of action. Recent efforts have focused on the use of PAMAM dendrimers as penetration enhancers. Detailed in vivo oral bioavailability of PAMAM dendrimer-drug conjugates, as a function of physicochemical properties will further need to be assessed. Copyright © 2011 Elsevier B.V. All rights reserved.

Drug membrane interaction and the importance for drug transport, distribution, accumulation, efficacy and resistance.

Science.gov (United States)

Seydel, J K; Coats, E A; Cordes, H P; Wiese, M

1994-10-01

Some aspects of drug membrane interaction and its influence on drug transport, accumulation, efficacy and resistance have been discussed. The interactions manifest themselves macroscopically in changes in the physical and thermodynamic properties of "pure membranes" or bilayers. As various amounts of foreign molecules enter the membrane, in particular the main gel to liquid crystalline phase transition can be dramatically changed. This may change permeability, cell-fusion, cell resistance and may also lead to changes in conformation of the embedded receptor proteins. Furthermore, specific interactions with lipids may lead to drug accumulation in membranes and thus to much larger concentrations at the active site than present in the surrounding water phase. The lipid environment may also lead to changes in the preferred conformation of drug molecules. These events are directly related to drug efficacy. The determination of essential molecular criteria for the interaction could be used to design new and more selective therapeutics. This excursion in some aspects of drug membrane interaction underlines the importance of lipids and their interaction with drug molecules for our understanding of drug action, but this is not really a new thought but has been formulated in 1884 by THUDICUM: "Phospholipids are the centre, life and chemical soul of all bioplasm whatsoever, that of plants as well as of animals".

Polypharmacy and Renal Failure in Nursing Home Residents: Results of the Inappropriate Medication in Patients with Renal Insufficiency in Nursing Homes (IMREN) Study.

Science.gov (United States)

Dörks, Michael; Herget-Rosenthal, Stefan; Schmiemann, Guido; Hoffmann, Falk

2016-01-01

Polypharmacy has become an emerging public health issue in recent years, since use of multiple medications or polypharmacy is beneficial for many conditions, but may also have negative effects like adverse drug reactions. The risk further increases in patients with chronic renal failure, a comorbidity very frequent in nursing home residents. Since more than 50% of all drugs were renally excreted, dose adjustments in patients with renal failure are required. To assess polypharmacy in German nursing homes, in particular in residents with renal failure. Multi-center cross-sectional study in 21 nursing homes in Bremen and Lower Saxony/Germany. Baseline data were analysed using descriptive statistics. Multivariable logistic regression model and 95% confidence intervals were used to study the association of renal failure and polypharmacy. Of all 852 residents, the analysis comprised those 685 with at least one serum creatinine value so that the estimated creatinine clearance could be calculated. Of those, 436 (63.6%) had a severe or moderate renal failure, defined as estimated creatinine clearance renal failure (estimated creatinine clearance renal failure are common in German nursing home residents and an association of both could be found. Further studies are needed to assess the appropriateness of polypharmacy in these patients.

Quantitative Rationalization of Gemfibrozil Drug Interactions: Consideration of Transporters-Enzyme Interplay and the Role of Circulating Metabolite Gemfibrozil 1-O-β-Glucuronide.

Science.gov (United States)

Varma, Manthena V S; Lin, Jian; Bi, Yi-an; Kimoto, Emi; Rodrigues, A David

2015-07-01

Gemfibrozil has been suggested as a sensitive cytochrome P450 2C8 (CYP2C8) inhibitor for clinical investigation by the U.S. Food and Drug Administration and the European Medicines Agency. However, gemfibrozil drug-drug interactions (DDIs) are complex; its major circulating metabolite, gemfibrozil 1-O-β-glucuronide (Gem-Glu), exhibits time-dependent inhibition of CYP2C8, and both parent and metabolite also behave as moderate inhibitors of organic anion transporting polypeptide 1B1 (OATP1B1) in vitro. Additionally, parent and metabolite also inhibit renal transport mediated by OAT3. Here, in vitro inhibition data for gemfibrozil and Gem-Glu were used to assess their impact on the pharmacokinetics of several victim drugs (including rosiglitazone, pioglitazone, cerivastatin, and repaglinide) by employing both static mechanistic and dynamic physiologically based pharmacokinetic (PBPK) models. Of the 48 cases evaluated using the static models, about 75% and 98% of the DDIs were predicted within 1.5- and 2-fold of the observed values, respectively, when incorporating the interaction potential of both gemfibrozil and its 1-O-β-glucuronide. Moreover, the PBPK model was able to recover the plasma profiles of rosiglitazone, pioglitazone, cerivastatin, and repaglinide under control and gemfibrozil treatment conditions. Analyses suggest that Gem-Glu is the major contributor to the DDIs, and its exposure needed to bring about complete inactivation of CYP2C8 is only a fraction of that achieved in the clinic after a therapeutic gemfibrozil dose. Overall, the complex interactions of gemfibrozil can be quantitatively rationalized, and the learnings from this analysis can be applied in support of future predictions of gemfibrozil DDIs. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Interventional treatment of transplanted renal artery stenosis

International Nuclear Information System (INIS)

Zhou Haihong; Chen Weiguo; Lu Wei; Chen Yong; Yan Xinmin; Zhou Jianyong; Li Yanhao

2002-01-01

Purpose: To evaluate the clinical application of percutaneous transluminal renal artery angioplasty (PTRA) in the treatment of transplanted renal artery stenosis. Methods: Nine patients with transplanted renal artery stenosis were treated by PTRA with balloon catheter through the f amoral artery. Metal stent was placed in 3 patients out of 9. Results: Technical success was obtained in all procedures. In 7 patients normal blood pressure was restored and serum creatinine remarkably decreased. But anti-hypertension drugs were still needed in rest 2 patients. Conclusion: PTRA and stent implantation are useful and valuable method in the treatment of transplanted renal artery stenosis

Interplay of drug metabolism and transport: a real phenomenon or an artifact of the site of measurement?

Science.gov (United States)

Endres, Christopher J; Endres, Michael G; Unadkat, Jashvant D

2009-01-01

The interdependence of both transport and metabolism on the disposition of drugs has recently gained heightened attention in the literature, and has been termed the "interplay of transport and metabolism". Such "interplay" is observed when inhibition of biliary clearance of a drug results in an "apparent" increase in the metabolic clearance of the drug or vice versa. In this manuscript, we derived and explored through simulations a physiological-based pharmacokinetic model that integrates both transport and metabolism and explains the "apparent" dependence of hepatic clearance on both these processes. In addition, we show that the phenomenon of hepatic "transport-metabolism interplay" is a result of using the plasma concentration as a point of reference when calculating metabolic or biliary clearance, and this interplay is maximal when the drug is actively transported into the hepatocytes (i.e., hepatocyte sinusoidal influx clearance is greater than the sinusoidal efflux clearance). When the hepatic drug concentration is used as a reference point to calculate metabolic or biliary clearance, this interplay ceases to exist. A mechanistic understanding of this interplay phenomenon can be used to explain the somewhat paradoxical results that may be observed in drug-drug interaction studies when a drug is cleared by both metabolism and biliary excretion. That is, when one of these two pathways is inhibited, the other pathway appears to be induced or activated. This interplay results in an increase in hepatic drug concentrations and therefore has implications for the hepatic efficacy and toxicity of a drug.

The dark side of the kidney in cardio-renal syndrome: renal venous hypertension and congestive kidney failure.

Science.gov (United States)

Di Nicolò, Pierpaolo

2018-03-01

Renal involvement in some forms of acute or chronic diseases, such as heart failure or sepsis, presents with a complex pathophysiological basis that is not always clearly distinguishable. In these clinical settings, kidney failure is traditionally and almost exclusively attributed to renal hypoperfusion and it is commonly accepted that causal elements are pre-renal, such as a reduction in the ejection fraction or absolute or relative hypovolemia acting directly on oxygen transport mechanisms and renal autoregulation systems, causing a reduction of glomerular filtration rate. Nevertheless, the concept emerging from accumulating clinical and experimental evidence is that in complex clinical pictures, kidney failure is strongly linked to the hemodynamic alterations occurring in the renal venous micro and macrocirculation. Accordingly, the transmission of the increased venous pressure to the renal venous compartment and the consequent increasing renal afterload has a pivotal role in determining and sustaining the kidney damage. The aim of this review was to clarify the physiopathological aspects of the link between worsening renal function and renal venous hypertension, analyzing the prognostic and therapeutic implications of the so-called congestive kidney failure in cardio-renal syndrome and in other clinical contexts of its possible onset.

21 CFR 876.4650 - Water jet renal stone dislodger system.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Water jet renal stone dislodger system. 876.4650... (CONTINUED) MEDICAL DEVICES GASTROENTEROLOGY-UROLOGY DEVICES Surgical Devices § 876.4650 Water jet renal stone dislodger system. (a) Identification. A water jet renal stone dislodger system is a device used to...

Mathematical modeling of coupled drug and drug-encapsulated nanoparticle transport in patient-specific coronary artery walls

KAUST Repository

Hossain, Shaolie S.

2011-08-20

The majority of heart attacks occur when there is a sudden rupture of atherosclerotic plaque, exposing prothrombotic emboli to coronary blood flow, forming clots that can cause blockages of the arterial lumen. Diseased arteries can be treated with drugs delivered locally to vulnerable plaques. The objective of this work was to develop a computational tool-set to support the design and analysis of a catheter-based nanoparticulate drug delivery system to treat vulnerable plaques and diffuse atherosclerosis. A threedimensional mathematical model of coupled mass transport of drug and drug-encapsulated nanoparticles was developed and solved numerically utilizing isogeometric finite element analysis. Simulations were run on a patient-specific multilayered coronary artery wall segment with a vulnerable plaque and the effect of artery and plaque inhomogeneity was analyzed. The method captured trends observed in local drug delivery and demonstrated potential for optimizing drug design parameters, including delivery location, nanoparticle surface properties, and drug release rate. © Springer-Verlag 2011.

Sandwich-Cultured Hepatocytes for Mechanistic Understanding of Hepatic Disposition of Parent Drugs and Metabolites by Transporter-Enzyme Interplay.

Science.gov (United States)

Matsunaga, Norikazu; Fukuchi, Yukina; Imawaka, Haruo; Tamai, Ikumi

2018-05-01

Functional interplay between transporters and drug-metabolizing enzymes is currently one of the hottest topics in the field of drug metabolism and pharmacokinetics. Uptake transporter-enzyme interplay is important to determine intrinsic hepatic clearance based on the extended clearance concept. Enzyme and efflux transporter interplay, which includes both sinusoidal (basolateral) and canalicular efflux transporters, determines the fate of metabolites formed in the liver. As sandwich-cultured hepatocytes (SCHs) maintain metabolic activities and form a canalicular network, the whole interplay between uptake and efflux transporters and drug-metabolizing enzymes can be investigated simultaneously. In this article, we review the utility and applicability of SCHs for mechanistic understanding of hepatic disposition of both parent drugs and metabolites. In addition, the utility of SCHs for mimicking species-specific disposition of parent drugs and metabolites in vivo is described. We also review application of SCHs for clinically relevant prediction of drug-drug interactions caused by drugs and metabolites. The usefulness of mathematical modeling of hepatic disposition of parent drugs and metabolites in SCHs is described to allow a quantitative understanding of an event in vitro and to develop a more advanced model to predict in vivo disposition. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Convective transport of highly plasma protein bound drugs facilitates direct penetration into deep tissues after topical application

Science.gov (United States)

Dancik, Yuri; Anissimov, Yuri G; Jepps, Owen G; Roberts, Michael S

2012-01-01

AIMS To relate the varying dermal, subcutaneous and muscle microdialysate concentrations found in man after topical application to the nature of the drug applied and to the underlying physiology. METHODS We developed a physiologically based pharmacokinetic model in which transport to deeper tissues was determined by tissue diffusion, blood, lymphatic and intersitial flow transport and drug properties. The model was applied to interpret published human microdialysis data, estimated in vitro dermal diffusion and protein binding affinity of drugs that have been previously applied topically in vivo and measured in deep cutaneous tissues over time. RESULTS Deeper tissue microdialysis concentrations for various drugs in vivo vary widely. Here, we show that carriage by the blood to the deeper tissues below topical application sites facilitates the transport of highly plasma protein bound drugs that penetrate the skin, leading to rapid and significant concentrations in those tissues. Hence, the fractional concentration for the highly plasma protein bound diclofenac in deeper tissues is 0.79 times that in a probe 4.5 mm below a superficial probe whereas the corresponding fractional concentration for the poorly protein bound nicotine is 0.02. Their corresponding estimated in vivo lag times for appearance of the drugs in the deeper probes were 1.1 min for diclofenac and 30 min for nicotine. CONCLUSIONS Poorly plasma protein bound drugs are mainly transported to deeper tissues after topical application by tissue diffusion whereas the transport of highly plasma protein bound drugs is additionally facilitated by convective blood, lymphatic and interstitial transport to deep tissues. PMID:21999217

Renal pathophysiologic role of cortical tubular inclusion bodies.

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Radi, Zaher A; Stewart, Zachary S; Grzemski, Felicity A; Bobrowski, Walter F

2013-01-01

Renal tubular inclusion bodies are rarely associated with drug administration. The authors describe the finding of renal cortical tubular intranuclear and intracytoplasmic inclusion bodies associated with the oral administration of a norepinephrine/serotonin reuptake inhibitor (NSRI) test article in Sprague-Dawley (SD) rats. Rats were given an NSRI daily for 4 weeks, and kidney histopathologic, ultrastructural pathology, and immunohistochemical examinations were performed. Round eosinophilic intranuclear inclusion bodies were observed histologically in the tubular epithelial cells of the renal cortex in male and female SD rats given the NSRI compound. No evidence of degeneration or necrosis was noted in the inclusion-containing renal cells. By ultrastructural pathology, inclusion bodies consisted of finely granular, amorphous, and uniformly stained nonmembrane-bound material. By immunohistochemistry, inclusion bodies stained positive for d-amino acid oxidase (DAO) protein. In addition, similar inclusion bodies were noted in the cytoplasmic tubular epithelial compartment by ultrastructural and immunohistochemical examination.  This is the first description of these renal inclusion bodies after an NSRI test article administration in SD rats. Such drug-induced renal inclusion bodies are rat-specific, do not represent an expression of nephrotoxicity, represent altered metabolism of d-amino acids, and are not relevant to human safety risk assessment.

Novel Approaches for the Treatment of the Patient with Resistant Hypertension: Renal Nerve Ablation

Science.gov (United States)

Gulati, Vinay; White, William B.

2013-01-01

Sympathetic innervation of the kidneys plays a major role in the pathogenesis of hypertension through modulation of renin secretion, glomerular filtration rate and renal absorption of sodium. Targeted interventions for renal nerve ablation are being developed for treatment of drug resistant hypertension in the USA and rest of the world. Early studies with the use of radiofrequency based renal denervation systems have shown encouraging results with significant reduction of blood pressure in patients inadequately controlled despite nearly maximal drug therapy regimens. Thus far, the renal denervation procedure has been associated with minimal side effects. Long term efficacy and safety beyond 3 years needs to be determined for renal nerve ablation. This review focuses on the physiology of the renal sympathetic system, the rationale for renal nerve ablation and current evidence in support of the available therapeutic renal denervation systems. PMID:24244757

Ex vivo preparations of human tissue for drug metabolism, toxicity and transport

NARCIS (Netherlands)

Groothuis, Genoveva

2012-01-01

Before new drugs are allowed on the market, their safety and metabolite profile should be extensively tested, as often reactive metabolites are the ultimate toxicant. The exposure of the target cell to the drug and its metabolites is determined by the expression levels of the transporters and the

Prolonged Intermittent Renal Replacement Therapy.

Science.gov (United States)

Edrees, Fahad; Li, Tingting; Vijayan, Anitha

2016-05-01

Prolonged intermittent renal replacement therapy (PIRRT) is becoming an increasingly popular alternative to continuous renal replacement therapy in critically ill patients with acute kidney injury. There are significant practice variations in the provision of PIRRT across institutions, with respect to prescription, technology, and delivery of therapy. Clinical trials have generally demonstrated that PIRRT is non-inferior to continuous renal replacement therapy regarding patient outcomes. PIRRT offers cost-effective renal replacement therapy along with other advantages such as early patient mobilization and decreased nursing time. However, due to lack of standardization of the procedure, PIRRT still poses significant challenges, especially pertaining to appropriate drug dosing. Future guidelines and clinical trials should work toward developing consensus definitions for PIRRT and ensure optimal delivery of therapy. Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Renal sympathetic denervation in hypertension.

Science.gov (United States)

Doumas, Michael; Faselis, Charles; Papademetriou, Vasilios

2011-11-01

Despite the abundance of antihypertensive drugs, resistant hypertension remains a major clinical problem. Recent technological advances render interventional management of resistant hypertension one of the hottest topics in the hypertension field. The aim of this review is to present the pathophysiologic background and the mechanisms mediating blood pressure reduction after renal sympathetic denervation, to analyze recent findings with this fascinating approach and to critically suggest future research directions. Catheter-based, ablation-induced renal sympathetic denervation was initially studied in 45 patients with resistant hypertension in a proof-of-concept study. Impressive blood pressure reductions of about 30/15  mmHg were achieved at 6 months, without serious complications. A second, controlled, randomized (but not blinded) study confirmed the results, verifying the efficacy and safety of the procedure. A recent report revealed the 2-year durability of blood pressure reduction. Data published so far indicate that ablation-induced renal denervation is a feasible, effective, and well tolerated interventional approach for the management of resistant hypertension. The groundbreaking studies of renal denervation in drug-resistant hypertension pave the way for further research in other disease conditions in which sympathetic overactivity seems to play a critical role. This initial wave of enthusiasm needs to be followed by rigorous investigation, for the proper identification of the potential and the limitations, indications, and contraindications of this approach.

