scholarly journals Cytotoxicity of Antiviral Nucleotides Adefovir and Cidofovir Is Induced by the Expression of Human Renal Organic Anion Transporter 1

2000 ◽  
Vol 11 (3) ◽  
pp. 383-393 ◽  
Author(s):  
EDMUND S. HO ◽  
DEBORAH C. LIN ◽  
DIRK B. MENDEL ◽  
TOMAS CIHLAR
Keyword(s):  
Organic Anion ◽  
Critical Role ◽  
Antiviral Agents ◽  
Chinese Hamster ◽  
Organic Anion Transporter ◽  
Nucleotide Analogs ◽  
Anion Transporter ◽  
Organ Specific

Abstract. The transport of organic anions in proximal convoluted tubules plays an essential role in the active secretion of a variety of small molecules by the kidney. In addition to other anionic substrates, the human renal organic anion transporter 1 (hOAT1) is capable of transporting the nucleotide analogs adefovir and cidofovir. To investigate the involvement of hOAT1 in the mechanism of nephrotoxicity associated with these two clinically important antiviral agents, Chinese hamster ovary (CHO) cells were stably transfected with hOAT1 cDNA. The resulting CHOhOAT cells showed probenecid-sensitive and pH-dependent uptake of p-aminohippurate (Km = 15.4 μM, Vmax = 20.6 pmol/106 cells · min), a prototypical organic anion substrate. In addition, the stably expressed hOAT1 mediated efficient transport of adefovir (Km = 23.8 μM, Vmax = 46.0 pmol/106 cells · min) and cidofovir (Km = 58.0 μM, Vmax = 103 pmol/106 cells · min) such that the levels of intracellular metabolites of both nucleotides were >100-fold higher in CHOhOAT cells than in parental CHO. Consequently, adefovir and cidofovir were approximately 500-fold and 400-fold more cytotoxic, respectively, in CHOhOAT cells compared to CHO. The cytotoxicity of both drugs in CHOhOAT cells was markedly reduced in the presence of hOAT1 inhibitors. The cyclic prodrug of cidofovir, which exhibits reduced in vivo nephrotoxicity, was a poor substrate for hOAT1 and showed only marginally increased cytotoxicity in CHOhOAT cells. In conclusion, these studies demonstrate that hOAT1 plays a critical role in the organ-specific toxicity of adefovir and cidofovir, and indicates that CHOhOAT cells may represent a useful in vitro model to investigate the potential nephrotoxicity of clinically relevant organic anion agents.

scholarly journals Application of a PBPK Model of Rivaroxaban to Prospective Simulations of Drug-Drug-Disease Interactions with Protein Kinase Inhibitors in CA-VTE

2021 ◽  
Author(s):  
Eleanor Jing Yi Cheong ◽  
Daniel Zhi Wei Ng ◽  
Sheng Yuan Chin ◽  
Ziteng Wang ◽  
Eric Chun Yong Chan
Keyword(s):  
Protein Kinase ◽  
Kinase Inhibitors ◽  
Pbpk Model ◽  
Organic Anion ◽  
Protein Kinase Inhibitors ◽  
Organic Anion Transporter ◽  
Pbpk Modelling ◽  
Anion Transporter

