Stereoselective verapamil disposition and dynamics in aging during racemic verapamil administration

Stereoselective verapamil disposition and dynamics were evaluated after racemic verapamil administration of single i.v. doses, simulated steady- state intravenous infusions, chronic (1 week) administration of oral immediate-release tablets (120 mg three times daily) and chronic (1 week) administration of oral sustained-release tablets (240 mg once daily) to 15 young (mean ± S.E.M. age 22 ± 1 year) and 15 older (69 ± 1 year) healthy male volunteers. After single i.v. doses S-verapamil clearance (young, 102 ± 6 vs. older, 77 ± 6 l/hr; P < .01) and R-verapamil clearance (young, 61 ± 3 vs. older, 45 ± 3 l/hr; P < .01) were similarly decreased. Electrocardiographic P-R prolongation using S-verapamil concentrations and an E(max) model (young E(max), 69 ± 8 vs. older, 42 ± 6 msec; P < .05: young EC₅₀, 15 ± 1 vs. older, 23 ± 3 ng/ml; P < .05) was greater in the young. Simulated steady-state i.v. S-verapamil clearance (young, 76 ± 3 vs. older, 49 ± 2 l/hr; P < .01) and R-verapamil clearance (young, 47 ± 2 vs. older, 28 ± 1 l/hr; P < .01) were similarly less in older subjects and this was unrelated to infusion rate. Qualitatively similar findings were observed during chronic oral (immediate release) treatment and chronic oral (sustained release) treatment. Plasma protein binding of S-verapamil was less in both groups (young, 8.5 ± 0.4 and older, 8.0 ± 0.5% unbound) than that of R- verapamil (young, 5.4 ± 0.2 and older, 5.1 ± 0.3% unbound) and not different between groups. Clearance of both pharmacologically active S- verapamil and R-verapamil is less in older subjects after nonsteady-state and steady-state i.v. and oral racemic verapamil administration. Verapamil- induced cardiac A-V nodal conduction delay is greater in young subjects and this is not due to age-related stereoselective verapamil disposition.