75 FR 13009 - Procedures for Transportation Workplace Drug and Alcohol Testing Programs

Science.gov (United States)

2010-03-18

... DEPARTMENT OF TRANSPORTATION Office of the Secretary 49 CFR Part 40 [Docket DOT-OST-2008-0088] RIN OST 2105-AD84 Procedures for Transportation Workplace Drug and Alcohol Testing Programs Correction In rule document 2010-3731 beginning on page 8528 in the issue of Thursday, February 25, 2010, make the...

Eligibility for renal denervation

DEFF Research Database (Denmark)

Persu, Alexandre; Jin, Yu; Baelen, Marie

2014-01-01

-resistant hypertension (ENCOReD). The analysis included 731 patients. Age averaged 61.6 years, office blood pressure at screening was 177/96 mm Hg, and the number of blood pressure-lowering drugs taken was 4.1. Specialists referred 75.6% of patients. The proportion of patients eligible for renal denervation according...... undetected secondary causes of hypertension (11.1%). In conclusion, after careful screening and treatment adjustment at hypertension expert centers, only ≈40% of patients referred for renal denervation, mostly by specialists, were eligible for the procedure. The most frequent cause of ineligibility...... (approximately half of cases) was blood pressure normalization after treatment adjustment by a hypertension specialist. Our findings highlight that hypertension centers with a record in clinical experience and research should remain the gatekeepers before renal denervation is considered....

The renal urate transporter SLC17A1 locus: confirmation of association with gout.

Science.gov (United States)

Hollis-Moffatt, Jade E; Phipps-Green, Amanda J; Chapman, Brett; Jones, Gregory T; van Rij, Andre; Gow, Peter J; Harrison, Andrew A; Highton, John; Jones, Peter B; Montgomery, Grant W; Stamp, Lisa K; Dalbeth, Nicola; Merriman, Tony R

2012-04-27

Two major gout-causing genes have been identified, the urate transport genes SLC2A9 and ABCG2. Variation within the SLC17A1 locus, which encodes sodium-dependent phosphate transporter 1, a renal transporter of uric acid, has also been associated with serum urate concentration. However, evidence for association with gout is equivocal. We investigated the association of the SLC17A1 locus with gout in New Zealand sample sets. Five variants (rs1165196, rs1183201, rs9358890, rs3799344, rs12664474) were genotyped across a New Zealand sample set totaling 971 cases and 1,742 controls. Cases were ascertained according to American Rheumatism Association criteria. Two population groups were studied: Caucasian and Polynesian. At rs1183201 (SLC17A1), evidence for association with gout was observed in both the Caucasian (odds ratio (OR) = 0.67, P = 3.0 × 10-6) and Polynesian (OR = 0.74, P = 3.0 × 10-3) groups. Meta-analysis confirmed association of rs1183201 with gout at a genome-wide level of significance (OR = 0.70, P = 3.0 × 10-8). Haplotype analysis suggested the presence of a common protective haplotype. We confirm the SLC17A1 locus as the third associated with gout at a genome-wide level of significance.

Quantitative analysis of elevation of serum creatinine via renal transporter inhibition by trimethoprim in healthy subjects using physiologically-based pharmacokinetic model.

Science.gov (United States)

Nakada, Tomohisa; Kudo, Toshiyuki; Kume, Toshiyuki; Kusuhara, Hiroyuki; Ito, Kiyomi

2018-02-01

Serum creatinine (SCr) levels rise during trimethoprim therapy for infectious diseases. This study aimed to investigate whether the elevation of SCr can be quantitatively explained using a physiologically-based pharmacokinetic (PBPK) model incorporating inhibition by trimethoprim on tubular secretion of creatinine via renal transporters such as organic cation transporter 2 (OCT2), OCT3, multidrug and toxin extrusion protein 1 (MATE1), and MATE2-K. Firstly, pharmacokinetic parameters in the PBPK model of trimethoprim were determined to reproduce the blood concentration profile after a single intravenous and oral administration of trimethoprim in healthy subjects. The model was verified with datasets of both cumulative urinary excretions after a single administration and the blood concentration profile after repeated oral administration. The pharmacokinetic model of creatinine consisted of the creatinine synthesis rate, distribution volume, and creatinine clearance (CL cre ), including tubular secretion via each transporter. When combining the models for trimethoprim and creatinine, the predicted increments in SCr from baseline were 29.0%, 39.5%, and 25.8% at trimethoprim dosages of 5 mg/kg (b.i.d.), 5 mg/kg (q.i.d.), and 200 mg (b.i.d.), respectively, which were comparable with the observed values. The present model analysis enabled us to quantitatively explain increments in SCr during trimethoprim treatment by its inhibition of renal transporters. Copyright © 2017 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

Treatment of Renal Cell Carcinoma with 2-Stage Total en bloc Spondylectomy after Marked Response to Molecular Target Drugs

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Yasuhiro Inoue

2013-01-01

Full Text Available Metastatic renal cell carcinoma of the bone occurs at a high rate, and the prognosis is poor. In general, total en bloc spondylectomy is considered when there is only one vertebral metastasis and the primary disease is treated. However, palliative surgery is selected when the primary disease is not being treated or metastasis occurs to an important organ. We encountered a patient in whom lung and vertebra metastases were already present at the time of the first examination at our department and the prognosis was considered poor. However, molecular targeted therapy was markedly effective and enabled 2-stage total en bloc spondylectomy. As of one year after total en bloc spondylectomy, the condition has improved to cane gait, and surgery for lung metastasis is planned. Molecular target drugs might markedly change the current therapeutic strategy for renal cell carcinoma.

Riboflavin transport in the central nervous system. Characterization and effects of drugs.

OpenAIRE

Spector, R

1980-01-01

The relationship of riboflavin transport to the transport of other substances including drugs in rabbit choroid plexus, the anatomical locus of the blood-cerebrospinal fluid barrier, and brain cells were studied in vivo and in vitro. In vitro, the ability of rabbit choroid plexus to transport riboflavin from the medium (cerebrospinal fluid surface) through the choroid plexus epithelial cells into the extracellular and vascular spaces of the choroid plexus was documented using fluorescence mic...

Pharmacokinetic profile of nifedipine GITS in hypertensive patients with chronic renal impairment.

Science.gov (United States)

Schneider, R; Stolero, D; Griffel, L; Kobelt, R; Brendel, E; Iaina, A

1994-01-01

25 hypertensive patients with normal or impaired renal function underwent pharmacokinetic and safety studies after single and multiple dose administration of nifedipine GITS (Gastro-Intestinal Therapeutic System) 60mg tablets. Complete pharmacokinetic data were obtained from 23 of these patients. Blood pressure and heart rate changes were compatible with the known properties of the drug. Impaired renal function did not affect the maximum plasma concentrations or bioavailability of nifedipine after single or multiple dose administration of nifedipine GITS, nor was there any evidence of excessive drug accumulation in the presence of renal impairment.

Adjusted drug treatment is superior to renal sympathetic denervation in patients with true treatment-resistant hypertension.

Science.gov (United States)

Fadl Elmula, Fadl Elmula M; Hoffmann, Pavel; Larstorp, Anne C; Fossum, Eigil; Brekke, Magne; Kjeldsen, Sverre E; Gjønnæss, Eyvind; Hjørnholm, Ulla; Kjaer, Vibeke N; Rostrup, Morten; Os, Ingrid; Stenehjem, Aud; Høieggen, Aud

2014-05-01

We aimed to investigate for the first time the blood pressure (BP)-lowering effect of renal sympathetic denervation (RDN) versus clinically adjusted drug treatment in true treatment-resistant hypertension (TRH) after excluding patients with confounding poor drug adherence. Patients with apparent TRH (n=65) were referred for RDN, and those with secondary and spurious hypertension (n=26) were excluded. TRH was defined as office systolic BP (SBP) >140 mm Hg, despite maximally tolerated doses of ≥3 antihypertensive drugs including a diuretic. In addition, ambulatory daytime SBP >135 mm Hg after witnessed intake of antihypertensive drugs was required, after which 20 patients had normalized BP and were excluded. Patients with true TRH were randomized and underwent RDN (n=9) performed with Symplicity Catheter System versus clinically adjusted drug treatment (n=10). The study was stopped early for ethical reasons because RDN had uncertain BP-lowering effect. Office SBP and diastolic BP in the drug-adjusted group changed from 160±14/88±13 mm Hg (±SD) at baseline to 132±10/77±8 mm Hg at 6 months (P<0.0005 and P=0.02, SBP and diastolic BP, respectively) and in the RDN group from 156±13/91±15 to 148±7/89±8 mm Hg (P=0.42 and P=0.48, SBP and diastolic BP, respectively). SBP and diastolic BP were significantly lower in the drug-adjusted group at 6 months (P=0.002 and P=0.004, respectively), and absolute changes in SBP were larger in the drug-adjusted group (P=0.008). Ambulatory BPs changed in parallel to office BPs. Our data suggest that adjusted drug treatment has superior BP lowering effects compared with RDN in patients with true TRH. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01673516.

Effect of Sodium-Glucose Co-Transporter 2 Inhibitor, Dapagliflozin, on Renal Renin-Angiotensin System in an Animal Model of Type 2 Diabetes.

Science.gov (United States)

Shin, Seok Joon; Chung, Sungjin; Kim, Soo Jung; Lee, Eun-Mi; Yoo, Young-Hye; Kim, Ji-Won; Ahn, Yu-Bae; Kim, Eun-Sook; Moon, Sung-Dae; Kim, Myung-Jun; Ko, Seung-Hyun

2016-01-01

Renal renin-angiotensin system (RAS) activation is one of the important pathogenic mechanisms in the development of diabetic nephropathy in type 2 diabetes. The aim of this study was to investigate the effects of a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, dapagliflozin, on renal RAS in an animal model with type 2 diabetes. Dapagliflozin (1.0 mg/kg, OL-DA) or voglibose (0.6 mg/kg, OL-VO, diabetic control) (n = 10 each) was administered to Otsuka Long-Evans Tokushima Fatty (OLETF) rats for 12 weeks. We used voglibose, an alpha-glucosidase inhibitor, as a comparable counterpart to SGLT2 inhibitor because of its postprandial glucose-lowering effect without proven renoprotective effects. Control Long-Evans Tokushima Otsuka (LT) and OLETF (OL-C) rats received saline (n = 10, each). Changes in blood glucose, urine albumin, creatinine clearance, and oxidative stress were measured. Inflammatory cell infiltration, mesangial widening, and interstitial fibrosis in the kidney were evaluated by histological analysis. The effects of dapagliflozin on renal expression of the RAS components were evaluated by quantitative RT-PCR in renal tissue. After treatment, hyperglycemia and urine microalbumin levels were attenuated in both OL-DA and OL-VO rather than in the OL-C group (P renal RAS component expression, oxidative stress and interstitial fibrosis in OLETF rats. We suggest that, in addition to control of hyperglycemia, partial suppression of renal RAS with an SGLT2 inhibitor would be a promising strategy for the prevention of treatment of diabetic nephropathy.

Magnetic resonance of the renal transplantation

International Nuclear Information System (INIS)

Cauquil, P.; Hiesse, C.; Say, C.; Verdier, J.P.; Cauquil, M.; Brunet, A.M.; Galindo, R.; Tessier, J.P.

1989-01-01

Renal transplantation is the treatment of choice for renal insufficiency. Progress of surgical techniques and immuno-suppression have lead to better results. One year graft survival rate are 80% in most series. In this article, the role of imaging in renal transplantation, is defined. In surgical complications (fluid collections, obstruction, vascular insufficiency) non invasive radiology and interventionnal radiologic procedures have a great impact. Despite the perspectives of duplex and magnetic resonance, sensibility and specificity are not yet specified in medical complications: rejection, acute tubular necrosis, infection, drug toxicity. Association of these lesions is frequent and complicate analysis of results. Finally, transplant biopsy is still necessary to confirm the diagnosis [fr

Metabolism of ATP-binding cassette drug transporter inhibitors: complicating factor for multidrug resistance.

NARCIS (Netherlands)

Cnubben, N.H.; Wortelboer, H.M.; Zanden, J.J. van; Rietjens, I.M.; Bladeren, P.J. van

2005-01-01

Membrane transport proteins belonging to the ATP-binding cassette (ABC) family of transport proteins play a central role in the defence of organisms against toxic compounds, including anticancer drugs. However, for compounds that are designed to display a toxic effect, this defence system diminishes

Vildagliptin restores renal myogenic function and attenuates renal sclerosis independently of effects on blood glucose or proteinuria in Zucker Diabetic Fatty rat

NARCIS (Netherlands)

Vavrinec, Peter; Henning, Robert H.; Landheer, Sjoerd W.; Wang, Yumei; Deelman, Leo E.; van Dokkum, Richard P. E.; Buikema, Hendrik

Type 2 diabetes mellitus (T2DM) is associated with risk for chronic kidney disease (CKD), which is associated with a decrease in renal myogenic tone - part of renal autoregulatory mechanisms. Novel class of drugs used for the treatment of T2DM, dipeptidyl peptidase-4 (DPP-4) inhibitors, have

Krogh’s principle or a multiple fish model approach to phosphate balance: is there a centrally regulated intestinal-skeletal-renal axis?

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Pedro Miguel Guerreiro

2015-10-01

Full Text Available Inorganic phosphate (Pi is a crucial ion for vertebrate life. In addition to many physiological roles it is, together with calcium, the major element forming the internal skeleton and Pi balance has been considered a secondary consequence of calciotropic endocrine factors. However, contrary to calcium which can be readily obtained from even Ca-poor environments, Pi is not available in water, and fish can only obtain it via the food. Intestinal absorption drives Pi into the blood stream, but a central part of Pi balance is renal excretion and conservation. Recently, several Pi specific regulatory factors have been brought to light, and we use fish models to investigate their role and the hypothesis of a centrally controlled intestinal-skeletal-renal Pi axis. Using tissues mounted in Ussing chambers under symmetrical and asymmetrical short-circuited conditions we measure unidirectional 33Pi fluxes and test PTHrP, but also STC and FGF23 as regulatory factors, as well as specific drugs to unveil the functional transporting mechanisms. Pi absorption is modified in starved and fed sea bass, an effect dependent on Pi availability in diet, which modifies gene expression of uptake mechanisms. Phosphate secretion across flounder primary renal cell cultures is increased by PTHrP, which reduces the expression of reabsorption mechanisms such as NaPiII and evokes an increase in GFR in cannulated fish, thus resulting in net Pi excretion. A similar effect occurs in the toadfish urinary bladder, which displays moderate Pi transport that is abolished by the drug ouabain and modified by endocrines. Finally we used the shark choroid plexus (CP to show active CSF-to-blood transport with biochemical properties consistent with PiT Na+-dependent transporters. RT-PCR revealed the PiT1/2, but no NaPiII gene expression and we localized PiT2 in CP apical membranes while PiT1 occurred in vascular endothelial cells. Shark CP expresses both PTHrP and its receptor. Could

Validation of in vitro cell models used in drug metabolism and transport studies; genotyping of cytochrome P450, phase II enzymes and drug transporter polymorphisms in the human hepatoma (HepG2), ovarian carcinoma (IGROV-1) and colon carcinoma (CaCo-2, LS180) cell lines

International Nuclear Information System (INIS)

Brandon, Esther F.A.; Bosch, Tessa M.; Deenen, Maarten J.; Levink, Rianne; Wal, Everdina van der; Meerveld, Joyce B.M. van; Bijl, Monique; Beijnen, Jos H.; Schellens, Jan H.M.; Meijerman, Irma

2006-01-01

Human cell lines are often used for in vitro biotransformation and transport studies of drugs. In vivo, genetic polymorphisms have been identified in drug-metabolizing enzymes and ABC-drug transporters leading to altered enzyme activity, or a change in the inducibility of these enzymes. These genetic polymorphisms could also influence the outcome of studies using human cell lines. Therefore, the aim of our study was to pharmacogenotype four cell lines frequently used in drug metabolism and transport studies, HepG2, IGROV-1, CaCo-2 and LS180, for genetic polymorphisms in biotransformation enzymes and drug transporters. The results indicate that, despite the presence of some genetic polymorphisms, no real effects influencing the activity of metabolizing enzymes or drug transporters in the investigated cell lines are expected. However, this characterization will be an aid in the interpretation of the results of biotransformation and transport studies using these in vitro cell models

Pleiotropic effects of type 2 diabetes management strategies on renal risk factors.

Science.gov (United States)

Muskiet, Marcel H A; Tonneijck, Lennart; Smits, Mark M; Kramer, Mark H H; Heerspink, Hiddo J Lambers; van Raalte, Daniël H

2015-05-01

In parallel with the type 2 diabetes pandemic, diabetic kidney disease has become the leading cause of end-stage renal disease worldwide, and is associated with high cardiovascular morbidity and mortality. As established in landmark randomised trials and recommended in clinical guidelines, prevention and treatment of diabetic kidney disease focuses on control of the two main renal risk factors, hyperglycaemia and systemic hypertension. Treatment of systemic hypertension with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers is advocated because these drugs seem to exert specific renoprotective effects beyond blood pressure lowering. Emerging evidence shows that obesity, glomerular hyperfiltration, albuminuria, and dyslipidaemia might also adversely affect the kidney in diabetes. Control of these risk factors could have additional benefits on renal outcome in patients with type 2 diabetes. However, despite multifactorial treatment approaches, residual risk for the development and progression of diabetic kidney disease in patients with type 2 diabetes remains, and novel strategies or therapies to treat the disease are urgently needed. Several drugs used in the treatment of type 2 diabetes are associated with pleiotropic effects that could favourably or unfavourably change patients' renal risk profile. We review the risk factors and treatment of diabetic kidney disease, and describe the pleiotropic effects of widely used drugs in type 2 diabetes management on renal outcomes, with special emphasis on antihyperglycaemic drugs. Copyright © 2015 Elsevier Ltd. All rights reserved.