Background and Purpose Rivaroxaban is emerging as a viable anticoagulant for the pharmacological management of cancer associated venous thromboembolism (CA-VTE). Being eliminated via CYP3A4/2J2-mediated metabolism and organic anion transporter 3 (OAT3)/P-glycoprotein-mediated renal secretion, rivaroxaban is susceptible to drug-drug interactions (DDIs) with protein kinase inhibitors (PKIs), erlotinib and nilotinib. Physiologically based pharmacokinetic (PBPK) modelling was applied to interrogate the DDIs for dose adjustment of rivaroxaban in CA-VTE. Experimental Approach The inhibitory potencies of erlotinib and nilotinib on CYP3A4/2J2-mediated metabolism of rivaroxaban were characterized. Using prototypical OAT3 inhibitor ketoconazole, in vitro OAT3 inhibition assays were optimized to ascertain the in vivo relevance of derived inhibitory constants (K). DDIs between rivaroxaban and erlotinib or nilotinib were investigated using iteratively verified PBPK model. Key Results Mechanism-based inactivation (MBI) of CYP3A4-mediated rivaroxaban metabolism by both PKIs and MBI of CYP2J2 by erlotinib were established. The importance of substrate specificity and nonspecific binding to derive OAT3-inhibitory K values of ketoconazole and nilotinib for the accurate prediction of DDIs was illustrated. When simulated rivaroxaban exposure variations with concomitant erlotinib and nilotinib therapy were evaluated using published dose-exposure equivalence metrics and bleeding risk analyses, dose reductions from 20 mg to 15 mg and 10 mg in normal and mild renal dysfunction, respectively, were warranted. Conclusion and Implications We established the PBPK-DDI platform to prospectively interrogate and manage clinically relevant interactions between rivaroxaban and PKIs in patients with underlying renal impairment. Rational dose adjustments were proposed, attesting to the capacity of PBPK modelling in facilitating precision medicine.

scholarly journals Mammalian colonocytes possess a carrier-mediated mechanism for uptake of vitamin B3 (niacin): studies utilizing human and mouse colonic preparations

2013 ◽  
Vol 305 (3) ◽  
pp. G207-G213 ◽  
Author(s):  
Jeyan S. Kumar ◽  
Veedamali S. Subramanian ◽  
Rubina Kapadia ◽  
Moti L. Kashyap ◽  
Hamid M. Said
Keyword(s):  
Nicotinic Acid ◽  
Large Intestine ◽  
Protein Tyrosine Kinase ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Vitamin B3 ◽  
Regulatory Pathways ◽  
Anion Transporter

Niacin (vitamin B3; nicotinic acid) plays an important role in maintaining redox state of cells and is obtained from endogenous and exogenous sources. The latter source has generally been assumed to be the dietary niacin, but another exogenous source that has been ignored is the niacin that is produced by the normal microflora of the large intestine. For this source of niacin to be bioavailable, it needs to be absorbed, but little is known about the ability of the large intestine to absorb niacin and the mechanism involved. Here we addressed these issues using the nontransformed human colonic epithelial NCM460 cells, native human colonic apical membrane vesicles (AMV) isolated from organ donors, and mouse colonic loops in vivo as models. Uptake of3H-nicotinic acid by NCM460 cells was: 1) acidic pH (but not Na+) dependent; 2) saturable (apparent Km= 2.5 ± 0.8 μM); 3) inhibited by unlabeled nicotinic acid, nicotinamide, and probenecid; 4) neither affected by other bacterially produced monocarboxylates, monocarboxylate transport inhibitor, or by substrates of the human organic anion transporter-10; 5) affected by modulators of the intracellular protein tyrosine kinase- and Ca2+-calmodulin-regulatory pathways; and 6) adaptively regulated by extracellular nicotinate level. Uptake of nicotinic acid by human colonic AMV in vitro and by mouse colonic loops in vivo was also carrier mediated. These findings report, for the first time, that mammalian colonocytes possess a high-affinity carrier-mediated mechanism for nicotinate uptake and show that the process is affected by intracellular and extracellular factors.

scholarly journals Hypouricemic and Anti-oxidant Effects of Chrysanthemum indicum L. and Cornus officinalis In Vitro and In Vivo Models

2021 ◽  
Author(s):  
Ok-kyung Kim ◽  
Jeong Moon Yun ◽  
Minhee Lee ◽  
Dakyung Kim ◽  
Jeongmin Lee
Keyword(s):  
Uric Acid ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
In Vivo Models ◽  
Expression Levels ◽  
Cornus Officinalis ◽  
Anion Transporter ◽  
Chrysanthemum Indicum

