Renal Organic Anion Transporter-Mediated Drug-Drug Interaction between Gemcabene and Quinapril

Human organic anion transporter 4 (hOAT4) belongs to a family of multispecific organic anion transporters that play critical roles in the disposition of numerous drugs and therefore are the major sites for drug-drug interaction. Drug-drug interactions contribute significantly to the individual variation in drug response. hOAT4 is expressed in the kidney and placenta. In the current study, we examined the interaction of 36 anticancer drugs with hOAT4 in kidney COS-7 cells and placenta BeWo cells. Among the drugs tested, only epirubicin hydrochloride and dabrafenib mesylate exhibited > 50% cis-inhibitory effect, in COS-7 cells, on hOAT4-mediated uptake of estrone sulfate, a prototypical substrate for the transporter. The IC50values for epirubicin hydrochloride and dabrafenib mesylate were 5.24±0.95μM and 8.30±3.30μM, respectively. Dixon plot analysis revealed that inhibition by epirubicin hydrochloride was noncompetitive with aKi= 3μM whereas inhibition by dabrafenib mesylate was competitive with aKi= 4.26μM. Our results established that epirubicin hydrochloride and dabrafenib mesylate are inhibitors of hOAT4. Furthermore, by comparing our data with clinically relevant exposures of these drugs, we conclude that although the tendency for dabrafenib mesylate to cause drug-drug interaction through hOAT4 is insignificant in the kidney, the propensity for epirubicin hydrochloride to cause drug-drug interaction is high.

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Cumulative Organic Anion Transporter-Mediated Drug-Drug Interaction Potential of Multiple Components in Salvia Miltiorrhiza (Danshen) Preparations

Pharmaceutical Research ◽

10.1007/s11095-014-1437-9 ◽

2014 ◽

Vol 31 (12) ◽

pp. 3503-3514 ◽

Cited By ~ 9

Author(s):

Li Wang ◽

Jürgen Venitz ◽

Douglas H. Sweet

Keyword(s):

Drug Interaction ◽

Interaction Potential ◽

Salvia Miltiorrhiza ◽

Organic Anion ◽

Organic Anion Transporter ◽

Multiple Components ◽

Anion Transporter ◽

Drug Drug Interaction

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Interaction of five anthraquinones from rhubarb with human organic anion transporter 1 (SLC22A6) and 3 (SLC22A8) and drug–drug interaction in rats

Journal of Ethnopharmacology ◽

10.1016/j.jep.2014.03.055 ◽

2014 ◽

Vol 153 (3) ◽

pp. 864-871 ◽

Cited By ~ 31

Author(s):

Liping Ma ◽

Lei Zhao ◽

Haihong Hu ◽

Yahong Qin ◽

Yicong Bian ◽

...

Keyword(s):

Drug Interaction ◽

Organic Anion ◽

Organic Anion Transporter ◽

Anion Transporter ◽

Drug Drug Interaction

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Evaluation for Potential Drug–Drug Interaction of MT921 Using In Vitro Studies and Physiologically–Based Pharmacokinetic Models

Pharmaceuticals ◽

10.3390/ph14070654 ◽

2021 ◽

Vol 14 (7) ◽

pp. 654

Author(s):

Hyo-jeong Ryu ◽

Hyun-ki Moon ◽

Junho Lee ◽

Gi-hyeok Yang ◽

Sung-yoon Yang ◽

...

Keyword(s):

Drug Interaction ◽

Bile Acid ◽

Pbpk Model ◽

Organic Anion ◽

Organic Anion Transporter ◽

Physiologically Based Pharmacokinetic ◽

Anion Transporter ◽

Physiologically Based ◽

Drug Drug Interaction

MT921 is a new injectable drug developed by Medytox Inc. to reduce submental fat. Cholic acid is the active pharmaceutical ingredient, a primary bile acid biosynthesized from cholesterol, endogenously produced by liver in humans and other mammals. Although individuals treated with MT921 could be administered with multiple medications, such as those for hypertension, diabetes, and hyperlipidemia, the pharmacokinetic drug–drug interaction (DDI) has not been investigated yet. Therefore, we studied in vitro against drug-metabolizing enzymes and transporters. Moreover, we predicted the potential DDI between MT921 and drugs for chronic diseases using physiologically-based pharmacokinetic (PBPK) modeling and simulation. The magnitude of DDI was found to be negligible in in vitro inhibition and induction of cytochrome P450s and UDP-glucuronosyltransferases. Organic anion transporting polypeptide (OATP)1B3, organic anion transporter (OAT)3, Na+-taurocholate cotransporting polypeptide (NTCP), and apical sodium-dependent bile acid transporter (ASBT) are mainly involved in MT921 transport. Based on the result of in vitro experiments, the PBPK model of MT921 was developed and evaluated by clinical data. Furthermore, the PBPK model of amlodipine was developed and evaluated. PBPK DDI simulation results indicated that the pharmacokinetics of MT921 was not affected by the perpetrator drugs. In conclusion, MT921 could be administered without a DDI risk based on in vitro study and related in silico simulation. Further clinical studies are needed to validate this finding.

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Involvement of Organic Anion Transporters in the Pharmacokinetics and Drug Interaction of Rosmarinic Acid

Pharmaceutics ◽

10.3390/pharmaceutics13010083 ◽

2021 ◽

Vol 13 (1) ◽

pp. 83

Author(s):

Yun Ju Kang ◽

Chul Haeng Lee ◽

Soo-Jin Park ◽

Hye Suk Lee ◽

Min-Koo Choi ◽

...

Keyword(s):

Drug Interaction ◽

Rosmarinic Acid ◽

Renal Excretion ◽

Organic Anion ◽

Plasma Concentrations ◽

Pharmacokinetic Interaction ◽

Organic Anion Transporter ◽

Hek293 Cells ◽

Anion Transporter

We investigated the involvement of drug transporters in the pharmacokinetics of rosmarinic acid in rats as well as the transporter-mediated drug interaction potential of rosmarinic acid in HEK293 cells overexpressing clinically important solute carrier transporters and also in rats. Intravenously injected rosmarinic acid showed bi-exponential decay and unchanged rosmarinic acid was mainly eliminated by urinary excretion, suggesting the involvement of transporters in its renal excretion. Rosmarinic acid showed organic anion transporter (OAT)1-mediated active transport with a Km of 26.5 μM and a Vmax of 69.0 pmol/min in HEK293 cells overexpressing OAT1, and the plasma concentrations of rosmarinic acid were increased by the co-injection of probenecid because of decreased renal excretion due to OAT1 inhibition. Rosmarinic acid inhibited the transport activities of OAT1, OAT3, organic anion transporting polypeptide (OATP)1B1, and OATP1B3 with IC50 values of 60.6 μM, 1.52 μM, 74.8 μM, and 91.3 μM, respectively, and the inhibitory effect of rosmarinic acid on OAT3 transport activity caused an in vivo pharmacokinetic interaction with furosemide by inhibiting its renal excretion and by increasing its plasma concentration. In conclusion, OAT1 and OAT3 are the major transporters that may regulate the pharmacokinetic properties of rosmarinic acid and may cause herb-drug interactions with rosmarinic acid, although their clinical relevance awaits further evaluation.

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