Effect of atorvastatin on the intravenous and oral pharmacokinetics of verapamil in rats.
The present study aimed to investigate the effect of atorvastatin on the intravenous and oral pharmacokinetics of verapamil in rats. The pharmacokinetic parameters of verapamil were measured after an oral (9 mg/kg) or intravenous (3 mg/kg) administration of verapamil to rats in the presence and absence of atorvastatin. Compared with the control given verapamil alone, the concurrent use of 1.5 mg/kg of atorvastatin significantly increased the oral exposure of verapamil in rats. The AUC and C(max) of verapamil increased by 70% and 61%, respectively in the presence of atorvastatin (1.5 mg/kg), while there was no significant change in T(max) and the terminal plasma half-life (T(1/2)) of verapamil. Accordingly, the presence of atorvastatin significantly (p<0.05) increased the bioavailability of verapamil in rats. In contrast, atorvastatin had no effect on any pharmacokinetic parameters of verapamil given intravenously, implying that atorvastatin may improve the oral bioavailability of verapamil by reducing the prehepatic extraction of verapamil most likely mediated by P-gp and/or CYP3A4. In conclusion, coadministration of atorvastatin significantly enhanced the oral exposure of verapamil in rats without a change in the systemic clearance of intravenous verapamil, suggesting a potential drug interaction between verapamil and atorvastatin via the modulation of prehepatic extraction.
Choi
Dong-Hyun
DH
College of Medicine, Chosun University, 375 Seosuk-dong, Dong-Gu, Gwangju, Korea.
Chang
Kyong-Sig
KS
Hong
Soon-Pyo
SP
Choi
Jun-Shik
JS
Han
Hyo-Kyung
HK
D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D019540:Area Under Curve; D000069059:Atorvastatin; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006207:Half-Life; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014700:Verapamil / Q000008:administration & dosage / Q000493:pharmacokinetics*
D002121:Calcium Channel Blockers; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D000069059:Atorvastatin; D014700:Verapamil