title: In vitro interaction of clopidogrel and its hydrolysate with OCT1, OCT2 and OAT1.
abstract: Clopidogrel (CP) is metabolized by CYPs to the active metabolite, or hydrolyzed by esterase to clopidogrel carboxylate (CPC) in liver, and CPC is partly excreted from urine. Therefore, the objective of the present study was to evaluate the interactions of CP and CPC with organic cation transporter 1 (OCT1) (in liver), and CPC with organic cation transporter 2 (OCT2) and organic anion transporter 1 (OAT1) (in kidney). Both CP and CPC inhibited the uptake of 1-methyl-4-phenylpyridinium (MPP(+)) and metformin, typical substrates of OCT1, in MDCK-hOCT1 cells with low IC₅₀ (0.307-14.0 μM). CPC (100 μM) reduced the uptake of MPP(+) and metformin mediated by OCT2 in MDCK-hOCT2 cells to 60.8% and 33.6% of the control, CPC (500 μM) decreased the uptake of 6-carboxyfluorescein (6-CFL) and para-aminohippuric acid (PAH), substrates of OAT1, in MDCK-hOAT1 cells to 64.6% and 79.4% of the control. CP and CPC were also found to inhibit other drugs of OCT1 substrates, such as lamivudine and amantadine, in MDCK-hOCT1 cells with the IC₅₀ of 1.97-4.15μM, except CPC on amantadine (IC₅₀>100 μM). The inhibition of CP and CPC on lamivudine uptake in primary rat hepatocytes was also confirmed with the IC₅₀ of 2.91 and 1.25μM, respectively. Additionally, CP and CPC were not substrates of OCT1 and OCT2, whereas CPC was a substrate of OAT1 with the Km of 5.61 μM. In conclusion, CP and CPC are strong inhibitors of OCT1, but weak inhibitors of OCT2 and OAT1, and CPC is a high affinity substrate of OAT1.
authors: Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, PR China.
authors: Liping
authors: L
authors: Li
authors: Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, PR China.
authors: Feifeng
authors: F
authors: Song
authors: Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, PR China.
authors: Meijuan
authors: M
authors: Tu
authors: Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, PR China.
authors: Kai
authors: K
authors: Wang
authors: Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, PR China.
authors: Lei
authors: L
authors: Zhao
authors: Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, PR China.
authors: Xiaodan
authors: X
authors: Wu
authors: Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, PR China.
authors: Hui
authors: H
authors: Zhou
authors: Third Affiliated Hospital of Suzhou University, Changzhou, Jiangsu, PR China. Electronic address: lysaxia@yahoo.com.cn.
authors: Zongling
authors: Z
authors: Xia
authors: Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, PR China. Electronic address: hdjiang@zju.edu.cn.
authors: Huidi
authors: H
authors: Jiang
mesh_terms: D000818:Animals; D001711:Biotransformation; D000077144:Clopidogrel; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D027362:Organic Anion Transport Protein 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D027702:Organic Cation Transporter 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D051381:Rats; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D014162:Transfection
chemical_list: D027362:Organic Anion Transport Protein 1; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D000075102:Organic Cation Transporter 2; C491013:SLC22A2 protein, human; C528640:clopidogrel carboxylic acid; D000077144:Clopidogrel; D013988:Ticlopidine
keywords: Clopidogrel; Clopidogrel carboxylate; Drug–drug interactions; Inhibition; Organic anion transporter; Organic cation transporter