title: Clarification of the Mechanism of Clopidogrel-Mediated Drug-Drug Interaction in a Clinical Cassette Small-dose Study and Its Prediction Based on In Vitro Information.
abstract: Clopidogrel is reported to be associated with cerivastatin-induced rhabdomyolysis, and clopidogrel and its metabolites are capable of inhibiting CYP2C8 and OATP 1B1 in vitro. The objective of the present study was to identify the mechanism of clopidogrel-mediated drug-drug interactions (DDIs) on the pharmacokinetics of OATP1B1 and/or CYP2C8 substrates in vivo. A clinical cassette small-dose study using OATPs, CYP2C8, and OATP1B1/CYP2C8 probe drugs (pitavastatin, pioglitazone, and repaglinide, respectively) with or without the coadministration of either 600 mg rifampicin (an inhibitor for OATPs), 200 mg trimethoprim (an inhibitor for CYP2C8), or 300 mg clopidogrel was performed, and the area under the concentration-time curve (AUC) ratios (AUCRs) for probe substrates were predicted using a static model. Clopidogrel increased the AUC of pioglitazone (2.0-fold) and repaglinide (3.1-fold) but did not significantly change the AUC of pitavastatin (1.1-fold). In addition, the AUC of pioglitazone M4, a CYP2C8-mediated metabolite of pioglitazone, was reduced to 70% of the control by coadministration of clopidogrel. The predicted AUCRs using the mechanism-based inhibition of CYP2C8 by clopidogrel acyl-β-glucuronide were similar to the observed AUCRs, and the predicted AUCR (1.1) of repaglinide using only the inhibition of OATP1B1 did not reach the observed AUCR (3.1). In conclusion, a single 300 mg of clopidogrel mainly inhibits CYP2C8-mediated metabolism by clopidogrel acyl-β-glucuronide, but its effect on the pharmacokinetics of OATP1B1 substrates is negligible. Clopidogrel is expected to have an effect not only on CYP2C8 substrates, but also dual CYP2C8/OATP1B1 substrates as seen in the case of repaglinide.
authors.affiliation: Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Cluster for Industry Partnerships, RIKEN, Yokohama, Japan (S. K., T.Y., Y.S.); Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (I.I.); Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugioka Memorial Hospital, Fukuoka, Japan (M.K., S.I.).
authors.forename: Soo-Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Cluster for Industry Partnerships, RIKEN, Yokohama, Japan (S. K., T.Y., Y.S.); Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (I.I.); Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugioka Memorial Hospital, Fukuoka, Japan (M.K., S.I.).
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshikado
authors.affiliation: Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Cluster for Industry Partnerships, RIKEN, Yokohama, Japan (S. K., T.Y., Y.S.); Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (I.I.); Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugioka Memorial Hospital, Fukuoka, Japan (M.K., S.I.).
authors.forename: Ichiro
authors.initials: I
authors.lastname: Ieiri
authors.affiliation: Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Cluster for Industry Partnerships, RIKEN, Yokohama, Japan (S. K., T.Y., Y.S.); Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (I.I.); Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugioka Memorial Hospital, Fukuoka, Japan (M.K., S.I.).
authors.forename: Kazuya
authors.initials: K
authors.lastname: Maeda
authors.affiliation: Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Cluster for Industry Partnerships, RIKEN, Yokohama, Japan (S. K., T.Y., Y.S.); Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (I.I.); Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugioka Memorial Hospital, Fukuoka, Japan (M.K., S.I.).
authors.forename: Miyuki
authors.initials: M
authors.lastname: Kimura
authors.affiliation: Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Cluster for Industry Partnerships, RIKEN, Yokohama, Japan (S. K., T.Y., Y.S.); Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (I.I.); Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugioka Memorial Hospital, Fukuoka, Japan (M.K., S.I.).
authors.forename: Shin
authors.initials: S
authors.lastname: Irie
authors.affiliation: Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Cluster for Industry Partnerships, RIKEN, Yokohama, Japan (S. K., T.Y., Y.S.); Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (I.I.); Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugioka Memorial Hospital, Fukuoka, Japan (M.K., S.I.).
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.affiliation: Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Cluster for Industry Partnerships, RIKEN, Yokohama, Japan (S. K., T.Y., Y.S.); Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (I.I.); Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugioka Memorial Hospital, Fukuoka, Japan (M.K., S.I.) ychi.sugiyama@riken.jp.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D019540:Area Under Curve; D000077144:Clopidogrel; D065727:Cytochrome P-450 CYP2C8 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology; D012293:Rifampin / Q000494:pharmacology; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D014295:Trimethoprim / Q000494:pharmacology
chemical_list: D010975:Platelet Aggregation Inhibitors; D011804:Quinolines; D000077144:Clopidogrel; D014295:Trimethoprim; D065727:Cytochrome P-450 CYP2C8; C108475:pitavastatin; D013988:Ticlopidine; D012293:Rifampin