Effects of lovastatin on the pharmacokinetics of verapamil and its active metabolite, norverapamil in rats: possible role of P-glycoprotein inhibition by lovastatin.
This study was to investigate the effect of lovastatin on the bioavailability or pharmacokinetics of verapamil and its major metabolite, norverapamil, in rats. The pharmacokinetic parameters of verapamil and norverapamil in rats were measured after the oral administration of verapamil (9 mg/kg) in the presence or absence of lovastatin (0.3 or 1.0 mg/kg). The pharmacokinetic parameters of verapamil were significantly altered by the presence of lovastatin compared to the control group (given verapamil alone). The presence of lovastatin significantly (p < 0.05, 0.3 mg/kg; p < 0.01, 1.0 mg/kg) increased the total area under the plasma concentration-time curve (AUC) of verapamil by 26.5-64.8%, and the peak plasma concentration (C(max)) of verapamil by 34.1-65.9%. Consequently, the relative bioavailability (R.B.) of verapamil was increased by 1.27- to 1.65-fold than that of the control group. However, there was not significant change in the time to reach the peak plasma concentration (T(max)) and the terminal half-life (t(1/2)) of verapamil in the presence of lovastatin. The AUC and C(max) of norverapamil were significantly (p < 0.05) higher than those of presence of 1.0 mg/kg of lovastatin compared with the control group. However, there was no significant change in the metabolite-parent ratio (M.R.) of norverapamil in the presence of lovastatin. The presence of lovastatin significantly enhanced the oral bioavailability of verapamil. The enhanced oral bioavailability of verapamil may be due to inhibition both of the CYP3A-mediated metabolism and the efflux pump P-glycoprotein (P-gp) in the intestine and/or in liver by the presence of lovastatin.
Hong
Soon-Pyo
SP
College of Medicine, Chosun University, Gwangju, Korea.
Chang
Kyoung-Sig
KS
Koh
Young-Youp
YY
Choi
Dong-Hyun
DH
Choi
Jun-Shik
JS
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002121:Calcium Channel Blockers / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004347:Drug Interactions; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D008148:Lovastatin / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D050216:Metabolic Detoxication, Phase I; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity; D014700:Verapamil / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002121:Calcium Channel Blockers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C016904:norverapamil; D008148:Lovastatin; D014700:Verapamil; D051544:Cytochrome P-450 CYP3A