Pharmacokinetic studies of i.v. and oral racemic verapamil and 14C-erythromycin breath tests (ERBT) were performed in 84 healthy men (n = 42) and women (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. Clearance 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) compared to men (0.20 +/- 0.09, p = 0.019) with a significant Gender x Formulation interaction (p = 0.04). ERBT were higher in women (p < 0.0001). Verapamil (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 = 0.041). The findings suggest that sex-specific differences in drug metabolism may occur in both the gut and the liver and involve multiple metabolic pathways and that pharmacokinetic differences will alter pharmacodynamic responses.
The data suggest that race, sex, and environmental factors are identifiable sources of interindividual variation in the oral clearance of nifedipine, a CYP3A substrate. Our experience also suggests that data from clinical populations may be biased with regard to age, sex, and formulation selection, and covariates may not be independently distributed, which can limit analyses.
Intravenous and oral verapamil clearance values were significantly correlated, and cumulative dextromethorphan/3-methoxymorphinan urinary ratios correlated with both plasma AUC(norverapamil)/AUC(verapamil) after oral verapamil dosing and with oral and intravenous verapamil clearance. The ERBT correlated only weakly with intravenous verapamil clearance. Results with verapamil are comparable to results with other intravenous and oral CYP3A4/5 probes. Lack of correlation between putative CYP3A4/5 probe results may be attributable to the route of administration; probe characteristics; and intersubject, intrasubject, between-day, and testing measurement variability.
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