RENAL CLEARANCE AND URINARY EXCRETION OF CIPROFLOXACIN IN GOATS

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Z. IQBAL, I. JAVED, B. ASLAM, F. MUHAMMAD AND I. U. JAN

2007-10-01

Full Text Available The renal clearance and urinary excretion of ciprofloxacin were investigated in eight healthy female goats. In each animal, ciprofloxacin was administered intramuscularly at the rate of 5 mg/kg body weight. Following drug administration, blood and urine samples were collected at different time intervals and analyzed for ciprofloxacin and creatinine. High performance liquid chromatography (HPLC was used to determine the drug concentration in the plasma and urine. The value of diuresis after single administration of ciprofloxacin was 0.073 ± 0.014 ml/min/kg. Mean (± SE values for renal clearance of creatinine and ciprofloxacin were 1.870 ± 0.385 and 0.982 ± 0.166 ml/min/kg, respectively. The ratio between the renal clearance of ciprofloxacin and that of creatinine remained less than one, which was indicative of back diffusion. The mean (± SE value for the cumulative percent of ciprofloxacin dose excreted at 10 hours following its intramuscular administration was 13.03 ± 2.07. Based on these results, it was evident that besides glomerular filtration, renal handling of drug involved back diffusion also. It was concluded that in local goats glomerular filtration rate (GFR was lower than that reported for their foreign counterparts.

Treatment of advanced rectal cancer after renal transplantation

Institute of Scientific and Technical Information of China (English)

Hai-Yi Liu; Xiao-Bo Liang; Yao-Ping Li; Yi Feng; Dong-Bo Liu; Wen-Da Wang

2011-01-01

Renal transplantation is a standard procedure for end-stage renal disease today. Due to immunosuppressive drugs and increasing survival time after renal trans-plantation, patients with transplanted kidneys carry an increased risk of developing malignant tumors. In this case report, 3 patients with advanced rectal can-cer after renal transplantation for renal failure were treated with anterior resection or abdominoperineal resection plus total mesorectal excision, followed by adjuvant chemotherapy. One patient eventually died of metastasized cancer 31 mo after therapy, although his organ grafts functioned well until his death. The other 2 patients were well during the 8 and 21 mo follow-up periods after rectal resection. We therefore strongly argue that patients with advanced rectal cancer should receive standard oncology treatment, including opera-tion and adjuvant treatment after renal transplantation. Colorectal cancer screening in such patients appears justified.

Bio-Inspired Multi-Functional Drug Transport Design Concept and Simulations.

Science.gov (United States)

Pidaparti, Ramana M; Cartin, Charles; Su, Guoguang

2017-04-25

In this study, we developed a microdevice concept for drug/fluidic transport taking an inspiration from supramolecular motor found in biological cells. Specifically, idealized multi-functional design geometry (nozzle/diffuser/nozzle) was developed for (i) fluidic/particle transport; (ii) particle separation; and (iii) droplet generation. Several design simulations were conducted to demonstrate the working principles of the multi-functional device. The design simulations illustrate that the proposed design concept is feasible for multi-functionality. However, further experimentation and optimization studies are needed to fully evaluate the multifunctional device concept for multiple applications.

[Clinical analysis of 41 children's urinary calculus and acute renal failure].

Science.gov (United States)

Li, Lu-Ping; Fan, Ying-Zhong; Zhang, Qian; Zhang, Sheng-Li

2013-04-01

To analyze the treatment of acute renal failure caused by irrational drug use. Data of 41 cases of acute renal failure seen from July 2008 to June 2012 in our hospital were reviewed. Bilateral renal parenchymas diffuse echo was found enhanced by ultrasound in all cases. Calculus image was not found by X-ray. All children had medical history of using cephalosporins or others. Alkalinization of urine and antispasmodic treatment were given to all children immediately, 17 children were treated with hemodialysis and 4 children accepted intraureteral cannula placement. In 24 children who accepted alkalinization of urine and antispasmodic treatment micturition could be restored within 24 hours, in 11 children micturition recovered after only one hemodialysis treatment and 2 children gradually restored micturition after hemodialysis twice, 4 children who accepted intraureteral cannula immediately restored micturition. In all children micturition recovered gradually after a week of treatment. Ultrasound examination showed that 39 children's calculus disappeared totally and renal parenchymas echo recovered to normal. The residual calculi with diameter less than 5 mm were found in 2 children, but they had no symptoms. The children received potassium sodium hydrogen citrate granules per os and were discharged from hospital. Ultrasound showed calculus disappeared totally one month later. Irrational drug use can cause children urolithiasis combined with acute renal failure, while renal dysfunction can reverse by drug withdrawal and early alkalinization of urine, antispasmodic treatment, intraureteral cannula or hemodialysis when necessary, most calculus can be expelled after micturition recovered to normal.

Sequential Scintigraphy in Renal Transplantation

Energy Technology Data Exchange (ETDEWEB)

Winkel, K. zum; Harbst, H.; Schenck, P.; Franz, H. E.; Ritz, E.; Roehl, L.; Ziegler, M.; Ammann, W.; Maier-Borst, W. [Institut Fuer Nuklearmedizin, Deutsches Krebsforschungszentrum, Heidelberg, Federal Republic of Germany (Germany)

1969-05-15

Based on experience gained from more than 1600 patients with proved or suspected kidney diseases and on results on extended studies with dogs, sequential scintigraphy was performed after renal transplantation in dogs. After intravenous injection of 500 {mu}Ci. {sup 131}I-Hippuran scintiphotos were taken during the first minute with an exposure time of 15 sec each and thereafter with an exposure of 2 min up to at least 16 min.. Several examinations were evaluated digitally. 26 examinations were performed on 11 dogs with homotransplanted kidneys. Immediately after transplantation the renal function was almost normal arid the bladder was filled in due time. At the beginning of rejection the initial uptake of radioactive Hippuran was reduced. The intrarenal transport became delayed; probably the renal extraction rate decreased. Corresponding to the development of an oedema in the transplant the uptake area increased in size. In cases of thrombosis of the main artery there was no evidence of any uptake of radioactivity in the transplant. Similar results were obtained in 41 examinations on 15 persons. Patients with postoperative anuria due to acute tubular necrosis showed still some uptake of radioactivity contrary to those with thrombosis of the renal artery, where no uptake was found. In cases of rejection the most frequent signs were a reduced initial uptake and a delayed intrarenal transport of radioactive Hippuran. Infarction could be detected by a reduced uptake in distinct areas of the transplant. (author)

Renal denervation: unde venis et quo vadis?

Science.gov (United States)

Nähle, C P; Düsing, R; Schild, H

2015-04-01

Renal denervation is a minimally invasive, catheter-based option for the treatment of refractory hypertension. Indications and contraindications for renal denervation have been defined in an interdisciplinary manner. The efficacy and safety of the procedure were evaluated. Currently, indication for renal denervation is limited to patients with primary hypertension and a systolic blood pressure of ≥ 160 mm Hg (or ≥ 150 mm Hg in diabetes type 2) despite optimal medical therapy with ≥ 3 different antihypertensive drugs. In this specific patient population, an average blood pressure reduction of 32/14 mmHg was observed in non-randomized/-controlled trials after renal denervation. These results were not confirmed in the first randomized controlled trial with a non-significantly superior blood pressure reduction of 14.1 ± 23.9 mm Hg compared to controls (-11.74 ± 25.94 mm Hg, difference -2.39 mm Hg p = 0.26 for superiority with a margin of 5 mm Hg) who underwent a sham procedure. The efficacy and long-term effects of renal denervation need to be re-evaluated in light of the HTN3 study results. To date, renal denervation should not be performed outside of clinical trials. Future trials should also assess if renal denervation can be performed with sufficient safety and efficacy in patients with hypertension-associated diseases. The use of renal denervation as an alternative therapy (e. g. in patients with drug intolerance) can currently not be advocated. The indication for renal denervation should be assessed in an interdisciplinary fashion and according to current guidelines with a special focus on ruling out secondary causes for arterial hypertension. 5 - 10 % of patients with hypertension suffer from refractory hypertension, but only about 1 % of patients meet the criteria for a renal denervation. Renal denervation leads to a significant decrease in office blood pressure; however, the impact on 24-hour blood pressure

Contribution of multidrug resistance protein 2 (MRP2/ABCC2) to the renal excretion of p-aminohippurate (PAH) and identification of MRP4 (ABCC4) as a novel PAH transporter.

NARCIS (Netherlands)

Smeets, P.H.E.; Aubel, R.A.M.H. van; Wouterse, A.C.; Heuvel, J.J.T.M.; Russel, F.G.M.

2004-01-01

p-Aminohippurate (PAH) is the classical substrate used in the characterization of organic anion transport in renal proximal tubular cells. Although basolateral transporters for PAH uptake from blood into the cell have been well characterized, there is still little knowledge on the apical urinary

Olfactory nerve transport of macromolecular drugs to the brain. A problem in olfactory impaired patients

International Nuclear Information System (INIS)

Shiga, Hideaki; Yamamoto, Junpei; Miwa, Takaki

2012-01-01

Nasal administration of macromolecular drugs (including peptides and nanoparticles) has the potential to enable drug delivery system beyond the blood brain barrier (BBB) via olfactory nerve transport. Basic research on drug deliver systems to the brain via nasal administration has been well reported. Insulin-like growth factor-I (IGF-I) is associated with the development and growth of the central nervous system. Clinical application of IGF-I with nasal administration is intended to enable drug delivery to brain through the BBB. Uptake of IGF-I in the olfactory bulb and central nervous system increased according to the dosage of nasally administered IGF-I in normal ICR mice, however IGF-I uptake in the trigeminal nerve remained unchanged. Olfactory nerve transport is important for the delivery of nasally administered IGF-I to the brain in vivo. Because a safe olfactory nerve tracer has not been clinically available, olfactory nerve transport has not been well studied in humans. Nasal thallium-201 ( 201 Tl) administration has been safely used to assess the direct pathway to the brain via the nose in healthy volunteers with a normal olfactory threshold. 201 Tl olfactory nerve transport has recently been shown to decrease in patients with hyposmia. The olfactory nerve transport function in patients with olfactory disorders will be determined using 201 Tl olfacto-scintigraphy for the exclusion of candidates in a clinical trial to assess the usefulness of nasal administration of IGF-I. (author)

Quasi-equilibrium analysis of the ion-pair mediated membrane transport of low-permeability drugs.

Science.gov (United States)

Miller, Jonathan M; Dahan, Arik; Gupta, Deepak; Varghese, Sheeba; Amidon, Gordon L

2009-07-01

The aim of this research was to gain a mechanistic understanding of ion-pair mediated membrane transport of low-permeability drugs. Quasi-equilibrium mass transport analyses were developed to describe the ion-pair mediated octanol-buffer partitioning and hydrophobic membrane permeation of the model basic drug phenformin. Three lipophilic counterions were employed: p-toluenesulfonic acid, 2-naphthalenesulfonic acid, and 1-hydroxy-2-naphthoic acid (HNAP). Association constants and intrinsic octanol-buffer partition coefficients (Log P(AB)) of the ion-pairs were obtained by fitting a transport model to double reciprocal plots of apparent octanol-buffer distribution coefficients versus counterion concentration. All three counterions enhanced the lipophilicity of phenformin, with HNAP providing the greatest increase in Log P(AB), 3.7 units over phenformin alone. HNAP also enhanced the apparent membrane permeability of phenformin, 27-fold in the PAMPA model, and 4.9-fold across Caco-2 cell monolayers. As predicted from a quasi-equilibrium analysis of ion-pair mediated membrane transport, an order of magnitude increase in phenformin flux was observed per log increase in counterion concentration, such that log-log plots of phenformin flux versus HNAP concentration gave linear relationships. These results provide increased understanding of the underlying mechanisms of ion-pair mediated membrane transport, emphasizing the potential of this approach to enable oral delivery of low-permeability drugs.

Glomerular filtration rate equations overestimate creatinine clearance in older individuals enrolled in the Baltimore Longitudinal Study on Aging: impact on renal drug dosing.

Science.gov (United States)

Dowling, Thomas C; Wang, En-Shih; Ferrucci, Luigi; Sorkin, John D

2013-09-01

To evaluate the performance of kidney function estimation equations and to determine the frequency of drug dose discordance in an older population. Cross-sectional analysis of data from community-dwelling volunteers randomly selected from the Baltimore Longitudinal Study of Aging from January 1, 2005, to December 31, 2010. A total of 269 men and women with a mean ± SD age of 81 ± 6 years, mean serum creatinine concentration (Scr ) of 1.1 ± 0.4 mg/dl, and mean 24-hour measured creatinine clearance (mClcr ) of 53 ± 13 ml/minute. Kidney function was estimated by using the following equations: Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). The performance of each equation was assessed by measuring bias and precision relative to mClcr . Dose calculation errors (discordance) were determined for 10 drugs requiring renal dosage adjustments to avoid toxicity when compared with the dosages approved by the Food and Drug Administration. The CG equation was the least biased estimate of mClcr . The MDRD and CKD-EPI equations were significantly positively biased compared with CG (mean ± SD 34 ± 20% and 22 ± 15%, respectively, prenal impairment. Thus equations estimating glomerular filtration rate should not be substituted in place of the CG equation in older adults for the purpose of renal dosage adjustments. In addition, the common practice of rounding or replacing low Scr values with an arbitrary value of 1.0 mg/dl for use in the CG equation should be avoided. Additional studies that evaluate alternative eGFR equations in the older populations that incorporate pharmacokinetic and pharmacodynamic outcomes measures are needed. © 2013 Pharmacotherapy Publications, Inc.

Drug Dosing in Patients with Renal Insufficiency in a Hospital Setting using Electronic Prescribing and Automated Reporting of Estimated Glomerular Filtration Rate

DEFF Research Database (Denmark)

Nielsen, Anita L.; Henriksen, Daniel Pilsgaard; Marinakis, Christianna

2014-01-01

In patients with impaired renal function, drug dose adjustment is often required. Non-adherence to clinical prescribing recommendations may result in severe adverse events. In previous studies, the prevalence rate of non-adherence to recommended dosing has been reported to be 19-67%. Using the cl...... decision support systems should be explored. This article is protected by copyright. All rights reserved....

Inhibition of bile salt transport by drugs associated with liver injury in primary hepatocytes from human, monkey, dog, rat, and mouse.

Science.gov (United States)

Zhang, Jie; He, Kan; Cai, Lining; Chen, Yu-Chuan; Yang, Yifan; Shi, Qin; Woolf, Thomas F; Ge, Weigong; Guo, Lei; Borlak, Jürgen; Tong, Weida

2016-08-05

Interference of bile salt transport is one of the underlying mechanisms for drug-induced liver injury (DILI). We developed a novel bile salt transport activity assay involving in situ biosynthesis of bile salts from their precursors in primary human, monkey, dog, rat, and mouse hepatocytes in suspension as well as LC-MS/MS determination of extracellular bile salts transported out of hepatocytes. Glycine- and taurine-conjugated bile acids were rapidly formed in hepatocytes and effectively transported into the extracellular medium. The bile salt formation and transport activities were time‒ and bile-acid-concentration‒dependent in primary human hepatocytes. The transport activity was inhibited by the bile salt export pump (BSEP) inhibitors ketoconazole, saquinavir, cyclosporine, and troglitazone. The assay was used to test 86 drugs for their potential to inhibit bile salt transport activity in human hepatocytes, which included 35 drugs associated with severe DILI (sDILI) and 51 with non-severe DILI (non-sDILI). Approximately 60% of the sDILI drugs showed potent inhibition (with IC50 values monkey, dog, rat and mouse hepatocytes. Species differences in potency were observed with mouse being less sensitive than other species to inhibition of bile salt transport. In summary, a novel assay has been developed using hepatocytes in suspension from human and animal species that can be used to assess the potential for drugs and/or drug-derived metabolites to inhibit bile salt transport and/or formation activity. Drugs causing sDILI, except those by immune-mediated mechanism, are highly associated with potent inhibition of bile salt transport. Published by Elsevier Ireland Ltd.

Contribution of renal impairment to potentially preventable medication-related hospital admissions

NARCIS (Netherlands)

A.J. Leendertse (Anne); E.A. van Dijk (Elisabeth); P.A. de Smet (Peter); T.C.G. Egberts (Toine); P.M.L.A. van den Bemt (Patricia)

2012-01-01

textabstractBackground: Medication errors and renal impairment contribute to severe adverse drug events, which may lead to hospital admission. Objective: To determine whether medication errors and renal impairment contribute to hospital admission and examine these errors for strategies to prevent

Blood oxygenation level dependent (BOLD). Renal imaging. Concepts and applications

International Nuclear Information System (INIS)

Nissen, Johanna C.; Haneder, Stefan; Schoenberg, Stefan O.; Michaely, Henrik J.

2010-01-01

Many renal diseases as well as several pharmacons cause a change in renal blood flow and/or renal oxygenation. The blood oxygenation level dependent (BOLD) imaging takes advantage of local field inhomogeneities and is based on a T2 * -weighted sequence. BOLD is a non-invasive method allowing an estimation of the renal, particularly the medullary oxygenation, and an indirect measurement of blood flow without administration of contrast agents. Thus, effects of different drugs on the kidney and various renal diseases can be controlled and observed. This work will provide an overview of the studies carried out so far and identify ways how BOLD can be used in clinical studies. (orig.)

Reversible diminished renal sup(99m)Tc-DMSA uptake during converting-enzyme inhibition in a patient with renal artery stenosis

Energy Technology Data Exchange (ETDEWEB)

Kremer Hovinga, T K; Beukhof, J R; Donker, A J.M.; Luyk, W H.J. van; Piers, D A

1984-03-01

A patient is described who had accelerated hypertension and unilateral renal artery stenosis, and who developed further deterioration in renal function during treatment with captopril, an angiotension-I (AI) converting-enzyme inhibitor. sup(99m)Tc-DMSA uptake was greatly diminished in the stenotic kidney, although renal blood flow and handling of /sup 131/I hippurate was preserved. Uptake of sup(99m)Tc-DMSA in the affected kidney returned after substitution of captopril by the vasodilator minoxidil, while a comparable degree of blood pressure control was maintained. This, caution must be taken when interpreting results of sup(99m)Tc-DMSA scintigraphy in patients with proven or suspected renal artery stenosis treated with an AI converting-enzyme inhibiting drug. Moreover, our finding points to the importance of glomerular filtration in the renal handling of /sup 99/Tc-DMSA.

