Effects of simvastatin on the pharmacokinetics of verapamil and its main metabolite, norverapamil, in rats.
The aim of this study was to investigate the effect of simvastatin on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rats. The pharmacokinetic parameters of verapamil and norverapamil in rats were determined after the oral administration of verapamil (9 mg/kg) in the presence or absence of simvastatin (0.3 and 1.0 mg/kg). The pharmacokinetics of verapamil were significantly altered by the coadministration of simvastatin compared with those in the control group (given verapamil alone). The area under the plasma concentration-time curve (AUC) and the peak plasma concentration (Cmax) of verapamil were significantly increased (P < 0.05 at 0.3 mg/kg; P < 0.01 at 1.0 mg/kg) by simvastatin. Consequently, the absolute bioavailability (A.B.) of verapamil with simvastatin (7.3% at 0.3 mg/kg, 9.3% at 1.0 mg/kg) were significantly higher than those in the control group (P < 0.05, 5.2%). The AUC and Cmax of norverapamil were not significantly increased in the rats coadministered with simvastatin compared with those in the control group. Moreover, the metabolite-parent ratio (M.R.) of norverapamil were significantly decreased in rats coadministered with simvastatin. These results implied that simvastatin significantly enhanced the oral bioavailability of verapamil by inhibiting the CYP3A-mediated metabolism in small intestine or in the liver and P-glycoprotein (P-gp) efflux pump in small intestine. Therefore, concurrent use of verapamil and simvastatin should be monitored closely to potential drug interactions for safe therapy of cardiovascular diseases.
Choi
Dong-Hyun
DH
College of Medicine, Chosun University, Gwangju 501-759, Republic of Korea.
Li
Cheng
C
Choi
Jun-Shik
JS
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007421:Intestine, Small / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000008:administration & dosage / Q000494:pharmacology*; D014700:Verapamil / Q000031:analogs & derivatives / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002121:Calcium Channel Blockers; D065692:Cytochrome P-450 CYP3A Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C016904:norverapamil; D019821:Simvastatin; D014700:Verapamil; D051544:Cytochrome P-450 CYP3A