Gender-specific effects on verapamil pharmacokinetics and pharmacodynamics in humans.
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.
Krecic-Shepard
M E
ME
Department of Medicine, Northwestern University Medical School, Chicago, IL 60611, USA.
Barnas
C R
CR
Slimko
J
J
Jones
M P
MP
Schwartz
J B
JB
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D001944:Breath Tests; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004917:Erythromycin; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007275:Injections, Intravenous; D008099:Liver / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism; D012737:Sex Factors; D014700:Verapamil / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D004917:Erythromycin; D003577:Cytochrome P-450 Enzyme System; D014700:Verapamil; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A