TY - JOUR T1 - Clopidogrel Has No Clinically Meaningful Effect on the Pharmacokinetics of the OATP1B1 and CYP3A4 Substrate Simvastatin JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.115.065938 SP - dmd.115.065938 AU - Matti K Itkonen AU - Aleksi Tornio AU - Mikko Neuvonen AU - Pertti J Neuvonen AU - Mikko Niemi AU - Janne T Backman Y1 - 2015/01/01 UR - http://dmd.aspetjournals.org/content/early/2015/09/01/dmd.115.065938.abstract N2 - 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 (CYP) 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 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 AUC0-12h was 132% (P=0.08) of that during placebo, whereas the AUC0-2h and the AUC0-12h 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 to placebo. The effect of clopidogrel seemed independent of SLCO1B1 c.521T>C genotype. In conclusion, as clopidogrel did not have significant effects on the total exposure to simvastatin or simvastatin acid, clopidogrel seems not to inhibit OATP1B1 or CYP3A4 to a clinically relevant extent. ER -