Quantitative Prediction of Human Renal Clearance and Drug-Drug Interactions of Organic Anion Transporter Substrates Using In Vitro Transport Data: A Relative Activity Factor Approach

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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Effects of Renal Impairment on the Pharmacokinetics of Morinidazole: Uptake Transporter-Mediated Renal Clearance of the Conjugated Metabolites

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02414-14 ◽

2014 ◽

Vol 58 (7) ◽

pp. 4153-4161 ◽

Cited By ~ 15

Author(s):

Kan Zhong ◽

Xiuli Li ◽

Cen Xie ◽

Yifan Zhang ◽

Dafang Zhong ◽

...

Keyword(s):

Renal Impairment ◽

Renal Clearance ◽

Healthy Subjects ◽

Severe Renal Impairment ◽

Organic Anion ◽

Organic Anion Transporter ◽

Anion Transporter ◽

Plasma And Urine Samples ◽

Conjugated Metabolites

ABSTRACTMorinidazole is a novel 5-nitroimidazole antimicrobial drug that undergoes extensive metabolism in humans viaN+-glucuronidation (N+-glucuronide ofS-morinidazole [M8-1] andN+-glucuronide ofR-morinidazole [M8-2]) and sulfation (sulfate conjugate of morinidazole [M7]). Our objectives were to assess the effects of renal impairment on the pharmacokinetics (PK) of morinidazole and to elucidate the potential mechanisms. In this parallel-group study, healthy subjects and patients with severe renal impairment received an intravenous infusion of 500 mg of morinidazole. Plasma and urine samples were collected and analyzed. The areas under the plasma concentration-time curves (AUC) for M7, M8-1, and M8-2 were 15.1, 20.4, and 17.4 times higher, respectively, in patients with severe renal impairment than in healthy subjects, while the AUC for morinidazole was 1.5 times higher. The urinary recovery of the major metabolites was not significantly different between the two groups over 0 to 48 h, but the renal clearances of M7, M8-1, and M8-2 in patients were 85.3%, 92.5%, and 92.2% lower, respectively.In vitrotransporter studies revealed that M7 is a substrate for organic anion transporter 1 (OAT1) and OAT3 (Km= 28.6 and 54.0 μM, respectively). Only OAT3 transported M8-1 and M8-2. Morinidazole was not a substrate for the transporter-transfected cells examined. These results revealed that the function or activity of renal uptake transporters might be impaired in patients with severe renal impairment, which accounted for dramatically increased plasma exposure and reduced renal clearance of the conjugated metabolites of morinidazole, the substrates of renal transporters in patients. It will help clinicians to adjust the dose in patients with severe renal impairment and to predict possible transporter-based drug-drug interactions.

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

BioMed Research International ◽

10.1155/2017/9868694 ◽

2017 ◽

Vol 2017 ◽

pp. 1-12 ◽

Cited By ~ 4

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.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00512-18 ◽

2018 ◽

Vol 62 (9) ◽

Cited By ~ 3

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.

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Islatravir Is Not Expected to Be a Victim or Perpetrator of Drug-Drug Interactions via Major Drug-Metabolizing Enzymes or Transporters

Viruses ◽

10.3390/v13081566 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1566

Author(s):

Kelly Bleasby ◽

Robert Houle ◽

Michael Hafey ◽

Meihong Lin ◽

Jingjing Guo ◽

...

Keyword(s):

Drug Interactions ◽

Selective Serotonin Reuptake Inhibitors ◽

Organic Anion ◽

Organic Cation Transporter ◽

Organic Anion Transporter ◽

Uridine Diphosphate ◽

Cancer Resistance ◽

Treatment And Prevention ◽

Anion Transporter

Islatravir (MK-8591) is a nucleoside reverse transcriptase translocation inhibitor in development for the treatment and prevention of HIV-1. The potential for islatravir to interact with commonly co-prescribed medications was studied in vitro. Elimination of islatravir is expected to be balanced between adenosine deaminase–mediated metabolism and renal excretion. Islatravir did not inhibit uridine diphosphate glucuronosyltransferase 1A1 or cytochrome p450 (CYP) enzymes CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4, nor did it induce CYP1A2, 2B6, or 3A4. Islatravir did not inhibit hepatic transporters organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, bile salt export pump (BSEP), multidrug resistance-associated protein (MRP) 2, MRP3, or MRP4. Islatravir was neither a substrate nor a significant inhibitor of renal transporters organic anion transporter (OAT) 1, OAT3, OCT2, multidrug and toxin extrusion protein (MATE) 1, or MATE2K. Islatravir did not significantly inhibit P-glycoprotein and breast cancer resistance protein (BCRP); however, it was a substrate of BCRP, which is not expected to be of clinical significance. These findings suggest islatravir is unlikely to be the victim or perpetrator of drug-drug interactions with commonly co-prescribed medications, including statins, diuretics, anti-diabetic drugs, proton pump inhibitors, anticoagulants, benzodiazepines, and selective serotonin reuptake inhibitors.

