Gender-specific effects on verapamil pharmacokinetics and pharmacodynamicsin humans

Pharmacokinetic studies of i.v. and oral racemic verapamil and C-14-erythro mycin breath tests (ERBT) were performed in 84 healthy men (n = 42) and wom en (n = 42). Verapamil was measured by HPLC, concentration versus time data were analyzed by noncompartmental; models, protein binding was measured by equilibrium dialysis, and statistical analyses were performed by ANOVA. Cl earance of i.v. and p.o. verapamil was 13.7 +/- 4.3 and 58.4 +/- 35 ml/min/ kg (mean + SD) in women compared to 12.6 +/- 3.4 and 82.6 +/- 70 ml/min/kg in men (p = 0.076). Bioavailability was higher in women (0.25 +/- 0.09) com pared to men 10.20 +/- 0.09, (p = 0.019) with a significant Gender x Formul ation interaction (p = 0.04). ERBT were higher in women (p < 0.0001). Verap amil (i.v. and p.o.) decreased blood pressure in all subjects with greater heart rate increases after p.o. verapamil in women compared to men (p = 0.0 41). The findings suggest that sex-specific differences in drug metabolism may occur in both the gut and the liver and involve multiple metabolic path ways and that pharmacokinetic differences will alter pharmacodynamic respon ses. (C) 2000 the American College of Clinical Pharmacology.