Reversible diminished renal sup(99m)Tc-DMSA uptake during converting-enzyme inhibition in a patient with renal artery stenosis

International Nuclear Information System (INIS)

Kremer Hovinga, T.K.; Beukhof, J.R.; Donker, A.J.M.; Luyk, W.H.J. van; Piers, D.A.

1984-01-01

A patient is described who had accelerated hypertension and unilateral renal artery stenosis, and who developed further deterioration in renal function during treatment with captopril, an angiotension-I (AI) converting-enzyme inhibitor. sup(99m)Tc-DMSA uptake was greatly diminished in the stenotic kidney, although renal blood flow and handling of 131 I hippurate was preserved. Uptake of sup(99m)Tc-DMSA in the affected kidney returned after substitution of captopril by the vasodilator minoxidil, while a comparable degree of blood pressure control was maintained. This, caution must be taken when interpreting results of sup(99m)Tc-DMSA scintigraphy in patients with proven or suspected renal artery stenosis treated with an AI converting-enzyme inhibiting drug. Moreover, our finding points to the importance of glomerular filtration in the renal handling of 99 Tc-DMSA. (orig.)

Renal Sympathetic Denervation: Hibernation or Resurrection?

Science.gov (United States)

Papademetriou, Vasilios; Doumas, Michael; Tsioufis, Costas

The most current versions of renal sympathetic denervation have been invented as minimally invasive approaches for the management of drug-resistant hypertension. The anatomy, physiology and pathophysiology of renal sympathetic innervation provide a strong background supporting an important role of the renal nerves in the regulation of blood pressure (BP) and volume. In addition, historical data with surgical sympathectomy and experimental data with surgical renal denervation indicate a beneficial effect on BP levels. Early clinical studies with transcatheter radiofrequency ablation demonstrated impressive BP reduction, accompanied by beneficial effects in target organ damage and other disease conditions characterized by sympathetic overactivity. However, the failure of the SYMPLICITY 3 trial to meet its primary efficacy end point raised a lot of concerns and put the field of renal denervation into hibernation. This review aims to translate basic research into clinical practice by presenting the anatomical and physiological basis for renal sympathetic denervation, critically discussing the past and present knowledge in this field, where we stand now, and also speculating about the future of the intervention and potential directions for research. © 2016 S. Karger AG, Basel.

Investigating the effects of ABC transporter-based acquired drug resistance mechanisms at the cellular and tissue scale.

Science.gov (United States)

Liu, Cong; Krishnan, J; Xu, Xiao Yun

2013-03-01

In this paper we systematically investigate the effects of acquired drug resistance at the cellular and tissue scale, with a specific focus on ATP-binding cassette (ABC) transporter-based mechanisms and contrast this with other representative intracellular resistance mechanisms. This is done by developing in silico models wherein the drug resistance mechanism is overlaid on a coarse-grained description of apoptosis; these cellular models are coupled with interstitial drug transport, allowing for a transparent examination of the effect of acquired drug resistances at the tissue level. While ABC transporter-mediated resistance mechanisms counteract drug effect at the cellular level, its tissue-level effect is more complicated, revealing unexpected trends in tissue response as drug stimuli are systematically varied. Qualitatively different behaviour is observed in other drug resistance mechanisms. Overall the paper (i) provides insight into the tissue level functioning of a particular resistance mechanism, (ii) shows that this is very different from other resistance mechanisms of an apparently similar type, and (iii) demonstrates a concrete instance of how the functioning of a negative feedback based cellular adaptive mechanism can have unexpected higher scale effects.

Bioavailability and transport of peptides and peptide drugs into the brain.

Science.gov (United States)

Egleton, R D; Davis, T P

1997-01-01

Rational drug design and the targeting of specific organs has become a reality in modern drug development, with the emergence of molecular biology and receptor chemistry as powerful tools for the pharmacologist. A greater understanding of peptide function as one of the major extracellular message systems has made neuropeptides an important target in neuropharmaceutical drug design. The major obstacle to targeting the brain with therapeutics is the presence of the blood-brain barrier (BBB), which controls the concentration and entry of solutes into the central nervous system. Peptides are generally polar in nature, do not easily cross the blood-brain barrier by diffusion, and except for a small number do not have specific transport systems. Peptides can also undergo metabolic deactivation by peptidases of the blood, brain and the endothelial cells that comprise the BBB. In this review, we discuss a number of the recent strategies which have been used to promote peptide stability and peptide entry into the brain. In addition, we approach the subject of targeting specific transport systems that can be found on the brain endothelial cells, and describe the limitations of the methodologies that are currently used to study brain entry of neuropharmaceuticals.

Molecular features of renal cell carcinoma: early diagnostics and perspectives for therapy

Directory of Open Access Journals (Sweden)

O. V. Kovaleva

2014-01-01

Full Text Available Kidney cancer (renal cell carcinoma is one of the major problems of modern urological oncology. In Russia renal cell carcinoma accountsfor 4.3 % of all cancers. The global incidence of renal cell carcinoma has increased over the past two decades. Worldwide renal cell carcinoma accounts for 3.6 % of all cancers and is 10th frequent malignancy. For some malignancies, for instance tumours of prostate, there are markers known that allowed improved early diagnostics. Kidney cancer, however, remains to be hard to diagnose and to treat, since the symptoms can be detected on advanced stages of the disease. In Russia 75.4 % of renal cell carcinoma cases detected at the stage of local and locally advanced disease. Though there are various target drugs on the market aimed to treat this disease, the results of renal cell carcinoma treatment did not reach any substantial success. Most of existing target drugs for kidney cancer treatment include inhibitors of a single signalingpathway regulated by VHL1, which expression is lost in the vast majority of renal-cell carcinomas. Till now existing drugs did not reach sufficient efficacy. Therefore, it is highly important to search for new signaling pathways, regulating such cellular processes as proliferation, migration and apoptosis. Further, prognostic markers and therapy targets identified so far are not sufficient and poorly specific. Therefore identification and validation of new markers, and especially new specific targets for the treatment of kindey oncopathologies is highly important and timely task.

Drug transporter gene expression in human colorectal tissue and cell lines: modulation with antiretrovirals for microbicide optimization.

Science.gov (United States)

Mukhopadhya, Indrani; Murray, Graeme I; Berry, Susan; Thomson, John; Frank, Bruce; Gwozdz, Garry; Ekeruche-Makinde, Julia; Shattock, Robin; Kelly, Charles; Iannelli, Francesco; Pozzi, Gianni; El-Omar, Emad M; Hold, Georgina L; Hijazi, Karolin

2016-02-01

The objectives of this study were to comprehensively assess mRNA expression of 84 drug transporters in human colorectal biopsies and six representative cell lines, and to investigate the alteration of drug transporter gene expression after exposure to three candidate microbicidal antiretroviral (ARV) drugs (tenofovir, darunavir and dapivirine) in the colorectal epithelium. The outcome of the objectives informs development of optimal ARV-based microbicidal formulations for prevention of HIV-1 infection. Drug transporter mRNA expression was quantified from colorectal biopsies and cell lines by quantitative real-time PCR. Relative mRNA expression was quantified in Caco-2 cells and colorectal explants after induction with ARVs. Data were analysed using Pearson's product moment correlation (r), hierarchical clustering and principal component analysis (PCA). Expression of 58 of the 84 transporters was documented in colorectal biopsies, with genes for CNT2, P-glycoprotein (P-gp) and MRP3 showing the highest expression. No difference was noted between individual subjects when analysed by age, gender or anatomical site (rectum or recto-sigmoid) (r = 0.95-0.99). High expression of P-gp and CNT2 proteins was confirmed by immunohistochemical staining. Similarity between colorectal tissue and cell-line drug transporter gene expression was variable (r = 0.64-0.84). PCA showed distinct clustering of human colorectal biopsy samples, with the Caco-2 cells defined as the best surrogate system. Induction of Caco-2 cell lines with ARV drugs suggests that darunavir-based microbicides incorporating tenofovir may result in drug-drug interactions likely to affect distribution of individual drugs to sub-epithelial target cells. These findings will help optimize complex formulations of rectal microbicides to realize their full potential as an effective approach for pre-exposure prophylaxis against HIV-1 infection. © The Author 2015. Published by Oxford University Press on behalf of the

Drug trafficking in mice: In vivo functions of OATP uptake and ABC efflux transporters

NARCIS (Netherlands)

Iusuf, D.

2013-01-01

In recent years, there has been increasing attention for drug uptake transporters of the Organic Anion-Transporting Polypeptide (human OATP, mouse Oatp, gene names SLCO, Slco) superfamily. Especially the OATP1A and OATP1B subfamilies turn out to have important physiological and pharmacological

Severe Malignant Hypertension following Renal Artery Embolization: A Crucial Role for the Renal Microcirculation in the Pathogenesis of Hypertension?

OpenAIRE

Khan, N; Jeans, J; Mahdi, S; Belli, AM; Antonios, TFT

2017-01-01

Malignant hypertension is the most severe form of hypertension that is usually fatal if not properly managed. It is usually associated with evidence of microvascular damage such as retinopathy and nephropathy. Renal artery embolization is a widely utilised tool for the management of a wide range of conditions including drug resistant renovascular hypertension in patients with end stage renal failure. In this report we describe two patients with mild-to-moderate hypertension who underwent rena...

Traffic risk behaviors at nightlife: drinking, taking drugs, driving, and use of public transport by young people.

Science.gov (United States)

Calafat, A; Blay, N; Juan, M; Adrover, D; Bellis, M A; Hughes, K; Stocco, P; Siamou, I; Mendes, F; Bohrn, K

2009-04-01

Road traffic crashes associated with nightlife alcohol and recreational drug use are a major health problem for young people. This study explores use of different forms of transport to and from nightlife environments and the relationships between traffic risk behaviors, drunkenness, and drug consumption. 1363 regular nightlife users from nine European cities in 2006 completed a self-administered and anonymous questionnaire. Sampling utilized a variation of respondent-driven sampling. Private car was the most frequent form of transport used when going out, especially by males and older individuals. Drug use was related to crashes and traffic risk behaviors, including having a lift from someone drunk or driving drunk or driving having taken drugs; drunkenness was related to risk behaviors but not to crashes (possibly because drunk people tend to use the private car less). Males showed higher levels of drunkenness and drug consumption, traffic risk behaviors, and traffic crashes. Age is not related to the traffic risk behaviors, but older individuals had less crashes. There are serious health problems related to transport and recreational nightlife activities. It is necessary to improve later public transport services, complemented by actions that deter the use of private cars. The relationships of both drunkenness and cannabis/cocaine use with traffic risk behaviors should be addressed and programs implemented to change risk perceptions on the effects of illegal drugs on driving.

Timing and Duration of Drug Exposure Affects Outcomes of a Drug-Nutrient Interaction During Ontogeny

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Jane Alcorn

2010-10-01

Full Text Available Significant drug-nutrient interactions are possible when drugs and nutrients share the same absorption and disposition mechanisms. During postnatal development, the outcomes of drug-nutrient interactions may change with postnatal age since these processes undergo ontogenesis through the postnatal period. Our study investigated the dependence of a significant drug-nutrient interaction (cefepime-carnitine on the timing and duration of drug exposure relative to postnatal age. Rat pups were administered cefepime (5 mg/kg twice daily subcutaneously according to different dosing schedules (postnatal day 1-4, 1-8, 8-11, 8-20, or 1-20. Cefepime significantly reduced serum and heart L-carnitine levels in postnatal day 1-4, 1-8 and 8-11 groups and caused severe degenerative changes in ventricular myocardium in these groups. Cefepime also altered the ontogeny of several key L-carnitine homeostasis pathways. The qualitative and quantitative changes in levels of hepatic γ-butyrobetaine hydroxylase mRNA and activity, hepatic trimethyllysine hydroxlase mRNA, intestinal organic cation/carnitine transporter (Octn mRNA, and renal Octn2 mRNA depended on when during postnatal development the cefepime exposure occurred and duration of exposure. Despite lower levels of heart L-carnitine in earlier postnatal groups, levels of carnitine palmitoyltransferase mRNA and activity, heart Octn2 mRNA and ATP levels in all treatment groups remained unchanged with cefepime exposure. However, changes in other high energy phosphate substrates were noted and reductions in the phosphocreatine/ATP ratio were found in rat pups with normal serum L-carnitine levels. In summary, our data suggest a significant drug-nutrient transport interaction in developing neonates, the nature of which depends on the timing and duration of exposure relative to postnatal age.

Small Molecule Membrane Transporters in the Mammalian Podocyte: A Pathogenic and Therapeutic Target

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Cristina Zennaro

2014-11-01

Full Text Available The intriguingly complex glomerular podocyte has been a recent object of intense study. Researchers have sought to understand its role in the pathogenesis of common proteinuric diseases such as minimal change disease and focal segmental glomerular sclerosis. In particular, considerable effort has been directed towards the anatomic and functional barrier to macromolecular filtration provided by the secondary foot processes, but little attention has been paid to the potential of podocytes to handle plasma proteins beyond the specialization of the slit diaphragm. Renal membrane transporters in the proximal tubule have been extensively studied for decades, particularly in relation to drug metabolism and elimination. Recently, uptake and efflux transporters for small organic molecules have also been found in the glomerular podocyte, and we and others have found that these transporters can engage not only common pharmaceuticals but also injurious endogenous and exogenous agents. We have also found that the activity of podocyte transporters can be manipulated to inhibit pathogen uptake and efflux. It is conceivable that podocyte transporters may play a role in disease pathogenesis and may be a target for future drug development.

Predictors of advanced chronic kidney disease and end-stage renal disease in HIV-positive persons

DEFF Research Database (Denmark)

Nielsen, Lene Ryom; Mocroft, Amanda; Kirk, Ole

2014-01-01

Whilst several antiretroviral drugs have been associated with moderate chronic kidney disease (CKD), their contribution to advanced CKD and end-stage renal disease (ESRD) remain unknown.......Whilst several antiretroviral drugs have been associated with moderate chronic kidney disease (CKD), their contribution to advanced CKD and end-stage renal disease (ESRD) remain unknown....

Arterial embolization for treating post-transplanted renal failure

International Nuclear Information System (INIS)

Yang Xizhang; Yang Li; Chen Ziqian; Yang Yongyan

2008-01-01

Objective: To investigate the significance of renal arterial embolization nephrectomy for treating post-transplanted renal failure. Methods: 15 cases of post-transplanted renal failure received renal arterial embolization. The post-procedural efficacies were followed up for about 6 months to 4 years. Results: Among the 15 cases, 11 showed blood pressure decreasing to normal level, 3 with reduction of the drug dose for anti-hypertension and 1 of no response. In addition, 12 suffered from postprocedural anuria, and 3 with obvious hypourocrinia associated with significant decrease of proteinuia; 5 with positive lymphcytic population response antigen (PRA > 20%), but turning negative with 3 of them after 3 weeks. All the transplanted kidneys revealed different degrees of atrophy but 4 of them obtained chances of successful retransplantation 3- 6 months after the procedure, 3 of them with follow up of 1-3 years were being well. Conclusions: Renal arterial embolization is a safe, efficient measure for treating post-transplanted renal failure with obvious decrease of correlative clinical symptoms and providing conditions for renal retransplantation. (authors)

Angiotensin converting enzyme (ACE) inhibitors and renal function. A review of the current status

DEFF Research Database (Denmark)

Kamper, A L

1991-01-01

studies have been published to date. In chronic renal failure, ACE inhibitors may worsen anaemia and hyperkalaemia. Renovascular hypertension can be treated with ACE inhibitors, but the treatment may lead to a compromised renal function. The dosage of these drugs should be reduced in renal failure...

Drug Transport Mechanism of Oral Antidiabetic Nanomedicines

Science.gov (United States)

Gundogdu, Evren; Yurdasiper, Aysu

2014-01-01

Context: Over the last few decades, extensive efforts have been made worldwide to develop nanomedicine delivery systems, especially via oral route for antidiabetic drugs. Absorption of insulin is hindered by epithelial cells of gastrointestinal tract, acidic gastric pH and digestive enzymes. Evidence Acquisition: Recent reports have identified and explained the beneficial role of several structural molecules like mucoadhesive polymers (polyacrylic acid, sodium alginate, chitosan) and other copolymers for the efficient transport and release of insulin to its receptors. Results: Insulin nanomedicines based on alginate-dextran sulfate core with a chitosan-polyethylene glycol-albumin shell reduced glycaemia in a dose dependent manner. Orally available exendin-4 formulations exerted their effects in a time dependent manner. Insulin nanoparticles formed by using alginate and dextran sulfate nucleating around calcium and binding to poloxamer, stabilized by chitosan, and subsequently coated with albumin showed a threefold increase of the hypoglycemic effect in comparison to free insulin in animal models. Solid lipid nanoparticles showed an enhancement of the bioavailability of repaglinide (RG) within optimized solid lipid nanoparticle formulations when compared with RG alone. Conclusions: Nanoparticles represent multiparticulate delivery systems designed to obtain prolonged or controlled drug delivery and to improve bioavailability as well as stability. Nanoparticles can also offer advantages like limiting fluctuations within therapeutic range, reducing side effects, protecting drugs from degradation, decreasing dosing frequency, and improving patient compliance and convenience PMID:24696697

Drug transport mechanism of oral antidiabetic nanomedicines.

