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 (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 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 Cmax and area under the serum concentration-time curve of R-verapamil and R- and S-norverapamil. All subjects showed a significant decrease in the CLoral 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 Cmax 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 Cmax (P = .37) and CLoral (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.