Abstract Background: Hyperuricemia, abnormally excess accumulation of uric acid, is caused by an imbalance between the production and excretion of uric acid and is a major cause of gout. We compared the effects of extracts from Chrysanthemum indicum L. (Ci) and Cornus officinalis Siebold & Zucc (Co) on hyperuricemia, both individually and in combination (FSU-CC), Methods: We used hypoxanthine-treated human liver cancer (HepG2) cells and primary mouse renal proximal tubule cells for in vitro model, and potassium oxonate-induced hyperuricemic mice for in vivo model.Results: We found that treatment of Ci, Co, and FSU-CC suppressed the activity of xanthine oxidase and mRNA expression of xanthine dehydrogenase, while inducing an increase in the expression levels of the organic anion transporter 1 and organic anion transporter 3 proteins and a decrease in the expression levels of glucose transporter 9 and urate transporter 1 proteins. Particularly, treatment and supplementation with FSU-CC showed stronger effects than those of supplementation with either Ci or Co alone. We observed that the excretion of creatinine and uric acid in the combination of Ci and Co was higher than that observed in their individual supplementations and was similar to that of the normal group.Conclusions: Therefore, our data suggest that a combination of Ci and Co may potentially be used for the development of effective natural anti-hyperuricemic functional foods.

Reduced folate derivatives are endogenous substrates for cMOAT in rats

1998 ◽  
Vol 275 (4) ◽  
pp. G789-G796 ◽  
Author(s):  
Hiroyuki Kusuhara ◽  
Yong-Hae Han ◽  
Minoru Shimoda ◽  
Eiichi Kokue ◽  
Hiroshi Suzuki ◽  
...  
Keyword(s):  
Biliary Excretion ◽  
Organic Anion ◽  
Membrane Vesicles ◽  
Organic Anion Transporter ◽  
Sprague Dawley ◽  
Anion Transporter ◽  
Bile Drainage ◽  
Endogenous Substrates

We examined the role of the canalicular multispecific organic anion transporter (cMOAT) in the biliary excretion of reduced folate derivatives in vivo and in vitro using normal [Sprague-Dawley rats (SDR)] and mutant [Eisai hyperbilirubinemic rats (EHBR)] rats whose cMOAT is hereditarily deficient. In vivo, the biliary excretion of endogenous tetrahydrofolate (H4PteGlu), 5-methyltetrahydrofolate (5-CH3-H4PteGlu), and 5,10-methylenetetrahydrofolate (5,10-CH2-H4PteGlu) in EHBR was reduced to 8.2%, 1.9%, and 5.5% of those in SDR, respectively, whereas that of 10-formyltetrahydrofolate (10-HCO-H4PteGlu) was detected only in SDR and not in EHBR. Bile drainage caused reduction of endogenous plasma folate concentrations in SDR but not in EHBR. In vitro, significant ATP-dependent uptake of3H-labeled 5-CH3-H4PteGlu into canalicular membrane vesicles was observed only in SDR. This ATP-dependent uptake was saturable with a Michaelis constant ( K m) value of 126 μM, which was comparable with its inhibitor constant ( K i) value of 121 μM for the ATP-dependent uptake of a typical cMOAT substrate, 2,4-dinitrophenyl- S-glutathione (DNP-SG). Vice versa, DNP-SG inhibited the uptake of 5-CH3-H4PteGlu with a K i of 35 μM, which was similar to its K m value. In addition, H4PteGlu and 5,10-CH2-H4PteGlu also inhibited the ATP-dependent uptake of DNP-SG. These results indicate that 5-CH3-H4PteGlu and other derivatives are transported via cMOAT. Therefore, reduced folate derivatives are the first endogenous substrates for cMOAT that do not contain glutathione, glucuronide, or sulfate moieties.

scholarly journals Salvia miltiorrhizaRoots against Cardiovascular Disease: Consideration of Herb-Drug Interactions

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Feng Chen ◽  
Li Li ◽  
Dan-Dan Tian
Keyword(s):  
Drug Interactions ◽  
Phenolic Acids ◽  
Salvia Miltiorrhiza ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Published Data ◽  
Inhibitory Effects ◽  
Anion Transporter

