Drug interaction between oral atorvastatin and verapamil in healthy subjects: effects of atorvastatin on the pharmacokinetics of verapamil and norverapamil

Abstract

It has been reported that verapamil and atorvastatin are inhibitors of both P-glycoprotein (P-gp) and microsomal cytochrome P450 (CYP) 3A4, and verapamil is a substrate of both P-gp and CYP3A4. Thus, it could be expected that atorvastatin would alter the absorption and metabolism of verapamil. The pharmacokinetic parameters of verapamil and one of its metabolites, norverapamil, were compared after oral administration of verapamil (60 mg) in the presence or absence of oral atorvastatin (40 mg) in 12 healthy volunteers. Pharmacokinetics of verapamil were significantly altered by the coadministration of atorvastatin compared with those of without atorvastatin. For example, the total area under the plasma-concentration time curve to the last measured time, 24 h, in plasma (AUC(0-24) (h)) of verapamil increased significantly by 42.8%. Thus, the relative bioavailability increased by the same magnitude with atorvastatin. Although the AUC(0-24) (h) of norverapamil was not significantly different between two groups of humans, the AUC(0-24) (h, norverapamil)/ AUC(0-24) (h, verapamil) ratio was significantly reduced (27.5% decrease) with atorvastatin. The above data suggest that atorvastatin could inhibit the absorption of verapamil via inhibition of P-gp and/or the metabolism of verapamil by CYP3A4 in humans.