Faster clearance of sustained release verapamil in men versus women: continuing observations on sex-specific differences after oral administration of verapamil

Abstract

Pharmacokinetic studies after administration of 120 mg oral sustained- and regular-release racemic verapamil were performed in 13 healthy subjects (seven men, age 74 +/- 4 years [mean +/- SD], weight 69.9 +/- 5.4 kg, and body mass index 24.6 +/- 2.2]; and six women, age 65 +/- 13 years, weight 65 +/- 9.9 kg, and body mass index 25.3 +/- 3). Verapamil was measured by HPLC, concentration versus time data analyzed by noncompartmental models, and statistical analyses performed by ANOVA for repeated measurements. The area under the concentration versus time curve (AUC) after administration of sustained-release verapamil was 48,951 +/- 18,079 ng/mL x min(-1) in women compared with 25,595 +/- 10,245 in men and lower than after administration of regular-release verapamil (63,055 +/- 24,411 for women and 34,686 +/- 25,279 in men; P = .05 for sex-related effect and P < .02 for formulation effect). AUC ratios of norverapamil (N-demethylated metabolite) to verapamil after administration of sustained-release verapamil were 1.43 +/- 0.26 in women compared with 1.74 +/- 0.41 in men and 1.43 +/- 0.26 in women compared with 1.78 +/- 0.37 in men after administration of regular-release verapamil (P = .1 for sex-related effect and P = .9 for formulation effect). Apparent oral clearance was 43 +/- 15 mL/min/kg in women compared with 75 +/- 29 in men after administration of sustained-release verapamil and 35 +/- 16 mL/min/kg in women compared with 65 +/- 31 in men after administration of regular-release verapamil (P < .05 for sex-related effect and P < .02 for formulation effect). Apparent oral clearance of both regular- and sustained-release formulations of verapamil was faster in men compared with women in contrast to findings after intravenous administration of verapamil, suggesting that intestinal processes are a factor in sex-specific difference in drug clearance. Greater verapamil and norverapamil bioavailability after administration of regular- compared with sustained-release verapamil also suggests saturable processes at the intestinal level.