Aging effects on stereoselective pharmacokinetics and pharmacodynamics of verapamil.

Abstract

Pharmacokinetics and pharmacodynamics were studied after separate single 15-min infusions of each of verapamil's enantiomers (d, 10-11 mg/kg; l, 0.10-0.11 mg/kg) in 16 healthy non-smoking subjects ranging in age from 24 to 40 (young) and from 63 to 83 years (elderly). Verapamil clearance was found to be decreased in an age-related stereoselective manner, with significant reductions in l-verapamil clearance in older subjects (P < .03), but no age-related change in d-verapamil clearance. Greater l- vs. d-verapamil clearance rates were only seen in younger male subjects. Trends for increased elimination half-lives for both enantiomers were seen with increasing age (for d-, P < .09, l- P = .10). Protein binding was stereoselective, with greater binding of d- vs. l-verapamil in both age groups (P < .0001) with no age-related differences in binding detected. Vd beta was greater for d- vs. l-verapamil (P < .05). l-Verapamil was more potent than d-verapamil (P < .001) for all pharmacodynamic variables measured. Both verapamil enantiomers decreased blood pressure (P < .0001), increased P-R intervals during sinus rhythm (P < .0001) and atrioventricular Wenckebach block cycle lengths (P < .0001) and transiently increased heart rate (P < .0001) in both young and elderly subjects. Age-related differences in responses were seen for blood pressure (greater decreases in systolic pressure in the elderly after d-verapamil, P < .002), heart rate (smaller and only transient increases followed by decreases after d-verapamil) and P-R intervals during sinus rhythm (less prolongation in the elderly after both enantiomers, P < .02).(ABSTRACT TRUNCATED AT 250 WORDS)