Verapamil kinetics in normal subjects and patients with coronary artery spasm

Abstract

Verapamil kinetics after i.v. and single and long-term oral dosing were studied in 12 patients with coronary artery spasm and 4 normal subjects. The decline in plasma concentration after i.v. doses was described by a triexponential decay equation, with a terminal half-life (t1/2) of 5 h. After a single oral dose the bioavailability was only 24%, probably because of first-pass metabolism. During long-term oral doses of 80 mg every 6 h, mean peak and trough concentrations were 255 .+-. 90 and 105 .+-. 38 ng/ml, and mean time at which peak concentration occurred was 1.2 .+-. 0.5 h. Norverapamil, the major active metabolite of verapamil, cumulated during oral dosing and may account for a small proportion of the overall pharmacologic effect. Mean elimination t1/2 during long-term oral dosing was longer than after a single dose (9.6 and 5.7 h, P < 0.05). Also, during long-term dosing the area under the curve was more than double that of a single dose, and the apparent oral clearance fell from 4.2 to 1.8 l/min (P < 0.01). These changes may partly be explained by reduction in presystemic metabolism during long-term therapy. Kinetic predictions based on single doses will not give reliable estimates for long-term oral dosage. Less frequent dose schedules may be possible for prolonged therapy.