Effects of pioglitazone on the pharmacokinetics of nifedipine and its main metabolite, dehydronifedipine, in rats.

The purpose of this study was to investigate the possible effects of pioglitazone on the pharmacokinetics of nifedipine and its main metabolite, dehydronifedipine, in rats. The effects of pioglitazone on P-glycoprotein (P-gp) and cytochrome P450 (CYP)3A4 activities were also evaluated. Nifedipine was mainly metabolized by CYP3A4. The pharmacokinetic parameters of nifedipine and dehydronifedipine were determined after oral and intravenous administrations of nifedipine to rats in the presence and absence of pioglitazone (0.3 and 1.0 mg/kg). Pioglitazone inhibited the CYP3A4 enzyme activity in a concentration-dependent manner. Inhibitory concentration (IC50) was 12.1 μM. In addition, pioglitazone significantly increased the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. The areas under the plasma concentration-time curve (AUC0-∞) and the peak plasma concentration (C max) of nifedipine were significantly increased by 52.1 and 59.1 %, respectively, in the presence of pioglitazone (1.0 mg/kg) compared with control group. The total body clearance (CL/F) of nifedipine was significantly (1.0 mg/kg) decreased by pioglitazone (35.8 %). Consequently, the absolute bioavailability (AB) of nifedipine in the presence of pioglitazone (1.0 mg/kg) was significantly higher (25.3 %) than that of the control. The metabolite-parent AUC ratio (MR) in the presence of pioglitazone (1.0 mg/kg) significantly decreased (23.9 %) compared to that of the control group. The increased bioavailability of nifedipine in the presence of pioglitazone may be due to an inhibition of the P-gp-mediated efflux transporter in the small intestine and to the inhibition of the metabolism by inhibition of CYP3A4 in the small intestine and/or the liver, and/or to a reduction of CL/F of nifedipine by pioglitazone.