Science.gov (United States)

Gundogdu, Evren; Yurdasiper, Aysu

2014-01-01

Over the last few decades, extensive efforts have been made worldwide to develop nanomedicine delivery systems, especially via oral route for antidiabetic drugs. Absorption of insulin is hindered by epithelial cells of gastrointestinal tract, acidic gastric pH and digestive enzymes. Recent reports have identified and explained the beneficial role of several structural molecules like mucoadhesive polymers (polyacrylic acid, sodium alginate, chitosan) and other copolymers for the efficient transport and release of insulin to its receptors. Insulin nanomedicines based on alginate-dextran sulfate core with a chitosan-polyethylene glycol-albumin shell reduced glycaemia in a dose dependent manner. Orally available exendin-4 formulations exerted their effects in a time dependent manner. Insulin nanoparticles formed by using alginate and dextran sulfate nucleating around calcium and binding to poloxamer, stabilized by chitosan, and subsequently coated with albumin showed a threefold increase of the hypoglycemic effect in comparison to free insulin in animal models. Solid lipid nanoparticles showed an enhancement of the bioavailability of repaglinide (RG) within optimized solid lipid nanoparticle formulations when compared with RG alone. Nanoparticles represent multiparticulate delivery systems designed to obtain prolonged or controlled drug delivery and to improve bioavailability as well as stability. Nanoparticles can also offer advantages like limiting fluctuations within therapeutic range, reducing side effects, protecting drugs from degradation, decreasing dosing frequency, and improving patient compliance and convenience.

Sonographic findings in primary diseases of renal pyramids

International Nuclear Information System (INIS)

Rao, B.K.

1987-01-01

Primary pathologic processes involving the renal pyramids such as papillary necrosis, drug-induced necrosis or calcinosis, cysts, neoplasms, and medullary nephrocalcinosis are rare. Thirty-four patients with primary renal pyramid diseases underwent US evaluation for altered morphology; a 5-MHz transducer was used. In 20 patients site-specific changes in the pyramid (e.g., papillary necrosis at the apex, small cysts at the base in medullary cystic disease, tubular calcification in MSK, corticomedullary hyperechogenicity in oxalosis) were noted on US. Sonographic delineation of the site and pattern of pathologic changes in the renal pyramid may help to identify specific diseases

Compartment model for the measurement of the effective renal plasma flow by radionuclidenephrography

International Nuclear Information System (INIS)

Ryabov, S.I.; Degtyareva, O.A.

1988-01-01

By reason of model ideas on hippuran kinetics radionuclide nephrograms were split up into a renal component and a component of the tissue background. New indices for the evaluation of renal function symmetry were proposed comprising the proportional determination of the effective renal plasma flow as well as of the symmetrical blood flow. For early diagnosis of latent renal dysfunction a new index is proposed characterizing the excretory renal transport as to local renal blood supply. Empirical indices of 120 patients suffering from chronic glomerulonephritis and pyelonephritis, resp., are stated

Renal function in healthy dogs therapy with anti-inflammatory drugs

OpenAIRE

Borges, Marina

2011-01-01

Os anti-inflamatórios não-esteroidais têm uso extremamente difundido na clínica de pequenos animais, devido às suas propriedades analgésicas e anti-inflamatórias. Entretanto, o uso desses fármacos pode produzir alterações da função renal. O presente estudo teve como objetivo avaliar a função renal de cães saudáveis, submetidos à terapia com anti-inflamatórios não-esteroidais não seletivos, COX-2 preferenciais e COX-2 seletivos. Foram utilizados 30 cães, sem raça definida, adultos, machos e fê...

Role of Erythropoietin in Renal Anemia Therapy

African Journals Online (AJOL)

of erythropoietin and others drugs in renal anemia treatment, as well as the cause of erythropoietin resistance. .... mouth health, atrophy prevention, prevention of artery hardening ... Secondary hyperthyroidism can lead to osteitis fibrosa ...

Anesthesia for parturient with renal transplantation

Directory of Open Access Journals (Sweden)

Beena K Parikh

2012-01-01

Full Text Available Management of successful pregnancy after renal transplantation is a unique challenge to nephrologist, obstetrician, and anesthesiologist, as these patients have altered physiology and are immune-compromised. We present the anesthetic management of three postrenal transplant patients scheduled for cesarean section. While conducting such cases, cardiovascular status, hematological status, and function of transplanted kidney should be assessed thoroughly. Side effects of immunosuppressant drugs and their interaction with anesthetic agents should be taken into consideration. Main goal of anesthetic management is to maintain optimum perfusion pressure of renal allograft to preserve its function.

In vitro drug response and efflux transporters associated with drug resistance in pediatric high grade glioma and diffuse intrinsic pontine glioma.

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Susanna J E Veringa

Full Text Available Pediatric high-grade gliomas (pHGG, including diffuse intrinsic pontine gliomas (DIPG, are the leading cause of cancer-related death in children. While it is clear that surgery (if possible, and radiotherapy are beneficial for treatment, the role of chemotherapy for these tumors is still unclear. Therefore, we performed an in vitro drug screen on primary glioma cells, including three DIPG cultures, to determine drug sensitivity of these tumours, without the possible confounding effect of insufficient drug delivery. This screen revealed a high in vitro cytotoxicity for melphalan, doxorubicine, mitoxantrone, and BCNU, and for the novel, targeted agents vandetanib and bortezomib in pHGG and DIPG cells. We subsequently determined the expression of the drug efflux transporters P-gp, BCRP1, and MRP1 in glioma cultures and their corresponding tumor tissues. Results indicate the presence of P-gp, MRP1 and BCRP1 in the tumor vasculature, and expression of MRP1 in the glioma cells themselves. Our results show that pediatric glioma and DIPG tumors per se are not resistant to chemotherapy. Treatment failure observed in clinical trials, may rather be contributed to the presence of drug efflux transporters that constitute a first line of drug resistance located at the blood-brain barrier or other resistance mechanism. As such, we suggest that alternative ways of drug delivery may offer new possibilities for the treatment of pediatric high-grade glioma patients, and DIPG in particular.

[Acetaminophen (paracetamol) causing renal failure: report on 3 pediatric cases].

Science.gov (United States)

Le Vaillant, J; Pellerin, L; Brouard, J; Eckart, P

2013-06-01

Renal failure secondary to acetaminophen poisoning is rare and occurs in approximately 1-2 % of patients with acetaminophen overdose. The pathophysiology is still being debated, and renal acetaminophen toxicity consists of acute tubular necrosis, without complication if treated promptly. Renal involvement can sometimes occur without prior liver disease, and early renal manifestations usually occur between the 2nd and 7th day after the acute acetaminophen poisoning. While therapy is exclusively symptomatic, sometimes serious metabolic complications can be observed. The monitoring of renal function should therefore be considered as an integral part of the management of children with acute, severe acetaminophen intoxication. We report 3 cases of adolescents who presented with acute renal failure as a result of voluntary drug intoxication with acetaminophen. One of these 3 girls developed severe renal injury without elevated hepatic transaminases. None of the 3 girls' renal function required hemodialysis, but one of the 3 patients had metabolic complications after her acetaminophen poisoning. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Role of renal sympathetic nerve activity in prenatal programming of hypertension.

Science.gov (United States)

Baum, Michel

2018-03-01

Prenatal insults, such as maternal dietary protein deprivation and uteroplacental insufficiency, lead to small for gestational age (SGA) neonates. Epidemiological studies from many different parts of the world have shown that SGA neonates are at increased risk for hypertension and early death from cardiovascular disease as adults. Animal models, including prenatal administration of dexamethasone, uterine artery ligation and maternal dietary protein restriction, result in SGA neonates with fewer nephrons than controls. These models are discussed in this educational review, which provides evidence that prenatal insults lead to altered sodium transport in multiple nephron segments. The factors that could result in increased sodium transport are discussed, focusing on new information that there is increased renal sympathetic nerve activity that may be responsible for augmented renal tubular sodium transport. Renal denervation abrogates the hypertension in programmed rats but has no effect on control rats. Other potential factors that could cause hypertension in programmed rats, such as the renin-angiotensin system, are also discussed.

Modeling the drug transport in the anterior segment of the eye.

Science.gov (United States)

Avtar, Ram; Tandon, Deepti

2008-10-02

The aim of the present work is the development of a simple mathematical model for the time course concentration profile of topically administered drugs in the anterior chamber aqueous humor and investigation of the effects of various model parameters on the aqueous humor concentration of lipophilic and hydrophilic drugs. A simple pharmacokinetic model for the transient drug transport in the anterior segment has been developed by using the conservation of mass in the precorneal tear film, Fick's law of diffusion and Michaelis-Menten kinetics of drug metabolism in cornea, and the conservation of mass in the anterior chamber. An analytical solution describing the drug concentration in the anterior chamber has been obtained. The model predicts that an increase in the drug metabolic (consumption) rate in the corneal epithelium reduces the drug concentration in the anterior chamber for both lipophilic and hydrophilic molecules. A decrease in the clearance rate and distribution volume of the drug in the anterior chamber raises the aqueous humor concentration significantly. It is also observed that decay rate of drug concentration in the anterior chamber is higher for lipophilic molecules than that for hydrophilic molecules. The bioavailability of drugs applied topically to the eye may be improved by a rise in the precorneal tear volume, diffusion coefficient in corneal epithelium and distribution coefficient across the endothelium anterior chamber interface, and by reducing the drug metabolism, drug clearance rate and distribution volume in anterior chamber.

Nephrotic Syndrome and Acute Renal Failure Apparently Induced by Sunitinib

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Ying-Shou Chen

2009-10-01

Full Text Available We report a case of nephrotic syndrome and acute renal failure apparently induced by sunitinib. A 67-year-old man with a history of metastatic renal cell carcinoma presented with progressive kidney dysfunction with proteinuria, general edema, and body weight gain of 21 kg after undergoing 3 weeks of sunitinib therapy. The patient had taken no other over-the-counter medications, and all other possible causes of nephrotic syndrome were excluded. The Naranjo Adverse Drug Reaction Probability Scale score for this event was 6, indicating a high probability that the observed presentations were associated with use of the drug. However, despite the discontinuation of sunitinib, his condition deteriorated, and hemodialysis was initiated for respiratory distress. A renal biopsy was performed, which revealed ischemic acute tubular necrosis with minimal change nephropathy. In conclusion, nephrologists and oncologists should be aware that nephrotic syndrome with ischemic acute tubular necrosis is a possible adverse effect of sunitinib. For early diagnosis of this condition and to avoid renal damage, we recommend differential diagnosis of serum creatinine and proteinuria in patients undergoing sunitinib therapy.

Hydrodynamic Impacts on Dissolution, Transport and Absorption from Thousands of Drug Particles Moving within the Intestines

Science.gov (United States)

Behafarid, Farhad; Brasseur, James G.

2017-11-01

Following tablet disintegration, clouds of drug particles 5-200 μm in diameter pass through the intestines where drug molecules are absorbed into the blood. Release rate depends on particle size, drug solubility, local drug concentration and the hydrodynamic environment driven by patterned gut contractions. To analyze the dynamics underlying drug release and absorption, we use a 3D lattice Boltzmann model of the velocity and concentration fields driven by peristaltic contractions in vivo, combined with a mathematical model of dissolution-rate from each drug particle transported through the grid. The model is empirically extended for hydrodynamic enhancements to release rate by local convection and shear-rate, and incorporates heterogeneity in bulk concentration. Drug dosage and solubility are systematically varied along with peristaltic wave speed and volume. We predict large hydrodynamic enhancements (35-65%) from local shear-rate with minimal enhancement from convection. With high permeability boundary conditions, a quasi-equilibrium balance between release and absorption is established with volume and wave-speed dependent transport time scale, after an initial transient and before a final period of dissolution/absorption. Supported by FDA.

Expression profiles of genes involved in xenobiotic metabolism and disposition in human renal tissues and renal cell models

Energy Technology Data Exchange (ETDEWEB)

Van der Hauwaert, Cynthia; Savary, Grégoire [EA4483, Université de Lille 2, Faculté de Médecine de Lille, Pôle Recherche, 59045 Lille (France); Buob, David [Institut de Pathologie, Centre de Biologie Pathologie Génétique, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille (France); Leroy, Xavier; Aubert, Sébastien [Institut de Pathologie, Centre de Biologie Pathologie Génétique, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille (France); Institut National de la Santé et de la Recherche Médicale, UMR837, Centre de Recherche Jean-Pierre Aubert, Equipe 5, 59045 Lille (France); Flamand, Vincent [Service d' Urologie, Hôpital Huriez, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille (France); Hennino, Marie-Flore [EA4483, Université de Lille 2, Faculté de Médecine de Lille, Pôle Recherche, 59045 Lille (France); Service de Néphrologie, Hôpital Huriez, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille (France); Perrais, Michaël [Institut National de la Santé et de la Recherche Médicale, UMR837, Centre de Recherche Jean-Pierre Aubert, Equipe 5, 59045 Lille (France); and others

2014-09-15

Numerous xenobiotics have been shown to be harmful for the kidney. Thus, to improve our knowledge of the cellular processing of these nephrotoxic compounds, we evaluated, by real-time PCR, the mRNA expression level of 377 genes encoding xenobiotic-metabolizing enzymes (XMEs), transporters, as well as nuclear receptors and transcription factors that coordinate their expression in eight normal human renal cortical tissues. Additionally, since several renal in vitro models are commonly used in pharmacological and toxicological studies, we investigated their metabolic capacities and compared them with those of renal tissues. The same set of genes was thus investigated in HEK293 and HK2 immortalized cell lines in commercial primary cultures of epithelial renal cells and in proximal tubular cell primary cultures. Altogether, our data offers a comprehensive description of kidney ability to process xenobiotics. Moreover, by hierarchical clustering, we observed large variations in gene expression profiles between renal cell lines and renal tissues. Primary cultures of proximal tubular epithelial cells exhibited the highest similarities with renal tissue in terms of transcript profiling. Moreover, compared to other renal cell models, Tacrolimus dose dependent toxic effects were lower in proximal tubular cell primary cultures that display the highest metabolism and disposition capacity. Therefore, primary cultures appear to be the most relevant in vitro model for investigating the metabolism and bioactivation of nephrotoxic compounds and for toxicological and pharmacological studies. - Highlights: • Renal proximal tubular (PT) cells are highly sensitive to xenobiotics. • Expression of genes involved in xenobiotic disposition was measured. • PT cells exhibited the highest similarities with renal tissue.

Iontoforese no transporte ocular de drogas Iontophoresis for ocular drug delivery

Directory of Open Access Journals (Sweden)

Sílvia Ligório Fialho

2004-10-01

Full Text Available O método mais comum de administração de drogas no olho é por meio de colírios. Entretanto, por este método, não é possível atingir a concentração terapêutica nos fluidos e tecidos posteriores do olho. A administração sistêmica apresenta reduzido acesso ao segmento posterior do olho devido à presença das barreiras oculares. Injeções subconjuntivais e retrobulbares não são capazes de proporcionar níveis adequados da droga, e a injeção intravítrea é método invasivo, inconveniente e que apre-senta riscos de perfuração do bulbo ocular ou descolamento da retina. A iontoforese, no entanto, apresenta-se como alternativa para o transporte de doses terapêuticas de drogas para o segmento posterior do olho. A iontoforese é uma técnica que consiste na administração de drogas para o organismo através dos tecidos, utilizando um campo elétrico. O eletrodo ativo, que se encontra em contato com a droga, é colocado no local a ser tratado, e um segundo eletrodo, com a finalidade de fechar o circuito elétrico, é colocado em outro local do organismo. O campo elétrico facilita o transporte da droga, que deve se encontrar, preferencialmente, na forma ionizada. A iontoforese pode ser considerada como um método seguro e não invasivo de transporte de drogas para locais específicos do olho. Aplicada experimentalmente para o tratamento de doenças oculares, esta técnica tem evoluído muito nos últimos anos e, atualmente, testes clínicos de fase III encontram-se em andamento.The most traditional method of ocular drug delivery is through the use of eyedrops. However, by this method, the therapeutic concentration in deep ocular fluids and tissues can not be efficiently reached. Systemic administration presents poor access to the posterior segment of the eye due to ocular barriers. Subconjuntival and retrobulbar injections are not able to produce adequate levels of the drug, and intravitreal injection is an invasive and problematic

Clinical Validation of Therapeutic Drug Monitoring of Imipenem in Spent Effluent in Critically Ill Patients Receiving Continuous Renal Replacement Therapy: A Pilot Study.

Science.gov (United States)

Wen, Aiping; Li, Zhe; Yu, Junxian; Li, Ren; Cheng, Sheng; Duan, Meili; Bai, Jing

2016-01-01

The primary objective of this pilot study was to investigate whether the therapeutic drug monitoring of imipenem could be performed with spent effluent instead of blood sampling collected from critically ill patients under continuous renal replacement therapy. A prospective open-label study was conducted in a real clinical setting. Both blood and effluent samples were collected pairwise before imipenem administration and 0.5, 1, 1.5, 2, 3, 4, 6, and 8 h after imipenem administration. Plasma and effluent imipenem concentrations were determined by reversed-phase high-performance liquid chromatography with ultraviolet detection. Pharmacokinetic and pharmacodynamic parameters of blood and effluent samples were calculated. Eighty-three paired plasma and effluent samples were obtained from 10 patients. The Pearson correlation coefficient of the imipenem concentrations in plasma and effluent was 0.950 (Pimipenem concentration ratio was 1.044 (95% confidence interval, 0.975 to 1.114) with Bland-Altman analysis. No statistically significant difference was found in the pharmacokinetic and pharmacodynamic parameters tested in paired plasma and effluent samples with Wilcoxon test. Spent effluent of continuous renal replacement therapy could be used for therapeutic drug monitoring of imipenem instead of blood sampling in critically ill patients.

Exercise renogram. A new approach documents renal involvement in systemic hypertension

International Nuclear Information System (INIS)

Clorius, J.H.; Schmidlin, P.