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Organic anion transporter OAT1 is involved in renal handling of citrulline

AJP Renal Physiology ◽

10.1152/ajprenal.90662.2008 ◽

2009 ◽

Vol 297 (1) ◽

pp. F71-F79 ◽

Cited By ~ 20

Author(s):

Masanori Nakakariya ◽

Yoichiro Shima ◽

Yoshiyuki Shirasaka ◽

Keisuke Mitsuoka ◽

Takeo Nakanishi ◽

...

Keyword(s):

Rat Kidney ◽

Organic Anion ◽

Relative Activity ◽

Organic Anion Transporter ◽

Renal Handling ◽

Functional Sites ◽

Kidney Slices ◽

Anion Transporter ◽

Activity Factor ◽

Sodium Dependent

Because citrulline plasma concentration is elevated in kidney failure, citrulline could be a biomarker of renal insufficiency, although the mechanism regulating its disposition in the kidney has not been clarified. In rat kidney slices, citrulline uptake was apparently Na+ dependent, saturable with Km 556 μM, and significantly inhibited by anionic (PAH) and cationic (TEA) compounds, but not by probenecid at 1 mM. Preincubation of kidney slices with glutarate increased citrulline uptake, while such an increase was not observed after preincubation of the slices in Na+-free buffer. This result suggested that a sodium-dependent dicarboxylate cotransporter is involved in citrulline uptake by rat kidney slices. In studies using transporter-overexpressing cells, human organic anion transporter 1 (OAT1) and rat Oat1 exhibited citrulline transport activity with Km values of 238 and 373 μM, respectively, while other OATs and organic cation transporters (OCTs) did not transport citrulline. Based on the relative activity factor method, the contribution of rat Oat1 to the overall uptake of citrulline in rat kidney slices was ∼70%. Moreover, the interaction among citrulline, PAH, and probenecid uptakes via rat Oat1 suggested that there are multiple functional sites on Oat1 and that the citrulline site may be distinct from the PAH and probenecid site. Thus OAT1/Oat1 appears to be one of the major contributors to renal basolateral uptake of citrulline, and impaired activities of these transporters may contribute substantially to the increase in plasma citrulline in renal failure. Accordingly, citrulline may be useful for diagnosis of kidney function as is creatinine.

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In Vitro Inhibitory Effects of APINACA on Human Major Cytochrome P450, UDP-Glucuronosyltransferase Enzymes, and Drug Transporters

Molecules ◽

10.3390/molecules24163000 ◽

2019 ◽

Vol 24 (16) ◽

pp. 3000 ◽

Cited By ~ 6

Author(s):

Sunjoo Kim ◽

Won-Gu Choi ◽

Mihwa Kwon ◽

Sowon Lee ◽

Yong-Yeon Cho ◽

...

Keyword(s):

Drug Interactions ◽

Organic Anion ◽

Liver Microsomes ◽

Organic Cation Transporter ◽

Organic Anion Transporter ◽

Drug Abusers ◽

Cancer Resistance ◽

Inhibitory Effects ◽

Anion Transporter

APINACA (known as AKB48, N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide), an indazole carboxamide synthetic cannabinoid, has been used worldwide as a new psychoactive substance. Drug abusers take various drugs concomitantly, and therefore, it is necessary to characterize the potential of APINACA-induced drug–drug interactions due to the modulation of drug-metabolizing enzymes and transporters. In this study, the inhibitory effects of APINACA on eight major human cytochrome P450s (CYPs) and six uridine 5′-diphospho-glucuronosyltransferases (UGTs) in human liver microsomes, as well as on the transport activities of six solute carrier transporters and two efflux transporters in transporter-overexpressed cells, were investigated. APINACA exhibited time-dependent inhibition of CYP3A4-mediated midazolam 1′-hydroxylation (Ki, 4.5 µM; kinact, 0.04686 min−1) and noncompetitive inhibition of UGT1A9-mediated mycophenolic acid glucuronidation (Ki, 5.9 µM). APINACA did not significantly inhibit the CYPs 1A2, 2A6, 2B6, 2C8/9/19, or 2D6 or the UGTs 1A1, 1A3, 1A4, 1A6, or 2B7 at concentrations up to 100 µM. APINACA did not significantly inhibit the transport activities of organic anion transporter (OAT)1, OAT3, organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic cation transporter (OCT)1, OCT2, P-glycoprotein, or breast cancer resistance protein at concentrations up to 250 μM. These data suggest that APINACA can cause drug interactions in the clinic via the inhibition of CYP3A4 or UGT1A9 activities.

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

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2012/967182 ◽

2012 ◽

Vol 2012 ◽

pp. 1-12 ◽

Cited By ~ 3

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.

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Role of organic anion transporter 3 in the renal excretion of biapenem and potential drug-drug interactions

European Journal of Pharmaceutical Sciences ◽

10.1016/j.ejps.2021.105814 ◽

2021 ◽

pp. 105814

Author(s):

Wenyan Li ◽

Zheng Jiao ◽

Yanhui Liu ◽

Jiacheng Yao ◽

Guodong Li ◽

...

Keyword(s):

Drug Interactions ◽

Renal Excretion ◽

Organic Anion ◽

Organic Anion Transporter ◽

Potential Drug ◽

Anion Transporter ◽

Organic Anion Transporter 3

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

10.22541/au.162502338.80368982/v1 ◽

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.

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