Clinical pharmacokinetics of verapamil in patients with atrial fibrillation

Abstract

The pharmacokinetic parameters and oral bioavailability of the antiarrhythmic drug verapamil were determined in six patients with atrial fibrillation. Plasma samples were taken following i.v. injection of verapamil 10 mg (Isoptin 2 ml), and oral verapamil 80 mg (Isoptin 2 tablets of 40 mg). Verapamil and its N-demethylated metabolite, norverapamil, were analyzed to 1 ng/ml plasma by gas chromatography-mass spectrometry using deuterated standards. Following intravenous injection, the disposition of verapamil followed a biexponential pattern with a fast distribution phase and a slower elimination of phase (t 1/2 beta = 5.79 h), corresponding to a plasma clearance of 0.26 l/kg/h. After oral administration, only an elimination phase was evident, with the same elimination rate (t 1/2 beta = 5.53 h). The oral bioavailability was 10.5% +/- 7.5%. The norverapamil formed after i.v. and oral administration of verapamil had plasma half-lives of 5.86 h and 6.77 h, respectively. The elimination of verapamil in patients with atria fibrillation was decreased compared to that in healthy young volunteers and the oral bioavailability was lower. Very good correlation between the percentage reduction in heart rate and the log plasma concentration of verapamil was found in every patient during the elimination phase, irrespective of the route of administration. There was also a high correlation when the plasma concentration -- effect data from the patients were pooled (r = 0.59, n = 71; p less than 0.0005).