1983-01-01

Hippurate functional scintiscans were obtained in 51 hypertensive patients and in 15 controls. The authors investigated the influence that posture and exercise have on hippurate kinetics in patients with hypertension. A posture- or exercise-induced disturbance of renal hippurate transport was sought. All persons were examined in prone and standing positions, as well as during exercise. When prone and upright renograms were compared, 24% of the hypertensives demonstrated bilateral orthostatic renal dysfunction. Exercise caused the hippurate transport disturbance to increase. Fifty-seven percent of all hypertensives developed evidence of marked, bilateral, renal dysfunction during ergometric stress, so that exercise renography was shown to be a more sensitive test of the presence of transient tubular dysfunction in hypertension than the standing renogram. In normotensive controls the hippurate functional scintigram failed to be influenced by posture and exercise. The results suggest presence in hypertension of transient, posture- and exercise-mediated alterations of renal cortical blood flow

Lipopolysaccharide-induced acute renal failure in conscious rats

DEFF Research Database (Denmark)

Jonassen, Thomas E N; Graebe, Martin; Promeneur, Dominique

2002-01-01

In conscious, chronically instrumented rats we examined 1) renal tubular functional changes involved in lipopolysaccharide (LPS)-induced acute renal failure; 2) the effects of LPS on the expression of selected renal tubular water and sodium transporters; and 3) effects of milrinone......-alpha and lactate, inhibited the LPS-induced tachycardia, and exacerbated the acute LPS-induced fall in GFR. Furthermore, Ro-20-1724-treated rats were unable to maintain MAP. We conclude 1) PDE3 or PDE4 inhibition exacerbates LPS-induced renal failure in conscious rats; and 2) LPS treated rats develop an escape......, a phosphodiesterase type 3 (PDE3) inhibitor, and Ro-20-1724, a PDE4 inhibitor, on LPS-induced changes in renal function. Intravenous infusion of LPS (4 mg/kg b.wt. over 1 h) caused an immediate decrease in glomerular filtration rate (GFR) and proximal tubular outflow without changes in mean arterial pressure (MAP...

Interactions with selected drug renal transporters and transporter-mediated cytotoxicity in antiviral agents from the group of acyclic nucleoside phosphonates

Czech Academy of Sciences Publication Activity Database

Mandíková, J.; Volková, M.; Pávek, P.; Česnek, Michal; Janeba, Zlatko; Kubíček, V.; Trejtnar, F.

2013-01-01

Roč. 311, č. 3 (2013), s. 135-146 ISSN 0300-483X Institutional support: RVO:61388963 Keywords : hOAT1 * hCNTs * MDR1 * BCRP * nephrotoxicity * transmembrane transport Subject RIV: FR - Pharmacology ; Medidal Chemistry Impact factor: 3.745, year: 2013

Interaction of nonsteroidal anti-inflammatory drugs with multidrug resistance protein (MRP) 2/ABCC2- and MRP4/ABCC4-mediated methotrexate transport.

NARCIS (Netherlands)

El-Sheikh, A.A.K.; Heuvel, J.J.M.W. van den; Koenderink, J.B.; Russel, F.G.M.

2007-01-01

Methotrexate (MTX) has been used in combination with nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of inflammatory diseases as well as malignancies. Especially at high MTX dosages, severe adverse effects with this combination may occur, usually resulting from an impaired renal

Efficacy of prophylactic irradiation in altering renal allograft survival

International Nuclear Information System (INIS)

Faber, R.; Johnson, H.K.; Braren, H.V.; Richie, R.E.

1974-01-01

Renal allograft rejection is a complex phenomenon involving both cell-mediated and humoral antibody responses. Most transplant programs have used a combination of therapeutic modalites to combat the immune system in an attempt to prolong both allograft and patient survival. Corticosteroids (methylprednisolone (Solu-Medrol) and prednisone and azathioprine (Imuran) are widely accepted as immunosuppressive drugs; however, both are non-specific and have the disadvantage of compromising the recipients' defense mechanisms. Nevertheless, these drugs have proved to be essential to the success of renal transplantation and they are routinely used while the efficacy of other modalities continues to be evaluated. We could find no reports of a prospective study to evaluate the efficacy of prophylactic irradiation in the complex therapeutic situation of renal transplantation with the only variable being the administration of local graft irradiation. The purpose of this study was to evaluate prophylactic graft irradiation for its effectiveness in preventing graft rejection in conjunction with Imuran and corticosteroids

Sodium glucose co-transporter 2 inhibitors: blocking renal tubular reabsorption of glucose to improve glycaemic control in patients with diabetes.

Science.gov (United States)

Jabbour, S A; Goldstein, B J

2008-08-01

The kidney plays a central role in the regulation of plasma glucose levels, although until recently this has not been widely appreciated or considered a target for therapeutic intervention. The sodium glucose co-transporter type 2 (SGLT2) located in the plasma membrane of cells lining the proximal tubule mediates the majority of renal glucose reabsorption from the tubular fluid, which normally prevents the loss of glucose in the urine. Competitive inhibitors of SGLT2 that provoke the renal excretion of glucose have been discovered, thereby providing a unique mechanism to potentially lower the elevated blood glucose levels in patients with diabetes. To explore the physiology of SGLT2 action and discuss several SGLT2 inhibitors that have entered early clinical development. All publicly available data were identified by searching the internet for 'SGLT2' and 'SGLT2 inhibitor' through 1 November 2007. Published articles, press releases and abstracts presented at national and international meetings were considered. Sodium glucose co-transporter type 2 inhibition is a novel treatment option for diabetes, which has been studied in preclinical models and a few potent and selective SGLT2 inhibitors have been reported and are currently in clinical development. These agents appear to be safe and generally well tolerated, and will potentially be a beneficial addition to the growing battery of oral antihyperglycaemic agents.

Treatment of acute renal artery embolism

International Nuclear Information System (INIS)

Fava, C.; Grosso, M.; Malara, D.; Barile, C.

1987-01-01

The possible ways of treating renal artery embolisms are reviewed with an examination of their advantages and defects. Surgical treatment has a fairly high mortality rate but quickly cures any type of vascular occlusion and will cures any type of vascular occlusion and will cure any concomitant problems such as arterial stenosis. Medical treatement with anticoagulant or mortality rate and is effective even on narrow blood vessels but the response varies according to the type of thromboembolic damage and the way the drugs are administred. Recently developed forms of radiological treatment are also examined. A personal technique successfully applied to an embolism in a patient with only one functioning kidney is described. It consists of a two-stepmechanical and pharmacological attack. First the occluded artery was opened by means of a balloon catheter that was pushedbeyond the embolism and withdrawn into the aorta after inflation of the balloon. Thrombolytic drugs (Urokinase) were then infused through the catheter into the bed of the renal artery in order to cure the secondary thrombosis found, as is generally the case, downstream of the embolism. The technique appears ideal for the treatment of patients with embolisms and total involvement of the renal parenchyma, especially when their general condition makes surgery inadvisable

Drugs, ionophoric peptides, and steroids as substrates of the yeast multidrug transporter Pdr5p

NARCIS (Netherlands)

Kolaczkowski, M; vanderRest, M; CybularzKolaczkowska, A; Soumillion, JP; Konings, WN; Goffeau, A

1996-01-01

Pdr5p is the yeast Saccharomyces cerevisiae ATP-binding cassette transporter conferring resistance to several unrelated drugs. Its high overproduction in Pdr1p transcription factor mutants allows us to study the molecular mechanism of multidrug transport and substrate specificity. We have developed

Organic anion transporter (Slc22a) family members as mediators of toxicity

International Nuclear Information System (INIS)

Sweet, Douglas H.

2005-01-01

Exposure of the body to toxic organic anions is unavoidable and occurs from both intentional and unintentional sources. Many hormones, neurotransmitters, and waste products of cellular metabolism, or their metabolites, are organic anions. The same is true for a wide variety of medications, herbicides, pesticides, plant and animal toxins, and industrial chemicals and solvents. Rapid and efficient elimination of these substances is often the body's best defense for limiting both systemic exposure and the duration of their pharmacological or toxicological effects. For organic anions, active transepithelial transport across the renal proximal tubule followed by elimination via the urine is a major pathway in this detoxification process. Accordingly, a large number of organic anion transport proteins belonging to several different gene families have been identified and found to be expressed in the proximal nephron. The function of these transporters, in combination with the high volume of renal blood flow, predisposes the kidney to increased toxic susceptibility. Understanding how the kidney mediates the transport of organic anions is integral to achieving desired therapeutic outcomes in response to drug interactions and chemical exposures, to understanding the progression of some disease states, and to predicting the influence of genetic variation upon these processes. This review will focus on the organic anion transporter (OAT) family and discuss the known members, their mechanisms of action, subcellular localization, and current evidence implicating their function as a determinant of the toxicity of certain endogenous and xenobiotic agents

Mechanistic insights of intestinal absorption and renal conservation of folate in chronic alcoholism.

Science.gov (United States)

Wani, Nissar Ahmad; Thakur, Shilpa; Najar, Rauf Ahmad; Nada, Ritambhara; Khanduja, Krishan Lal; Kaur, Jyotdeep

2013-03-01

Folate mediated one-carbon metabolism is of fundamental importance for various cellular processes, including DNA synthesis and methylation of biological molecules. Due to the exogenous requirement of folate in mammals, there exists a well developed epithelial folate transport system for regulation of normal folate homeostasis. The intestinal and renal folate uptake is tightly and diversely regulated and disturbances in folate homeostasis like in alcoholism have pathological consequences. The study was sought to delineate the regulatory mechanism of folate uptake in intestine and reabsorption in renal tubular cells that could evaluate insights of malabsorption during alcoholism. The folate transporters PCFT and RFC were found to be associated with lipid rafts of membrane surfaces in intestine and kidney. Importantly, the observed lower intestinal and renal folate uptake was associated with decreased levels of folate transporter viz. PCFT and RFC in lipid rafts of intestinal and renal membrane surfaces. The decreased association of folate transporters in lipid rafts was associated with decreased protein and mRNA levels. In addition, immunohistochemical studies showed that alcoholic conditions deranged that localization of PCFT and RFC. These findings could explain the possible mechanistic insights that may result in folate malabsorption during alcoholism. Copyright © 2013 Elsevier Inc. All rights reserved.

The Ussing Chamber Assay to Study Drug Metabolism and Transport in the Human Intestine.

Science.gov (United States)

Kisser, Beatrice; Mangelsen, Eva; Wingolf, Caroline; Partecke, Lars Ivo; Heidecke, Claus-Dieter; Tannergren, Christer; Oswald, Stefan; Keiser, Markus

2017-06-22

The Ussing chamber is an old but still powerful technique originally designed to study the vectorial transport of ions through frog skin. This technique is also used to investigate the transport of chemical agents through the intestinal barrier as well as drug metabolism in enterocytes, both of which are key determinants for the bioavailability of orally administered drugs. More contemporary model systems, such as Caco-2 cell monolayers or stably transfected cells, are more limited in their use compared to the Ussing chamber because of differences in expression rates of transporter proteins and/or metabolizing enzymes. While there are limitations to the Ussing chamber assay, the use of human intestinal tissue remains the best laboratory test for characterizing the transport and metabolism of compounds following oral administration. Detailed in this unit is a step-by-step protocol for preparing human intestinal tissue, for designing Ussing chamber experiments, and for analyzing and interpreting the findings. © 2017 by John Wiley & Sons, Inc. Copyright © 2017 John Wiley & Sons, Inc.

Do the recommended standards for in vitro biopharmaceutic classification of drug permeability meet the "passive transport" criterion for biowaivers?

Science.gov (United States)

Žakelj, Simon; Berginc, Katja; Roškar, Robert; Kraljič, Bor; Kristl, Albin

2013-01-01

BCS based biowaivers are recognized by major regulatory agencies. An application for a biowaiver can be supported by or even based on "in vitro" measurements of drug permeability. However, guidelines limit the application of biowaivers to drug substances that are transported only by passive mechanisms. Regarding published permeability data as well as measurements obtained in our institution, one can rarely observe drug substances that conform to this very strict criterion. Therefore, we measured the apparent permeability coefficients of 13 drugs recommended by FDA's Guidance to be used as standards for "in vitro" permeability classification. The asymmetry of permeability data determined for both directions (mucosal-to-serosal and serosalto- mucosal) through the rat small intestine revealed significant active transport for four out of the nine high-permeability standards and for all four low-permeability standard drugs. As could be expected, this asymmetry was abolished at 4°C on rat intestine. The permeability of all nine high-permeability, but none of the low permeability standards, was also much lower when measured with intestinal tissue, Caco-2 cell monolayers or artificial membranes at 4°C compared to standard conditions (37°C). Additionally, concurrent testing of several standard drugs revealed that membrane transport can be affected by the use of internal permeability standards. The implications of the results are discussed regarding the regulatory aspects of biopharmaceutical classification, good practice in drug permeability evaluation and regarding the general relevance of transport proteins with broad specificity in drug absorption.

Selective renal vasoconstriction, exaggerated natriuresis and excretion rates of exosomic proteins in essential hypertension

DEFF Research Database (Denmark)

Damkjaer, M.; Jensen, Pia Hønnerup; Schwämmle, Veit

2014-01-01

AimIn essential hypertension (EH), the regulation of renal sodium excretion is aberrant. We hypothesized that in mild EH, (i) abnormal dynamics of plasma renin concentration (PRC) and atrial natriuretic peptide (ANP) are responsible for the exaggerated natriuresis, and (ii) exosomic protein...... patterns reflect the renal tubular abnormality involved in the dysregulation of sodium excretion. MethodsAfter 2-week drug washout and 4-day diet, systemic and renal hemodynamics, cardio-renal hormones, glomerular filtration and renal excretion were studied in male patients during saline loading (SL...

Wnt Signaling in Renal Cell Carcinoma

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Qi Xu

2016-06-01

Full Text Available Renal cell carcinoma (RCC accounts for 90% of all kidney cancers. Due to poor diagnosis, high resistance to the systemic therapies and the fact that most RCC cases occur sporadically, current research switched its focus on studying the molecular mechanisms underlying RCC. The aim is the discovery of new effective and less toxic anti-cancer drugs and novel diagnostic markers. Besides the PI3K/Akt/mTOR, HGF/Met and VHL/hypoxia cellular signaling pathways, the involvement of the Wnt/β-catenin pathway in RCC is commonly studied. Wnt signaling and its targeted genes are known to actively participate in different biological processes during embryonic development and renal cancer. Recently, studies have shown that targeting this pathway by alternating/inhibiting its intracellular signal transduction can reduce cancer cells viability and inhibit their growth. The targets and drugs identified show promising potential to serve as novel RCC therapeutics and prognostic markers. This review aims to summarize the current status quo regarding recent research on RCC focusing on the involvement of the Wnt/β-catenin pathway and how its understanding could facilitate the identification of potential therapeutic targets, new drugs and diagnostic biomarkers.

Effect of indomethacin and salt depletion on renal proton MR imaging; An experimental study in the rat

Energy Technology Data Exchange (ETDEWEB)

Heyman, S.N.; Mammen, M. (Harvard Medical School, Boston, MA (United States). Charles A Dana Research Inst. Beth Israel Hospital, Boston, MA (United States))

1991-11-01

Blockade of the synthesis of vasodilating prostaglandins with non-steroidal anti-inflammatory drugs (NSAID) renders the renal medulla susceptible to hypoxic injury with reduced renal function, especially in clinical conditions characterized by volume depletion. Alterations in renal hemodynamics and urine production may effect renal MR imaging under these circumstances. We injected salt-depleted and control rats undergoing proton MR imaging with indomethacin 10 mg/kg. Indomethacin abolished the cortico-medullary T2-gradient and markedly diminished the overall renal signal in salt-depleted rats only. These changes, which progressed over a period of 40 min after indomethacin was injected, probably result from renal oligemia and decreased urine production, with an associated decrease in T2-values. We suggest that a history of consumption of non-steroidal anti-inflammatory drugs should be obtained and taken into account in the evaluation of renal proton MR imaging, especially in the presence of salt and volume depletion. (orig.).

Is the renal kallikrein-kinin system a factor that modulates hypercalciuria?

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Armando Luis Negri

2017-01-01

Full Text Available Renal tubular calcium reabsorption is one of the principal factors that determine serum calcium concentration and calcium excretion. Calcium excretion is regulated by the distal convoluted tubule and connecting tubule, where the epithelial calcium channel TRPV5 can be found, which limits the rate of transcellular calcium transport. The dynamic presence of the TRPV5 channel on the surface of the tubular cell is mediated by an endosomal recycling process. Different intrarenal factors are involved in calcium channel fixation in the apical membrane, including the anti-ageing hormone klotho and tissue kallikrein (TK. Both proteins are synthesised in the distal tubule and secreted in the tubular fluid. TK stimulates active calcium reabsorption through the bradykinin receptor B2 that compromises TRPV5 activation through the protein kinase C pathway. TK-deficient mice show hypercalciuria of renal origin comparable to that seen in TRPV5 knockout mice. There is a polymorphism with loss of function of the human TK gene R53H (allele H that causes a marked decrease in enzymatic activity. The presence of the allele H seems to be common at least in the Japanese population (24%. These individuals have a tendency to greater calcium and sodium excretion in urine that is more evident during furosemide infusion. Future studies should analyse if manipulating the renal kallikrein-kinin system can correct idiopathic hypercalciuria with drugs other than thiazide diuretics.

Renal protection in diabetes--an emerging role for calcium antagonists

DEFF Research Database (Denmark)

Parving, H H; Tarnow, L; Rossing, P

1997-01-01

The combination of diabetes and hypertension increases the changes of progressive renal disorder and ultimately renal failure. Roughly 40% of all diabetics, whether insulin dependent or not, develop diabetic nephropathy. Diabetic nephropathy is the single most important cause of end-stage renal...... disease in the western world and accounts for more than a quarter of all end-stage renal diseases. It is also a major cause of increased morbidity and mortality in diabetic patients. Increased arterial blood pressure is an early and common phenomenon in incipient and overt diabetic nephropathy...... the ability to retard renal growth and possibly to attenuate mesangial entrapment of macromolecules and to attenuate the mitogenic effects of diverse growth factors. Calcium antagonists (except the old short-acting dihydropyridine drugs) reduce microalbuminuria and preserve kidney function in diabetic...

