The effect of gender on the pharmacokinetics of verapamil and norverapamil in human

Abstract

The effects of gender on the pharmacokinetics of verapamil and its active metabolite, norverapamil, following single oral dose (80 mg, Isoptin) to 12 healthy male (mean age: 25.75+/-2.42 years, mean body weight: 70.59+/-9.94 kg) and 12 healthy female subjects (mean age: 24.08+/-2.84 years, mean body weight: 56.67+/-5.23 kg) were investigated in the present study. Plasma concentrations of verapamil and norverapamil were analysed using a modified high-pressure liquid chromatography method. Pharmacokinetic parameters were calculated by non-compartmental analysis for each subject. For verapamil the half-life (t1/2) and mean residence time (MRT) were significantly shorter in women than men (p<0.01 and p<0.05, respectively). For other pharmacokinetic parameters of verapamil there were no significant differences between males and females. For norverapamil, t1/2, MRT and time to reach to the maximum plasma concentration (Tmax) showed statistically significant differences between the two genders. The AUC(0-24) and AUC(0-infinity) ratios of norverapamil to verapamil were also calculated. The ratios were significantly higher in women compared with men. These observations indicate that the elimination rate of verapamil is faster in women than men which may be attributed to the higher activity of CYP3A4 or lower activity of P-glycoprotein in women compared with men. A contribution of both factors in the appearance of gender differences in verapamil pharmacokinetics is also possible.

Atrial fibrillation in women: treatment

“…However, in the study of pharmacokinetics, women had higher plasma concentrations of β‐blockers 119–122 and possibly also of verapamil 123–125 than men. The differences in concentrations seemed to be related to differences in activity of drug-metabolism pathways and gastrointestinal absorption.…”

Evaluation of gender in the oral pharmacokinetics of clindamycin in humans

“…Gender variability in the pharmacokinetics of drugs metabolized by different enzymatic pathways has been described [6,7]. Although differences in the activity of CYP3A4 between genders have been reported [8][9][10], pharmacokinetic differences in drugs metabolized by this enzymatic pathway are not always observed [11][12][13][14]. Due to this controversy, it is difficult to establish a priori if gender differences in the pharmacokinetics of drugs metabolized by CYP3A4 will be present.…”

Gender Differences in Cardiovascular Drugs

“…In the sinoatrial (SA) and atrioventricular (AV) nodes of the heart, CCBs slow the Ca 2+ -dependent upstroke of the action potential, thereby reducing automaticity of the SA node and slowing impulse conduction through the AV node. Gender-related pharmacokinetic differences for several CCBs, including amlodipine and verapamil, have been described [68,69]. Women achieve higher plasma concentrations of amlodipine and display faster oral elimination rates for verapamil compared to men.…”

“…Women achieve higher plasma concentrations of amlodipine and display faster oral elimination rates for verapamil compared to men. This difference can be partially attributed to the lower body weight, higher activity of CYP3A4 and lower activity of P-gp in women compared to men [68,69]. An 18 week, open-labeled, prospective study demonstrated that amlodipine exerted a greater antihypertensive effect in women compared to hypertensive men across all age groups [70,71].…”