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

Soo Jin Kim, Takashi Yoshikado, Ichiro Ieiri, Kazuya Maeda, Miyuki Kimura, Shin Irie, Hiroyuki Kusuhara, Yuichi Sugiyama

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Abstract

Clopidogrel is reported to be associated with cerivastatin-induced rhabdomyolysis, and clopidogrel and itsmetabolites are capable of inhibiting CYP2C8 and OATP 1B1 in vitro. The objective of the present study was to identify the mechanism of clopidogrelmediated 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-mediatedmetabolite 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.

Original languageEnglish
Pages (from-to)1622-1632
Number of pages11
JournalDrug Metabolism and Disposition
Volume44
Issue number10
DOIs
Publication statusPublished - Oct 1 2016

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clopidogrel
repaglinide
pioglitazone
Drug Interactions
Pharmaceutical Preparations
Area Under Curve
Glucuronides
Pharmacokinetics
Cytochrome P-450 CYP2C8
In Vitro Techniques
Trimethoprim
Rifampin

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science

Cite this

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. / Kim, Soo Jin; Yoshikado, Takashi; Ieiri, Ichiro; Maeda, Kazuya; Kimura, Miyuki; Irie, Shin; Kusuhara, Hiroyuki; Sugiyama, Yuichi.

In: Drug Metabolism and Disposition, Vol. 44, No. 10, 01.10.2016, p. 1622-1632.

Research output: Contribution to journalArticle

Kim, Soo Jin ; Yoshikado, Takashi ; Ieiri, Ichiro ; Maeda, Kazuya ; Kimura, Miyuki ; Irie, Shin ; Kusuhara, Hiroyuki ; Sugiyama, Yuichi. / 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. In: Drug Metabolism and Disposition. 2016 ; Vol. 44, No. 10. pp. 1622-1632.
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N2 - Clopidogrel is reported to be associated with cerivastatin-induced rhabdomyolysis, and clopidogrel and itsmetabolites are capable of inhibiting CYP2C8 and OATP 1B1 in vitro. The objective of the present study was to identify the mechanism of clopidogrelmediated 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-mediatedmetabolite 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.

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