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Research ArticleArticle

Clopidogrel Has No Clinically Meaningful Effect on the Pharmacokinetics of the Organic Anion Transporting Polypeptide 1B1 and Cytochrome P450 3A4 Substrate Simvastatin

Matti K. Itkonen, Aleksi Tornio, Mikko Neuvonen, Pertti J. Neuvonen, Mikko Niemi and Janne T. Backman
Drug Metabolism and Disposition November 2015, 43 (11) 1655-1660; DOI: https://doi.org/10.1124/dmd.115.065938
Matti K. Itkonen
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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Aleksi Tornio
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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Mikko Neuvonen
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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Pertti J. Neuvonen
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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Mikko Niemi
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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Janne T. Backman
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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Abstract

Simvastatin and clopidogrel are commonly used together in the treatment of cardiovascular diseases. Organic anion transporting polypeptide (OATP) 1B1 activity markedly affects the hepatic uptake of simvastatin acid, whereas both simvastatin and simvastatin acid are sensitive to changes in cytochrome P450 3A4 activity. Clopidogrel and its metabolites inhibit OATP1B1 and CYP3A4 in vitro. We studied the effect of clopidogrel on the pharmacokinetics of simvastatin in a randomized crossover study. Twelve healthy volunteers ingested either a dose of placebo (control) or 300 mg of clopidogrel on day 1 and 75 mg on days 2 and 3. Simvastatin 40 mg was administered 1 hour after placebo and after clopidogrel on days 1 and 3. Plasma drug concentrations were measured for up to 12 hours. Clopidogrel 300 mg (day 1) increased the concentrations of simvastatin and simvastatin acid during the absorption phase. After clopidogrel 300 mg, the area under the concentration time curve (AUC) of simvastatin from 0 to 2 hours was 156% (P = 0.02) and its AUC0–12 hours was 132% (P = 0.08) of that during placebo, whereas the AUC0–2 hours and the AUC0–12 hours of simvastatin acid were 148% (P = 0.04) and 112% (P = 0.52) of control. Clopidogrel 75 mg (day 3) had no significant effect on the pharmacokinetic variables of simvastatin or simvastatin acid compared with placebo. The effect of clopidogrel seemed independent of the SLCO1B1 c.521T>C genotype. In conclusion, as clopidogrel did not have significant effects on the total exposure to simvastatin or simvastatin acid, clopidogrel does not seem to inhibit OATP1B1 or CYP3A4 to a clinically relevant extent.

Footnotes

    • Received June 13, 2015.
    • Accepted August 31, 2015.
  • The study was supported by grants from the Helsinki University Central Hospital Research Fund and the Sigrid Jusélius Foundation (Helsinki, Finland).

  • dx.doi.org/10.1124/dmd.115.065938.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (11)
Drug Metabolism and Disposition
Vol. 43, Issue 11
1 Nov 2015
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Research ArticleArticle

Effect of Clopidogrel on the Pharmacokinetics of Simvastatin

Matti K. Itkonen, Aleksi Tornio, Mikko Neuvonen, Pertti J. Neuvonen, Mikko Niemi and Janne T. Backman
Drug Metabolism and Disposition November 1, 2015, 43 (11) 1655-1660; DOI: https://doi.org/10.1124/dmd.115.065938

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Research ArticleArticle

Effect of Clopidogrel on the Pharmacokinetics of Simvastatin

Matti K. Itkonen, Aleksi Tornio, Mikko Neuvonen, Pertti J. Neuvonen, Mikko Niemi and Janne T. Backman
Drug Metabolism and Disposition November 1, 2015, 43 (11) 1655-1660; DOI: https://doi.org/10.1124/dmd.115.065938
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