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 month. 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 less than 0.001). This unexpected cumulation was associated with prolongation of verapamil half-life (t1/2) 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 state. We conclude that verapamil cumulates to a greater extent than predicted from its t1/2, due to reduction in hepatic clearance.