Salvia miltiorrhizaroot (Danshen) is widely used in Asia for its cardiovascular benefits and contains both hydrophilic phenolic acids and lipophilic tanshinones, which are believed to be responsible for its therapeutic efficacy. This review summarized the effects of these bioactive components fromS. miltiorrhizaroots on pharmacokinetics of comedicated drugs with mechanic insights regarding alterations of protein binding, enzyme activity, and transporter activity based on the published data stemming from bothin vitroandin vivohuman studies.In vitrostudies indicated that cytochrome P450 (CYP450), carboxylesterase enzyme, catechol-O-methyltransferase, organic anion transporter 1 (OAT1) and OAT3, and P-glycoprotein were the major targets involved inS. miltiorrhiza-drug interactions. Lipophilic tanshinones had much more potent inhibitory effects towards CYPs activities compared to hydrophilic phenolic acids, evidenced by much lowerKivalues of the former. ClinicalS. miltiorrhiza-drug interaction studies were mainly conducted using CYP1A2 and CYP3A4 probe substrates. In addition, the effects of coexisting components on the pharmacokinetic behaviors of those noted bioactive compounds were also included herein.

scholarly journals Comprehensive Substrate Characterization of 22 Antituberculosis Drugs for Multiple Solute Carrier (SLC) Uptake TransportersIn Vitro

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
M. M. Parvez ◽  
Nazia Kaisar ◽  
Ho Jung Shin ◽  
Yoon Jae Lee ◽  
Jae-Gook Shin
Keyword(s):  
Drug Interactions ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Antituberculosis Drugs ◽  
Hek 293 ◽  
Slc Transporters ◽  
Anion Transporter ◽  
Solute Carrier

ABSTRACTThe substrate potentials of antituberculosis drugs on solute carrier (SLC) transporters are not well characterized to date, despite a well-established understanding of their drug dispositions and pharmacokinetics. In this study, we investigated comprehensively the substrate potentials of the 22 currently available antituberculosis drugs for SLC family transporter-mediated uptake, usingXenopus laevisoocytes and stably transfected HEK-293 cellsin vitro. The result suggested that ethambutol, isoniazid, amoxicillin, and prothionamide act as novel substrates for the SLC transporters. In addition, in the presence of representative transporter inhibitors, the uptake of the antituberculosis drugs was markedly decreased compared with the uptake in the absence of inhibitor, suggesting involvement of the corresponding transporters. A cellular uptake study was performed, and theKmvalues of ethambutol were found to be 526.1 ± 15.6, 212.0 ± 20.1, 336.8 ± 20.1, and 455.0 ± 28 μM for organic cation transporter 1 (OCT1), OCT2, OCTN1, and OCTN2, respectively. Similarly, theKmof prothionamide was 805.8 ± 23.4 μM for OCT1, while theKmvalues of isoniazid and amoxicillin for organic anion transporter 3 (OAT3) were 233.7 ± 14.1 and 161.4 ± 10.6 μM, respectively. The estimatedin vivodrug-drug interaction indexes fromin vitrotransporter inhibition kinetics for verapamil, probenecid, and ibuprofen against ethambutol, prothionamide, isoniazid, and amoxicillin were found to show potential for clinical drug interactions. In conclusion, this is the first study that demonstrated 22 antituberculosis drug interactions with transporters. This study will be helpful for mechanistic understanding of the disposition, drug-drug interactions, and pharmacokinetics of these antituberculosis drugs.

Overlapping in vitro and in vivo specificities of the organic anion transporters OAT1 and OAT3 for loop and thiazide diuretics

2008 ◽  
Vol 294 (4) ◽  
pp. F867-F873 ◽  
Author(s):  
Volker Vallon ◽  
Timo Rieg ◽  
Sun Young Ahn ◽  
Wei Wu ◽  
Satish A. Eraly ◽  
...  
Keyword(s):  
Organic Anion ◽  
Tubular Secretion ◽  
Organic Anion Transporter ◽  
Thiazide Diuretics ◽  
Renal Secretion ◽  
Altered Expression ◽  
Anion Transporter ◽  
Sites Of Action

