¹Department of Medicine, Indiana University School of Medicine, Indianapolis, and Schering-Plough, Kenilworth

Correspondence: Stephen D. Hall, PhD, Division of Clinical Pharmacology, Indiana University School of Medicine, Wishard Memorial Hospital, WD Myers Bldg, W7123, 1001 W 10th St, Indianapolis, IN 46202-2879 E-mail: sdhall@iupui.edu

^*Supported by National Institutes of Health grants T32GM08425 and M01-RR00750, Food and Drug Administration Co-operative agreement FDT-001756, and a Merck Fellowship.

Received 6 June 2005; Accepted 1 November 2005; Published online 7 February 2006.

Abstract

Background: 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.

Methods: 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.

Results: The mean SD maximum serum concentration (C_max) 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 nghmL^-1 [P = .00047], respectively) and 38 (42 27 ng/mL [P = .019] and 433 256 nghmL^-1 [P = .0081], respectively) compared with day 1 (21 12 ng/mL and 222 156 nghmL^-1, respectively). The oral clearance (CL_oral) of S-verapamil decreased significantly from 702 304 L/h on day 1 to 377 210 L/h on day 10 (P = .0029) and 449 419 L/h on day 38 (P = .05). Similar trends were observed for the C_max and area under the serum concentration–time curve of R-verapamil and R- and S-norverapamil. All subjects showed a significant decrease in the CL_oral of fexofenadine after a single dose (98 54 L/h, P = .00105) and 10-day dosing (102 40 L/h, P = .0011) of verapamil compared with the control value (156 69 L/h). The C_max of fexofenadine was significantly increased by a single dose (165 42 ng/mL, P = .0005) and 10-day dosing (148 39 ng/mL, P = .0008) of verapamil compared with the control value (114 45 ng/mL). No significant difference in fexofenadine C_max (P = .37) and CL_oral (P = .43) was observed between the control values and values at 38 days of verapamil treatment.

Conclusion: Verapamil inhibited CYP3A activity, with a maximum effect occurring within 10 days. Short-term administration of verapamil caused net inhibition of intestinal P-gp, whereas long-term administration of verapamil induced P-gp activity.