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 (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 AUC_0-12h was 132% (P=0.08) of that during placebo, whereas the AUC_0-2h and the AUC_0-12h 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.