title: Bezafibrate-mizoribine interaction: Involvement of organic anion transporters OAT1 and OAT3 in rats.
abstract: A patient with rheumatoid arthritis developed rhabdomyolysis while undergoing treatment with mizoribine concomitantly with bezafibrate. The symptoms rapidly disappeared and laboratory test results normalized when she discontinued the two drugs. The purpose of the present study was to elucidate the transporter-mediated molecular pharmacokinetic mechanisms of drug-drug interactions between bezafibrate and mizoribine. Comparing bezafibrate-mizoribine group with bezafibrate group, the Tmax and Cmax of bezafibrate were essentially unchanged in rats. The AUC of bezafibrate was significantly increased and t1/2β was prolonged markedly with an obviously reduction in plasma clearance and cumulative urinary excretion. The changes were similar to oral studies following intravenous co-administration. In rat kidney slices, the uptake of bezafibrate was markedly inhibited by p-aminohippurate, benzylpenicillin and probenecid but not by tetraethyl ammonium. Mizoribine not only decreased the uptake of bezafibrate, but also inhibited the uptake of p-aminohippurate and benzylpenicillin. The uptakes of bezafibrate and mizoribine were significantly higher compared to vector-HEK293 cells. The uptakes of bezafibrate and mizoribine in highest concentration were increased 1.63 and 1.46 folds in hOAT1-transfected cells, 1.43 and 1.24 folds in hOAT3-transfected cells, respectively. The Km values of bezafibrate uptake by hOAT1/3hOAT1-/hOAT3-HEK293 K293 cells were increased 1.68 fold in hOAT1-HEK293 cell and 2.12 fold in hOAT3-HEK293 cell in the presence of mizoribine with no change of Vmax. It indicated that mizoribine could inhibit the uptake of bezafibrate by hOAT1/3-HEK293 cells in a competitive way. In conclusion, OAT1 and OAT3 are the target transporters of drug-drug interactions between bezafibrate and mizoribine in pharmacokinetic aspects.
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, China.
authors.forename: Changyuan
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Meng
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, China.
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Huo
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, China.
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, China.
authors.forename: Pengyuan
authors.initials: P
authors.lastname: Sun
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, China.
authors.forename: Huijun
authors.initials: H
authors.lastname: Sun
authors.affiliation: Division of Biotechnology Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China. Electronic address: jhqin@dicp.ac.cn.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Qin
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, China. Electronic address: kexinliu@dlmedu.edu.cn.
authors.forename: Kexin
authors.initials: K
authors.lastname: Liu
mesh_terms: D000818:Animals; D001629:Bezafibrate / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000652:urine; D004347:Drug Interactions; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D027362:Organic Anion Transport Protein 1 / Q000235:genetics / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism*; D017208:Rats, Wistar; D012263:Ribonucleosides / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; D012263:Ribonucleosides; C114338:organic anion transport protein 3; C010052:mizoribine; D001629:Bezafibrate
keywords: Bezafibrate; Drug–drug interactions; Kidney; Mizoribine; OATs; Transporter