Functional genomics in renal transplantation and chronic kidney disease

International Nuclear Information System (INIS)

Wilflingseder, J.

2010-01-01

For the past decade, the development of genomic technology has revolutionized modern biological research. Functional genomic analyses enable biologists to study genetic events on a genome wide scale. Examples of applications are gene discovery, biomarker determination, disease classification, and drug target identification. Global expression profiles performed with microarrays enable a better understanding of molecular signature of human disease, including acute and chronic kidney disease. About 10 % of the population in western industrialized nations suffers from chronic kidney disease (CKD). Treatment of end stage renal disease, the final stage of CKD is performed by either hemo- or peritoneal dialysis or renal transplantation. The preferred treatment is renal transplantation, because of the higher quality of life. But the pathophysiology of the disease on a molecular level is not well enough understood and early biomarkers for acute and chronic kidney disease are missing. In my studies I focused on genomics of allograft biopsies, prevention of delayed graft function after renal transplantation, anemia after renal transplantation, biocompatibility of hemodialysis membranes and peritoneal dialysis fluids and cardiovascular diseases and bone disorders in CKD patients. Gene expression profiles, pathway analysis and protein-protein interaction networks were used to elucidate the underlying pathophysiological mechanism of the disease or phenomena, identifying early biomarkers or predictors of disease state and potentially drug targets. In summery my PhD thesis represents the application of functional genomic analyses in chronic kidney disease and renal transplantation. The results provide a deeper view into the molecular and cellular mechanisms of kidney disease. Nevertheless, future multicenter collaborative studies, meta-analyses of existing data, incorporation of functional genomics into large-scale prospective clinical trials are needed and will give biomedical

Molecular Properties of Drugs Interacting with SLC22 Transporters OAT1, OAT3, OCT1, and OCT2: A Machine-Learning Approach.

Science.gov (United States)

Liu, Henry C; Goldenberg, Anne; Chen, Yuchen; Lun, Christina; Wu, Wei; Bush, Kevin T; Balac, Natasha; Rodriguez, Paul; Abagyan, Ruben; Nigam, Sanjay K

2016-10-01

Statistical analysis was performed on physicochemical descriptors of ∼250 drugs known to interact with one or more SLC22 "drug" transporters (i.e., SLC22A6 or OAT1, SLC22A8 or OAT3, SLC22A1 or OCT1, and SLC22A2 or OCT2), followed by application of machine-learning methods and wet laboratory testing of novel predictions. In addition to molecular charge, organic anion transporters (OATs) were found to prefer interacting with planar structures, whereas organic cation transporters (OCTs) interact with more three-dimensional structures (i.e., greater SP3 character). Moreover, compared with OAT1 ligands, OAT3 ligands possess more acyclic tetravalent bonds and have a more zwitterionic/cationic character. In contrast, OCT1 and OCT2 ligands were not clearly distinquishable form one another by the methods employed. Multiple pharmacophore models were generated on the basis of the drugs and, consistent with the machine-learning analyses, one unique pharmacophore created from ligands of OAT3 possessed cationic properties similar to OCT ligands; this was confirmed by quantitative atomic property field analysis. Virtual screening with this pharmacophore, followed by transport assays, identified several cationic drugs that selectively interact with OAT3 but not OAT1. Although the present analysis may be somewhat limited by the need to rely largely on inhibition data for modeling, wet laboratory/in vitro transport studies, as well as analysis of drug/metabolite handling in Oat and Oct knockout animals, support the general validity of the approach-which can also be applied to other SLC and ATP binding cassette drug transporters. This may make it possible to predict the molecular properties of a drug or metabolite necessary for interaction with the transporter(s), thereby enabling better prediction of drug-drug interactions and drug-metabolite interactions. Furthermore, understanding the overlapping specificities of OATs and OCTs in the context of dynamic transporter tissue

Dilemma of Renal Disease in Elderly

Directory of Open Access Journals (Sweden)

El Essawy Abdel

2008-01-01

Full Text Available The aging process results in profound anatomic and functional changes in a number of human body systems. Changes in kidney function with normal aging are the most dramatic of any human organ or organ system. These include anatomical, physiological, hemodynamic and immunological changes. Increased propensities of systemic diseases and exposure to poly-pharmacy of the aged group have an additive deleterious effect. The aforementioned changes have its implications on clinical presentations, management and prognosis of all renal diseases in elderly. Atypical presentation, more frequent and longer course are the characteristics of acute renal failure in this age group. Also, presentation of glomerular diseases, clinical course, prognosis, decision of performing a renal biopsy and use of immunosuppressive drugs in elderly specially those subgroup above 80 years of age are still a big challenges that needs a consensus and standardization.

Tratamento endovascular de aneurisma da artéria renal por embolização com micromolas preservando o fluxo sangüíneo renal: relato de caso Endovascular treatment of renal artery aneurysm using microcoil embolization and renal blood flow preservation: case report

Directory of Open Access Journals (Sweden)

Marco Aurélio Cardozo

2007-06-01

Full Text Available O tratamento endovascular da doença aneurismática da artéria renal tem sido, cada vez mais, aceito como uma alternativa à cirurgia convencional, especialmente em casos de aneurismas complexos intra-parenquimatosos ou que comprometam a bifurcação da artéria renal. Os autores relatam a experiência do tratamento endovascular de uma paciente com aneurisma sacular da bifurcação da artéria renal direita, associado à hipertensão renovascular de difícil controle. Foi realizada a cateterização seletiva da artéria renal, com a inserção de micromolas no saco aneurismático. O aneurisma foi completamente ocluído com preservação total do fluxo sanguíneo renal. A evolução clínica foi satisfatória com redução significativa das medicações anti-hipertensivas. A angio-tomografia de controle, após o oitavo mês do procedimento, confirmou o sucesso do tratamento.Endovascular treatment of renal artery aneurysmal disease has been increasingly accepted as an alternative to conventional surgery, especially in cases of renal artery bifurcation or complex intrarenal aneurysms. The authors report a case of endovascular treatment of a saccular aneurysm of the right renal artery bifurcation associated with poorly controlled renovascular hypertension. Selective catheterization of the renal artery was performed and microcoils were inserted into the aneurysmal sac. The aneurysm was completely obliterated with total preservation of renal blood flow. Clinical evolution was satisfactory with significant reduction in anti-hypertensive drugs. Control tomographic angiography, after eight months, confirmed treatment success.

75 FR 8526 - Procedures for Transportation Workplace Drug and Alcohol Testing Programs

Science.gov (United States)

2010-02-25

... 2105-AD64 Procedures for Transportation Workplace Drug and Alcohol Testing Programs AGENCY: Office of... required method. However, in response to comments requesting additional flexibility in testing methods, the... may increase flexibility and lower costs for employers who choose to use them over more expensive...

75 FR 8528 - Procedures for Transportation Workplace Drug and Alcohol Testing Programs

Science.gov (United States)

2010-02-25

... OST 2105-AD84 Procedures for Transportation Workplace Drug and Alcohol Testing Programs AGENCY: Office... of small entities, for purposes of the Regulatory Flexibility Act. The Department makes these... necessary for the Department to conduct a regulatory evaluation or Regulatory Flexibility Analysis for this...

Renal cancer in kidney transplanted patients.

Science.gov (United States)

Frascà, Giovanni M; Sandrini, Silvio; Cosmai, Laura; Porta, Camillo; Asch, William; Santoni, Matteo; Salviani, Chiara; D'Errico, Antonia; Malvi, Deborah; Balestra, Emilio; Gallieni, Maurizio

2015-12-01

Renal cancer occurs more frequently in renal transplanted patients than in the general population, affecting native kidneys in 90% of cases and the graft in 10 %. In addition to general risk factors, malignancy susceptibility may be influenced by immunosuppressive therapy, the use of calcineurin inhibitors (CNI) as compared with mammalian target of rapamycin inhibitors, and the length of dialysis treatment. Acquired cystic kidney disease may increase the risk for renal cancer after transplantation, while autosomal dominant polycystic kidney disease does not seem to predispose to cancer development. Annual ultrasound evaluation seems appropriate in patients with congenital or acquired cystic disease or even a single cyst in native kidneys, and every 2 years in patients older than 60 years if they were on dialysis for more than 5 years before transplantation. Immunosuppression should be lowered in patients who develop renal cancer, by reduction or withdrawal of CNI. Although more evidence is still needed, it seems reasonable to shift patients from CNI to everolimus or sirolimus if not already treated with one of these drugs, with due caution in subjects with chronic allograft nephropathy.

Na+-K+ pump in chronic renal failure

International Nuclear Information System (INIS)

Deepak, K.; Kahn, T.

1987-01-01

This review summarizes the evidence for the defect in Na + -K + pump in chronic renal failure, considers the role of various factors in causing this defect, and discusses the clinical implications thereof. Intracellular Na is elevated in erythrocytes, leukocytes, and muscle cells from some patients with chronic renal failure (CRF). Recent evidence suggest that this elevation of cell Na may be, in large part, a consequence of decreased number of Na + -K + pump units per cell. Maintenance dialysis over a period of weeks ameliorates the defect in intracellular Na + , and this improvement is contemporaneous with an increase in the number of Na + -K + pump sites per cell. In erythrocytes with normal cell Na + , acute hemodialysis increases the rate of 22 Na + and 42 K + transport. Many factors such as the presence of retained toxic metabolite or circulating inhibitor in the uremic plasma, or biochemical changes produced by acute hemodialysis, may explain this finding. In cells with high cell Na + , the pump-mediated 42 K + transport is normalized at the expense of a raised cell Na + . The decreased muscle membrane potential in uremic subjects has been attributed to a decreased activity of Na + -K + pump. The authors discuss the role of hormonal abnormalities and circulating inhibitors, which may cause an acute inhibition of the pump and of other factors such as K + depletion, which may cause more chronic alterations. The implications of alteration of Na + and K + pump transport and raised cell Na + on other non-pump-mediated transport pathways are discussed. Raised cell Na + may be a marker for the adequacy of maintenance dialysis in patients with end-stage renal failure

Precision-cut kidney slices (PCKS to study development of renal fibrosis and efficacy of drug targeting ex vivo

Directory of Open Access Journals (Sweden)

Fariba Poosti

2015-10-01

Full Text Available Renal fibrosis is a serious clinical problem resulting in the greatest need for renal replacement therapy. No adequate preventive or curative therapy is available that could be clinically used to target renal fibrosis specifically. The search for new efficacious treatment strategies is therefore warranted. Although in vitro models using homogeneous cell populations have contributed to the understanding of the pathogenetic mechanisms involved in renal fibrosis, these models poorly mimic the complex in vivo milieu. Therefore, we here evaluated a precision-cut kidney slice (PCKS model as a new, multicellular ex vivo model to study the development of fibrosis and its prevention using anti-fibrotic compounds. Precision-cut slices (200-300 μm thickness were prepared from healthy C57BL/6 mouse kidneys using a Krumdieck tissue slicer. To induce changes mimicking the fibrotic process, slices were incubated with TGFβ1 (5 ng/ml for 48 h in the presence or absence of the anti-fibrotic cytokine IFNγ (1 µg/ml or an IFNγ conjugate targeted to PDGFRβ (PPB-PEG-IFNγ. Following culture, tissue viability (ATP-content and expression of α-SMA, fibronectin, collagen I and collagen III were determined using real-time PCR and immunohistochemistry. Slices remained viable up to 72 h of incubation, and no significant effects of TGFβ1 and IFNγ on viability were observed. TGFβ1 markedly increased α-SMA, fibronectin and collagen I mRNA and protein expression levels. IFNγ and PPB-PEG-IFNγ significantly reduced TGFβ1-induced fibronectin, collagen I and collagen III mRNA expression, which was confirmed by immunohistochemistry. The PKCS model is a novel tool to test the pathophysiology of fibrosis and to screen the efficacy of anti-fibrotic drugs ex vivo in a multicellular and pro-fibrotic milieu. A major advantage of the slice model is that it can be used not only for animal but also for (fibrotic human kidney tissue.

Mecanismos del daño celular en la insuficiencia renal aguda Mechanisms of cell damage in acute renal failure

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José Martínez

1989-01-01

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Los mecanismos del da no celular en la insuficiencia renal aguda Incluyen alteraciones en la producción de energía, la permeabilidad celular y el transporte de calcio. Dichas alteraciones producen cambios progresivos en la estructura celular que pueden ser reversibles si desaparece la causa que llevó a la falla renal, excepto cuando se alcanza la fase final de la lesión de la membrana y se llega a necrosis celular. Este mismo fenómeno probablemente ocurre tambIén en situaciones clínicas.

The mechanisms of cellular damage In acute renal failure Include alterations In energy production, cell membrane permeability and calcium transport. These changes lead to progressive damage of the whole cellular structure which In general can be reversible If the precipitating cause disappears, except when the final stages of cell membrane lesion take place and cellular necrosis has occurred. This phenomenon probably applies for the clinical settling as well.

Association of drug transporter expression with mortality and progression-free survival in stage IV head and neck squamous cell carcinoma.

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Rolf Warta

Full Text Available Drug transporters such as P-glycoprotein (ABCB1 have been associated with chemotherapy resistance and are considered unfavorable prognostic factors for survival of cancer patients. Analyzing mRNA expression levels of a subset of drug transporters by quantitative reverse transcription polymerase chain reaction (qRT-PCR or protein expression by tissue microarray (TMA in tumor samples of therapy naïve stage IV head and neck squamous cell carcinoma (HNSCC (qRT-PCR, n = 40; TMA, n = 61, this in situ study re-examined the significance of transporter expression for progression-free survival (PFS and overall survival (OS. Data from The Cancer Genome Atlas database was used to externally validate the respective findings (n = 317. In general, HNSCC tended to lower expression of drug transporters compared to normal epithelium. High ABCB1 mRNA tumor expression was associated with both favorable progression-free survival (PFS, p = 0.0357 and overall survival (OS, p = 0.0535. Similar results were obtained for the mRNA of ABCC1 (MRP1, multidrug resistance-associated protein 1; PFS, p = 0.0183; OS, p = 0.038. In contrast, protein expression of ATP7b (copper transporter ATP7b, mRNA expression of ABCG2 (BCRP, breast cancer resistance protein, ABCC2 (MRP2, and SLC31A1 (hCTR1, human copper transporter 1 did not correlate with survival. Cluster analysis however revealed that simultaneous high expression of SLC31A1, ABCC2, and ABCG2 indicates poor survival of HNSCC patients. In conclusion, this study militates against the intuitive dogma where high expression of drug efflux transporters indicates poor survival, but demonstrates that expression of single drug transporters might indicate even improved survival. Prospectively, combined analysis of the 'transportome' should rather be performed as it likely unravels meaningful data on the impact of drug transporters on survival of patients with HNSCC.

The exercise renogram. A new approach documents renal involvement in systemic hypertension

International Nuclear Information System (INIS)

Clorius, J.H.; Schmidlin, P.

1983-01-01

Hippurate functional scintiscans were obtained in 51 hypertensive patients and in 15 controls. We investigated the influence that posture and exercise have on hippurate kinetics in patients with hypertension. A posture- or exercise-induced disturbance of renal hippurate transport was sought. All persons were examined in prone and standing positions, as well as during exercise. When prone and upright renograms were compared, 24% of the hypertensives demonstrated bilateral orthostatic renal dysfunction. Exercise caused the hippurate transport disturbance to increase. Fifty-seven percent of all hypertensives developed evidence of marked, bilateral, renal dysfunction during ergometric stress, so that exercise renography was shown to be a more sensitive test of the presence of transient tubular dysfunction in hypertension than the standing renogram. In normotensive controls the hippurate functional scintigram failed to be influenced by posture and exercise. The results suggest presence in hypertension of transient, posture- and exercise-mediated alterations of renal cortical blood flow

Immunization after renal transplantation: current clinical practice

NARCIS (Netherlands)

Struijk, G. H.; Lammers, A. J. J.; Brinkman, R. J.; Lombarts, M. J. M. H.; van Vugt, M.; van der Pant, K. A. M. I.; ten Berge, I. J. M.; Bemelman, F. J.

2015-01-01

The use of potent immunosuppressive drugs and increased travel by renal transplant recipients (RTR) has augmented the risk for infectious complications. Immunizations and changes in lifestyle are protective. The Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group has developed

Renal Nerve Stimulation-Induced Blood Pressure Changes Predict Ambulatory Blood Pressure Response After Renal Denervation.

Science.gov (United States)

de Jong, Mark R; Adiyaman, Ahmet; Gal, Pim; Smit, Jaap Jan J; Delnoy, Peter Paul H M; Heeg, Jan-Evert; van Hasselt, Boudewijn A A M; Lau, Elizabeth O Y; Persu, Alexandre; Staessen, Jan A; Ramdat Misier, Anand R; Steinberg, Jonathan S; Elvan, Arif

2016-09-01

Blood pressure (BP) response to renal denervation (RDN) is highly variable and its effectiveness debated. A procedural end point for RDN may improve consistency of response. The objective of the current analysis was to look for the association between renal nerve stimulation (RNS)-induced BP increase before and after RDN and changes in ambulatory BP monitoring (ABPM) after RDN. Fourteen patients with drug-resistant hypertension referred for RDN were included. RNS was performed under general anesthesia at 4 sites in the right and left renal arteries, both before and immediately after RDN. RNS-induced BP changes were monitored and correlated to changes in ambulatory BP at a follow-up of 3 to 6 months after RDN. RNS resulted in a systolic BP increase of 50±27 mm Hg before RDN and systolic BP increase of 13±16 mm Hg after RDN (Pefficacy of RDN and predict BP response to RDN. © 2016 American Heart Association, Inc.

Hemodynamic and neurochemical determinates of renal function in chronic heart failure.

