The effect of short- and long-term administration of verapamil on the disposition of cytochrome P450 3A and P-glycoprotein substrates

Clinical Pharmacology and Therapeutics
Girum L LemmaStephen D Hall

Abstract

Verapamil has the capability to inhibit and induce cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp), but the relative extent and time course of these events in vivo are unclear. The effect of verapamil on CYP3A and P-gp activity was determined by examining its effect on its own disposition and on the disposition of fexofenadine, respectively. Twelve healthy volunteers received 60 mg fexofenadine alone or after administration of 240 mg verapamil for 1, 10, and 38 days. The concentrations of verapamil and norverapamil, as well as their enantiomers, were quantified in serum by chiral HPLC. The concentrations of fexofenadine and its metabolite, azacyclonol, were quantified in serum and urine by liquid chromatography-mass spectrometry. The mean +/- SD maximum serum concentration (Cmax) and the area under the serum concentration-time curve of S-verapamil increased significantly on days 10 (40 +/- 21 ng/mL [P = .00044] and 433 +/- 316 ng.h.mL(-1) [P = .00047], respectively) and 38 (42 +/- 27 ng/mL [P = .019] and 433 +/- 256 ng.h.mL(-1) [P = .0081], respectively) compared with day 1 (21 +/- 12 ng/mL and 222 +/- 156 ng.h.mL(-1), respectively). The oral clearance (CLoral) of S-verapamil decreased significantly from 702 +/- 304 L/h on d...Continue Reading

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