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.

Sex-related differences in pharmacokinetics and pharmacodynamics of anti-hypertensive drugs

“…10 These data are in contrast to those in previous reports of faster Cl of i.v.-administerd racemic verapamil, Rverapamil and S-verapamil, and i.v.-administered erythromycin in women compared with men. 11 Krecic-Shepard et al 10 explained that the reasons for these different results include individual variations, alternative pathways in the metabolism of CYP3A4 substrates, route of drug administration, and differences in competition for transport mechanisms. Thus, they suggested a need for investigation of not only pathway-specific probes but also multiple routes of administration and formulation when studying differences in human subgroups or for elucidating dosing guidelines in human beings.…”

Sex Differences of Drug-metabolizing Enzyme: Female Predominant Expression of Human and Mouse Cytochrome P450 3A Isoforms

“…In contrast, the clearance of orally administrated verapamil is smaller in women than in men, suggesting that intestinal processes are a factor in the sex differences of drug clearance. 30,31) One possible explanation for this contradiction is higher CYP3A activity in the intestinal mucosa, but a recent study by Paine and coworkers found no significant difference between the sexes. 32) In terms of substrates, inducers and tissue specificity, P-glycoprotein (P-gp) has extensive overlap with CYP3A.…”

Nutrition and human health from a sex–gender perspective

“…More information is available on sex-related differences in drug absorption and bioavailability. For example, orally administered verapamil is cleared faster in men than women, a difference that is not observed after intravenous administration of this drug, suggesting that intestinal processes modulate sex-specific differences in verapamil pharmacokinetics (Krecic-Shepard et al, 2000). Ferrous sulfate absorption, measured with the aid of radioisotope labeling, is higher in prepubertal girls than boys (Woodhead et al, 1991), suggesting that hormonal differences may contribute to sex-based pharmacokinetic variability for this mineral salt (see also Section 3.1.3.6).…”