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Gilbert, Cameron; Cherney, David Z I; Parker, Andrea B; Mak, Susanna; Floras, John S; Al-Hesayen, Abdul; Parker, John D

2016-01-15

Abnormal renal function is common in acute and chronic congestive heart failure (CHF) and is related to the severity of congestion. However, treatment of congestion often leads to worsening renal function. Our objective was to explore basal determinants of renal function and their response to hemodynamic interventions. Thirty-seven patients without CHF and 59 patients with chronic CHF (ejection fraction; 23 ± 8%) underwent right heart catheterization, measurements of glomerular filtration rate (GFR; inulin) and renal plasma flow (RPF; para-aminohippurate), and radiotracer estimates of renal sympathetic activity. A subset (26 without, 36 with CHF) underwent acute pharmacological intervention with dobutamine or nitroprusside. We explored the relationship between baseline and drug-induced hemodynamic changes and changes in renal function. In CHF, there was an inverse relationship among right atrial mean pressure (RAM) pressure, RPF, and GFR. By contrast, mean arterial pressure (MAP), cardiac index (CI), and measures of renal sympathetic activity were not significant predictors. In those with CHF there was also an inverse relationship among the drug-induced changes in RAM as well as pulmonary artery mean pressure and the change in GFR. Changes in MAP and CI did not predict the change in GFR in those with CHF. Baseline values and changes in RAM pressure did not correlate with GFR in those without CHF. In the CHF group there was a positive correlation between RAM pressure and renal sympathetic activity. There was also an inverse relationship among RAM pressure, GFR, and RPF in patients with chronic CHF. The observation that acute reductions in RAM pressure is associated with an increase in GFR in patients with CHF has important clinical implications. Copyright © 2016 the American Physiological Society.

Cisplatin Therapy Does Not Worsen Renal Function in Severe Antenatal Bartter Syndrome.

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Welch, Thomas R; Shaffer, David R; Feldman, Darren R

2017-01-01

A 30-year-old man with severe antenatal Bartter syndrome, diagnosed and treated in infancy, developed testicular carcinoma. Despite the known renal complications of cisplatin, this drug was used for his chemotherapy because of its superior antineoplastic effect. Nonsteroidal anti-inflammatory drug administration was continued during cisplatin therapy. Despite an increase in his oral potassium requirement, renal function was maintained following completion of chemotherapy. In spite of its significant associated nephrotoxicity, cisplatin can be used in patients with severe antenatal Bartter syndrome if required for therapy of malignancy.

Renal denervation and hypertension.

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Schlaich, Markus P; Krum, Henry; Sobotka, Paul A; Esler, Murray D

2011-06-01

Essential hypertension remains one of the biggest challenges in medicine with an enormous impact on both individual and society levels. With the exception of relatively rare monogenetic forms of hypertension, there is now general agreement that the condition is multifactorial in nature and hence requires therapeutic approaches targeting several aspects of the underlying pathophysiology. Accordingly, all major guidelines promote a combination of lifestyle interventions and combination pharmacotherapy to reach target blood pressure (BP) levels in order to reduce overall cardiovascular risk in affected patients. Although this approach works for many, it fails in a considerable number of patients for various reasons including drug-intolerance, noncompliance, physician inertia, and others, leaving them at unacceptably high cardiovascular risk. The quest for additional therapeutic approaches to safely and effectively manage hypertension continues and expands to the reappraisal of older concepts such as renal denervation. Based on the robust preclinical and clinical data surrounding the role of renal sympathetic nerves in various aspects of BP control very recent efforts have led to the development of a novel catheter-based approach using radiofrequency (RF) energy to selectively target and disrupt the renal nerves. The available evidence from the limited number of uncontrolled hypertensive patients in whom renal denervation has been performed are auspicious and indicate that the procedure has a favorable safety profile and is associated with a substantial and presumably sustained BP reduction. Although promising, a myriad of questions are far from being conclusively answered and require our concerted research efforts to explore the full potential and possible risks of this approach. Here we briefly review the science surrounding renal denervation, summarize the current data on safety and efficacy of renal nerve ablation, and discuss some of the open questions that need

Renal artery stenting in solitary functioning kidneys: Technical and clinical results

International Nuclear Information System (INIS)

Sahin, Sinan; Cimsit, Cagatay; Andac, Nurten; Baltacioglu, Feyyaz; Tuglular, Serhan; Akoglu, Emel

2006-01-01

Objective: To evaluate the clinical and technical results of renal artery stenting for the treatment of renovascular hypertension and renal failure in patients with solitary functioning kidney. Materials and methods: Fifteen patients with solitary functioning kidney underwent renal artery stenting and were followed up for 12-60 months. Before the procedures, systolic and diastolic blood pressures and serum creatinine levels were measured and the number of antihypertensive drugs was recorded and followed up after stenting. In case of restenosis, either in-stent percutaneous transluminal renal angioplasty or stent-in-stent placement was performed. Results: Primary technical success rate was 100%. One lesion was nonostial while 14 were ostial. Primary patency rates were 100% for 6 months, 92.3% for 12 months, and 69.2% for 24 months. The secondary patency rate at 24 months was 100%. The differences between the baseline and postprocedural values of systolic blood pressures, diastolic blood pressures and the number of antihypertensive drug were statistically significant (P < 0.05), except the values of serum creatinine. Hypertension was cured in 1 (6.7%) patient, improved in 4 (26.6%) and stabilized in 10 (66.7%) patients. Renal function improved in 9 (60%), stabilized in 4 (26.6%), and deteriorated in 2 (13.4%) patients. Minor complication rate was 13.4% and major complication rate was 13.4%. Conclusion: Revascularization of renal artery stenosis using stent in solitary functioning kidneys is a safe and efficient procedure with high primary technical results, low restenosis rates and acceptable complication rates. It has an improving and controlling effect on blood pressure and renal functions

Renal artery stenting in solitary functioning kidneys: Technical and clinical results

Energy Technology Data Exchange (ETDEWEB)

Sahin, Sinan [Dr. Siyami Ersek Thoracic and Cardiovascular Surgery Hospital, Department of Radiology, Istanbul (Turkey)]. E-mail: sinan.sahin@e-kolay.net; Cimsit, Cagatay [Marmara University, School of Medicine, Department of Radiology, Istanbul (Turkey); Andac, Nurten [Marmara University, School of Medicine, Department of Radiology, Istanbul (Turkey); Baltacioglu, Feyyaz [Marmara University, School of Medicine, Department of Radiology, Istanbul (Turkey); Tuglular, Serhan [Marmara University, School of Medicine, Department of Nephrology, Istanbul (Turkey); Akoglu, Emel [Marmara University, School of Medicine, Department of Nephrology, Istanbul (Turkey)

2006-01-15

Objective: To evaluate the clinical and technical results of renal artery stenting for the treatment of renovascular hypertension and renal failure in patients with solitary functioning kidney. Materials and methods: Fifteen patients with solitary functioning kidney underwent renal artery stenting and were followed up for 12-60 months. Before the procedures, systolic and diastolic blood pressures and serum creatinine levels were measured and the number of antihypertensive drugs was recorded and followed up after stenting. In case of restenosis, either in-stent percutaneous transluminal renal angioplasty or stent-in-stent placement was performed. Results: Primary technical success rate was 100%. One lesion was nonostial while 14 were ostial. Primary patency rates were 100% for 6 months, 92.3% for 12 months, and 69.2% for 24 months. The secondary patency rate at 24 months was 100%. The differences between the baseline and postprocedural values of systolic blood pressures, diastolic blood pressures and the number of antihypertensive drug were statistically significant (P < 0.05), except the values of serum creatinine. Hypertension was cured in 1 (6.7%) patient, improved in 4 (26.6%) and stabilized in 10 (66.7%) patients. Renal function improved in 9 (60%), stabilized in 4 (26.6%), and deteriorated in 2 (13.4%) patients. Minor complication rate was 13.4% and major complication rate was 13.4%. Conclusion: Revascularization of renal artery stenosis using stent in solitary functioning kidneys is a safe and efficient procedure with high primary technical results, low restenosis rates and acceptable complication rates. It has an improving and controlling effect on blood pressure and renal functions.

Nanomedicines for renal disease: current status and future applications

DEFF Research Database (Denmark)

Kamaly, Nazila; He, John C.; Ausiello, Dennis A.

2016-01-01

, alongside research efforts in tissue regeneration and organ-on-a-chip investigations, are likely to provide novel solutions to treat kidney diseases. Our understanding of renal anatomy and of how the biological and physico-chemical properties of nanomedicines (the combination of a nanocarrier and a drug......Treatment and management of kidney disease currently presents an enormous global burden, and the application of nanotechnology principles to renal disease therapy, although still at an early stage, has profound transformative potential. The increasing translation of nanomedicines to the clinic......) influence their interactions with renal tissues has improved dramatically. Tailoring of nanomedicines in terms of kidney retention and binding to key membranes and cell populations associated with renal diseases is now possible and greatly enhances their localization, tolerability, and efficacy. This Review...

Skin Findings in Renal Transplantation Patients

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Demet Kartal

2013-03-01

Full Text Available Objective: It was aimed to identify skin findings those were seen in patients who undergone renal transplantation. Methods: Patients who have been followed in Erciyes University Nephrology Hospital renal transplantation outpatient clinic were included in the study. They were evaluated for dermatologic findings during routine controls. Age, gender, transplantation date, identity of organ donor, history of medications, dermatological history and dermatological findings during examination were recorded. Biopsy was performed when needed. Results: In total 94 patients, 25 female (26.6% and 69 male (73.4%, were recruited to the study. Mean age was 36±10 years. The most frequent skin finding was drug-related acne (n=20. Most common infectious disease was verruca (n=17. There were viral disease other than verruca such as herpes zoster (n=3, superficial mycosis such as onychomycosis (n=5, tinea versicolor, tinea pedis and bacterial skin disease (n=2, and paronychia (n=1 and pre-malign lesions such as actinic cheilitis and bowenoid papulosis. Besides these, stria (n=3, kserosis (n=2, cornu cutaneum, café-au-lait spots, sebaceous hyperplasia and seborrheic dermatitis, skin tag, hypertrichosis, unguis incarinatus and calcinosis were other skin findings those were seen. No malign skin lesion was observed in any of patients. Conclusion: Miscellaneous skin lesions should develop in patients those undergone renal transplantation due to long-term utilization of various immunosuppressive drugs.

Lansoprazole Exacerbates Pemetrexed-Mediated Hematologic Toxicity by Competitive Inhibition of Renal Basolateral Human Organic Anion Transporter 3.

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Ikemura, Kenji; Hamada, Yugo; Kaya, Chinatsu; Enokiya, Tomoyuki; Muraki, Yuichi; Nakahara, Hiroki; Fujimoto, Hajime; Kobayashi, Tetsu; Iwamoto, Takuya; Okuda, Masahiro

2016-10-01

Pemetrexed, a multitargeted antifolate, is eliminated by tubular secretion via human organic anion transporter 3 (hOAT3). Although proton pump inhibitors (PPIs) are frequently used in cancer patients, the drug interaction between PPIs and pemetrexed remains to be clarified. In this study, we examined the drug interaction between pemetrexed and PPIs in hOAT3-expressing cultured cells, and retrospectively analyzed the impact of PPIs on the development of hematologic toxicity in 108 patients who received pemetrexed and carboplatin treatment of nonsquamous non-small cell lung cancer for the first time between January 2011 and June 2015. We established that pemetrexed was transported via hOAT3 (Km = 68.3 ± 11.1 µM). Lansoprazole, rabeprazole, pantoprazole, esomeprazole, omeprazole, and vonoprazan inhibited hOAT3-mediated uptake of pemetrexed in a concentration-dependent manner. The inhibitory effect of lansoprazole was much greater than those of other PPIs and the apparent IC50 value of lansoprazole against pemetrexed transport via hOAT3 was 0.57 ± 0.17 µM. The inhibitory type of lansoprazole was competitive. In a retrospective study, multivariate analysis revealed that coadministration of lansoprazole, but not other PPIs, with pemetrexed and carboplatin was an independent risk factor significantly contributing to the development of hematologic toxicity (odds ratio: 10.004, P = 0.005). These findings demonstrated that coadministration of lansoprazole could exacerbate the hematologic toxicity associated with pemetrexed, at least in part, by competitive inhibition of hOAT3. Our results would aid clinicians to make decisions of coadministration drugs to avoid drug interaction-induced side effects for achievement of safe and appropriate chemotherapy with pemetrexed. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

75 FR 8524 - Procedures for Transportation Workplace Drug and Alcohol Testing Programs

Science.gov (United States)

2010-02-25

... 2105-AD67 Procedures for Transportation Workplace Drug and Alcohol Testing Programs AGENCY: Office of... IFR to mitigate this conflict between the DOT rules and what we view as beneficial State laws by.... It merely eliminated a conflict that would have precluded parties from complying with certain State...

Drug dosing in chronic kidney disease.

Science.gov (United States)

Gabardi, Steven; Abramson, Stuart

2005-05-01

Patients with chronic kidney disease (CKD) are at high risk for adverse drug reactions and drug-drug interactions. Drug dosing in these patients often proves to be a difficult task. Renal dysfunction-induced changes in human pathophysiology regularly results may alter medication pharmacodynamics and handling. Several pharmacokinetic parameters are adversely affected by CKD, secondary to a reduced oral absorption and glomerular filtration; altered tubular secretion; and reabsorption and changes in intestinal, hepatic, and renal metabolism. In general, drug dosing can be accomplished by multiple methods; however, the most common recommendations are often to reduce the dose or expand the dosing interval, or use both methods simultaneously. Some medications need to be avoided all together in CKD either because of lack of efficacy or increased risk of toxicity. Nevertheless, specific recommendations are available for dosing of certain medications and are an important resource, because most are based on clinical or pharmacokinetic trials.

The Evaluation of Angiotensin-Converting Enzyme Inhibitors in Renal Elimination with Selected Molecular Descriptors

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Trbojevic Jovana

2017-06-01

Full Text Available Angiotensin-converting enzyme (ACE inhibitors modulate the function of the renin-angiotensin-aldosterone system, and they are commonly prescribed antihypertensive drugs especially in patients with renal failure. In this study, the relationships between several molecular properties of eight ACE inhibitors (enalapril, quinapril, fosinopril, ramipril, benazepril, perindopril, moexipril, trandolapril and their renal elimination data, from relevant literature, were investigated. The ’molecular descriptors of the ACE inhibitors, which included aqueous solubility data (logS; an electronic descriptor, polar surface area (PSA;, a constitutional parameter, molecular mass (Mr; and a geometric descriptor, volume value (Vol, as well as lipophilicity descriptors (logP values, were calculated using different software packages. Simple linear regression analysis showed the best correlation between renal elimination data and lipophilicity descriptor AClogP values (R2 = 0.5742. In the next stage of the study, multiple linear regression was applied to assess a higher correlation between the ACE inhibitors’ renal elimination data and lipophilicity, AClogP, with one additional descriptor as an independent variable. Good correlations were established between renal elimination data from the literature and the AClogP lipophilicity descriptor using the constitutional parameter (molecular mass (R2 = 0.7425 or the geometric descriptor (volume value (R2 = 0.7224 as an independent variable. The application of computed molecular descriptors in evaluating drug elimination is of great importance in drug research.

The rebirth of interest in renal tubular function.

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Lowenstein, Jerome; Grantham, Jared J

2016-06-01

The measurement of glomerular filtration rate by the clearance of inulin or creatinine has evolved over the past 50 years into an estimated value based solely on plasma creatinine concentration. We have examined some of the misconceptions and misunderstandings of the classification of renal disease and its course, which have followed this evolution. Furthermore, renal plasma flow and tubular function, which in the past were estimated by the clearance of the exogenous aryl amine, para-aminohippurate, are no longer measured. Over the past decade, studies in experimental animals with reduced nephron mass and in patients with reduced renal function have identified small gut-derived, protein-bound uremic retention solutes ("uremic toxins") that are poorly filtered but are secreted into the lumen by organic anion transporters (OATs) in the proximal renal tubule. These are not effectively removed by conventional hemodialysis or peritoneal dialysis. Residual renal function, urine produced in patients with advanced renal failure or undergoing dialysis treatment, may represent, at least in part, secretion of fluid and uremic toxins, such as indoxyl sulfate, mediated by proximal tubule OATs and might serve as a useful survival function. In light of this new evidence of the physiological role of proximal tubule OATs, we suggest that measurement of renal tubular function and renal plasma flow may be of considerable value in understanding and managing chronic kidney disease. Data obtained in normal subjects indicate that renal plasma flow and renal tubular function might be measured by the clearance of the endogenous aryl amine, hippurate. Copyright © 2016 the American Physiological Society.

Identification of residues in ABCG2 affecting protein trafficking and drug transport, using co-evolutionary analysis of ABCG sequences.

Science.gov (United States)

Haider, Ameena J; Cox, Megan H; Jones, Natalie; Goode, Alice J; Bridge, Katherine S; Wong, Kelvin; Briggs, Deborah; Kerr, Ian D

2015-07-17

ABCG2 is an ABC (ATP-binding cassette) transporter with a physiological role in urate transport in the kidney and is also implicated in multi-drug efflux from a number of organs in the body. The trafficking of the protein and the mechanism by which it recognizes and transports diverse drugs are important areas of research. In the current study, we have made a series of single amino acid mutations in ABCG2 on the basis of sequence analysis. Mutant isoforms were characterized for cell surface expression and function. One mutant (I573A) showed disrupted glycosylation and reduced trafficking kinetics. In contrast with many ABC transporter folding mutations which appear to be 'rescued' by chemical chaperones or low temperature incubation, the I573A mutation was not enriched at the cell surface by either treatment, with the majority of the protein being retained in the endoplasmic reticulum (ER). Two other mutations (P485A and M549A) showed distinct effects on transport of ABCG2 substrates reinforcing the role of TM helix 3 in drug recognition and transport and indicating the presence of intracellular coupling regions in ABCG2. © 2015 Authors.