Abstract
The glucose-lowering drug pioglitazone undergoes hepatic cytochrome P450 (CYP) 2C8-mediated biotransformation to its main metabolites. The antiplatelet drug clopidogrel is metabolized to clopidogrel acyl-β-D-glucuronide, which was recently found to be a strong time-dependent inhibitor of CYP2C8 in humans. Therefore, we studied the effect of clopidogrel on the pharmacokinetics of pioglitazone. In a randomized crossover study, ten healthy volunteers ingested either 300 mg of clopidogrel on day 1, and 75 mg on days 2 and 3, or placebo. Pioglitazone 15 mg was administered 1 h after placebo and clopidogrel on day 1. Plasma concentrations of pioglitazone, clopidogrel, and their main metabolites were measured up to 72 h. Clopidogrel increased the area under the plasma concentration-time curve (AUC0-∞) of pioglitazone 2.1-fold (P<0.001, 90% CI 1.8-2.6) and prolonged its half-life (t½) from 6.7 to 11 h (P=0.002). The peak concentration of pioglitazone was unaffected but the concentration at 24 h was increased 4.5-fold (range 1.6 to 9.8; P<0.001, 90% CI 3.17-6.45) by clopidogrel. The M-IV-to-pioglitazone AUC0-∞ ratio was 49% (P<0.001, 90% CI 0.40-0.59) of that during the control phase, indicating that clopidogrel inhibited the CYP2C8-mediated biotransformation of pioglitazone. Clopidogrel increases the exposure to pioglitazone by inhibiting its CYP2C8-mediated biotransformation. In consequence, use of clopidogrel may increase the risk of fluid retention and other concentration-related adverse effects of pioglitazone.
- clinical pharmacology
- cytochrome P450
- drug-drug interactions
- enzyme inhibitors
- human/clinical
- in vivo probes
- pharmacokinetics
- The American Society for Pharmacology and Experimental Therapeutics