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

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Matti K ItkonenJanne T Backman

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 AUC(0-12 hours) was 132% (P = 0.08) of that during placebo, whereas the AUC(0-2 hours) and the AUC(0-12 hours) of simvastatin acid were 148% (P = 0.04) and 112% (P = 0.52) of control. Clopidogrel 75 mg (d...Continue Reading

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Citations

Jan 2, 2016·Pharmacological Reviews·Janne T BackmanPertti J Neuvonen
Jun 5, 2016·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Matti K ItkonenJanne T Backman
Jul 23, 2016·Clinical Pharmacology and Therapeutics·S W YeeK M Giacomini
Aug 1, 2006·Journal of Controlled Release : Official Journal of the Controlled Release Society·Tomoko SugiuraAkira Tsuji
Jan 10, 2017·International Journal of Molecular Sciences·Elena ArrigoniAntonello Di Paolo
Nov 25, 2017·Clinical Pharmacology and Therapeutics·Matti K ItkonenJanne T Backman
Apr 27, 2018·Clinical Pharmacology and Therapeutics·Matti K ItkonenJanne T Backman
Nov 16, 2017·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Helinä KahmaJanne T Backman
Jan 12, 2019·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Matti K ItkonenJanne T Backman
Aug 25, 2020·Expert Opinion on Drug Metabolism & Toxicology·Chang Hoon LeeDominick J Angiolillo
Jul 31, 2020·Expert Opinion on Drug Metabolism & Toxicology·Takeshi HirotaIchiro Ieiri
Oct 11, 2017·Basic & Clinical Pharmacology & Toxicology·Mikko NeuvonenMikko Niemi
May 1, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ying LiZhan-Jun Dong
Aug 20, 2021·Basic & Clinical Pharmacology & Toxicology·Aleksi TornioJanne T Backman

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