Effect of pioglitazone on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rats.
Pioglitazone, a thiazolidinedione antidiabetic drug, inhibits cytochrome P450 (CYP) 2C8 and CYP3A4 enzymes in vitro. This study investigated the effect of pioglitazone on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rats, after oral administration of verapamil (9 mg/kg) in the presence or absence of pioglitazone (0.3 or 1.0 mg/kg). Pioglitazone altered verapamil pharmacokinetics compared with verapamil alone. The presence of 1.0 mg/kg of pioglitazone significantly (p < 0.05) increased the area under the plasma concentration-time curve (AUC) and the peak concentration (C(max)) of verapamil by 49.0% and 46.8%, respectively, and significantly (p < 0.05) decreased the total plasma clearance (CL/F) of verapamil by 32.8%. The metabolite-parent AUC ratio in the presence of pioglitazone (1.0 mg/kg) significantly (p < 0.05) decreased by 21.9% compared to the control group. Thus, coadministration of pioglitazone inhibited the CYP3A4-mediated metabolism of verapamil.
Choi
Jun Shik
JS
College of Pharmacy, Chosun University, Gwangju, 501-759, Korea.
Burm
Jin Pil
JP
D000818:Animals; D019540:Area Under Curve; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004347:Drug Interactions; D006207:Half-Life; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D000077205:Pioglitazone; D051381:Rats; D017207:Rats, Sprague-Dawley; D045162:Thiazolidinediones / Q000494:pharmacology*; D014700:Verapamil / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D002121:Calcium Channel Blockers; D065607:Cytochrome P-450 Enzyme Inhibitors; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; C016904:norverapamil; D014700:Verapamil; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; D000077205:Pioglitazone