Organic anion transporter (OAT) genes have been implicated in renal secretion of organic anions, but the individual in vivo contributions of OAT1 (first identified as NKT) and OAT3 remain unclear. Potential substrates include loop diuretics (e.g., furosemide) and thiazide diuretics (e.g., bendroflumethiazide), which reach their tubular sites of action mainly by proximal tubular secretion. Previous experiments in Oat1 knockout (−/−) mice revealed an almost complete loss of renal secretion of the prototypic organic anion p-aminohippurate (PAH) and a role of OAT1 in tubular secretion of furosemide (Eraly SA, Vallon V, Vaughn D, Gangoiti JA, Richter K, Nagle M, Monte JC, Rieg T, Truong DM, Long JM, Barshop BA, Kaler G, Nigam SK. J Biol Chem 281: 5072–5083, 2006). In this study we found that both furosemide and bendroflumethiazide inhibited mOat1- and mOat3-mediated uptake of a labeled tracer in Xenopus oocytes injected with cRNA, consistent with their being substrates for mouse OAT1 and OAT3. Experiments in Oat3−/− mice revealed intact renal secretion of PAH, but the dose-natriuresis curves for furosemide and bendroflumethiazide were shifted to the right and urinary furosemide excretion was impaired similar to the defect in Oat1−/− mice. Thus, whereas OAT1 (in contrast to OAT3) is the classic basolateral PAH transporter of the proximal tubule, both OAT1 and OAT3 contribute similarly to normal renal secretion of furosemide and bendroflumethiazide, and a lack of either one is not fully compensated by the other. Although microarray expression analysis in the kidneys of Oat1−/− and Oat3−/− mice revealed somewhat altered expression of a small number of transport-related genes, none were common to both knockout models. When searching for polymorphisms involved in human diuretic responsiveness, it may be necessary to consider both OAT1 and OAT3, among other genes.

scholarly journals Evaluation of Chinese-Herbal-Medicine-Induced Herb-Drug Interactions: Focusing on Organic Anion Transporter 1

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Chang-Ching Lin ◽  
Hsien-Yuan Fan ◽  
Chien-Wen Kuo ◽  
Li-Heng Pao
Keyword(s):  
Drug Interactions ◽  
Mrna Expression ◽  
Prescription Drugs ◽  
Drug Transport ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Chinese Herbal ◽  
Anion Transporter

The consumption of Chinese herbal medicines (CHMs) is increasing exponentially. Many patients utilize CHMs concomitantly with prescription drugs in great frequency. Herb-drug interaction has hence become an important focus of study. Transporter-mediated herb-drug interactions have the potential to seriously influence drug efficacy and toxicity. Since organic anion transporter 1 (OAT1) is crucial in renal active secretion and drug-drug interactions, the possibility of modulation of OAT1-mediated drug transport should be seriously concerned. Sixty-three clinically used CHMs were evaluated in the study. An hOAT1-overexpressing cell line was used for thein vitroCHMs screening, and the effective candidates were administered to Wistar rats to access renal hemodynamics. The regulation of OAT1 mRNA expression was also examined for further evidence of CHMs affecting OAT1-mediated transport. Among all the 63 CHMs, formulae Gui Zhi Fu Ling Wan (GZ) and Chia Wei Hsiao Yao San (CW) exhibited significant inhibitions on hOAT1-mediated [3H]-PAH uptakein vitroand PAH clearance and net secretionin vivo. Moreover, GZ showed concentration-dependent manners bothin vitroandin vivo, and the decrease of rOAT1 mRNA expression indicated that GZ not only inhibited function of OAT1 but also suppressed expression of OAT1.

scholarly journals Organic anion transporter 3 (Oat3/Slc22a8) knockout mice exhibit altered clearance and distribution of penicillin G

2007 ◽  
Vol 293 (4) ◽  
pp. F1332-F1341 ◽  
Author(s):  
Adam L. VanWert ◽  
Rachel M. Bailey ◽  
Douglas H. Sweet
Keyword(s):  
Knockout Mice ◽  
Drug Disposition ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Penicillin G ◽  
Anion Transporter ◽  
Organic Anion Transporter 3

