Reduced verapamil clearance during long‐term oral administration

Plasma concentrations of verapamil and its metabolite, norverapamil, were measured in six patients with supraventricular tachycardia after the first and seventh dose of a regimen consisting of 120 mg every 8 hr by mouth. Steady state was reached by the seventh dose and the area under the concentration‐time curve (AUC) at steady state (1999 ± 435[SD] ng/ml · hr) was greater than that after the first dose (788 ± 224, P < 0.001). This unexpected cumulation was associated with prolongation of verapamil half‐life (t½) from 2.75 ± 1.14 to 4.52 ± 1.10 hr. Norverapamil AUC also rose from 1225 ± 405 to 2312 ± 963 ng/ml/hr during the attainment of steady stale. We conclude that verapamil cumulates to a greater extent than predicted from its t½, due to reduction in hepatic clearance. Clinical Pharmacology and Therapeutics (1981) 30, 701–703; doi: 10.1038/clpt.1981.223