The interaction of renal basolateral organic anion transporter 3 (Oat3) with commonly used pharmacotherapeutics (e.g., NSAIDs, β-lactams, and methotrexate) has been studied extensively in vitro. However, the in vivo role of Oat3 in drug disposition, in the context of other transporters, glomerular filtration, and metabolism, has not been established. Moreover, recent investigations have identified inactive human OAT3 polymorphisms. Therefore, this investigation was designed to elucidate the in vivo role of Oat3 in the disposition of penicillin G and prototypical substrates using an Oat3 knockout mouse model. Oat3 deletion resulted in a doubling of penicillin's half-life ( P < 0.05) and a reduced volume of distribution ( P < 0.01), together yielding a plasma clearance that was one-half ( P < 0.05, males) to one-third ( P < 0.001, females) of that in wild-type mice. Inhibition of Oat3 abolished the differences in penicillin G elimination between genotypes. Hepatic accumulation of penicillin was 2.3 times higher in male knockouts ( P < 0.05) and 3.7 times higher in female knockouts ( P < 0.001). Female knockouts also exhibited impaired estrone-3-sulfate clearance. Oat3 deletion did not impact p-aminohippurate elimination, providing correlative evidence to studies in Oat1 knockout mice that suggest Oat1 governs tubular uptake of p-aminohippurate. Collectively, these findings are the first to indicate that functional Oat3 is necessary for proper elimination of xenobiotic and endogenous compounds in vivo. Thus Oat3 plays a distinct role in determining the efficacy and toxicity of drugs. Dysfunctional human OAT3 polymorphisms or instances of polypharmacy involving OAT3 substrates may result in altered systemic accumulation of β-lactams and other clinically relevant compounds.

scholarly journals In Vitro Evaluation of the Drug Interaction Potential of Doravirine

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Kelly Bleasby ◽  
Kerry L. Fillgrove ◽  
Robert Houle ◽  
Bing Lu ◽  
Jairam Palamanda ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Reversible Inhibitor ◽  
Drug Metabolizing Enzymes ◽  
Cancer Resistance ◽  
Metabolizing Enzymes ◽  
Anion Transporter ◽  
Major Drug

ABSTRACT Doravirine is a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus type 1 infection. In vitro studies were conducted to assess the potential for drug interactions with doravirine via major drug-metabolizing enzymes and transporters. Kinetic studies confirmed that cytochrome P450 3A (CYP3A) plays a major role in the metabolism of doravirine, with ∼20-fold-higher catalytic efficiency for CYP3A4 versus CYP3A5. Doravirine was not a substrate of breast cancer resistance protein (BCRP) and likely not a substrate of organic anion transporting polypeptide 1B1 (OATP1B1) or OATP1B3. Doravirine was not a reversible inhibitor of major CYP enzymes (CYP1A2, -2B6, -2C8, -2C9, -2C19, -2D6, and -3A4) or of UGT1A1, nor was it a time-dependent inhibitor of CYP3A4. No induction of CYP1A2 or -2B6 was observed in cultured human hepatocytes; small increases in CYP3A4 mRNA (≤20%) were reported at doravirine concentrations of ≥10 μM but with no corresponding increase in enzyme activity. In vitro transport studies indicated a low potential for interactions with substrates of BCRP, P-glycoprotein, OATP1B1 and OATP1B3, the bile salt extrusion pump (BSEP), organic anion transporter 1 (OAT1) and OAT3, organic cation transporter 2 (OCT2), and multidrug and toxin extrusion 1 (MATE1) and MATE2K proteins. In summary, these in vitro findings indicate that CYP3A4 and CYP3A5 mediate the metabolism of doravirine, although with different catalytic efficiencies. Clinical trials reported elsewhere confirm that doravirine is subject to drug-drug interactions (DDIs) via CYP3A inhibitors and inducers, but they support the notion that DDIs (either direction) are unlikely via other major drug-metabolizing enzymes and transporters.

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