Biotransformation of cibenzoline to 2-(2,2-diphenylcyclopropyl)-1H-imidazole

Abstract

1. A microsomal metabolite of cibenzoline, 4,5-dihydro-2-(2,2-diphenylcyclopropyl)-1H-imidazole butanedioate, was identified by n.m.r. as the 4,5-dehydro analogue, 2-(2,2-diphenylcyclopropyl)-1H-imidazole.

2. Three dogs dosed orally with 13.8mg/kg ¹⁴C-cibenzoline base excreted 1.8–3.5% of the dose as this metabolite in the urine. Mean plasma concentrations of cibenzoline reached a peak of 1.5 μg/ml at 2h while mean concentrations of the metabolite of 0.4–0.5 μg/ml were found between 2 and 7h.

3. The metabolite was synthesized and found to decrease the frequency of ventricular premature depolarizations in conscious dogs having a two-stage occlusion of the left anterior descending coronary artery performed 48h before. It did not inhibit ventricular arrhythmia in rats induced by i.v. infusion of aconitine. Thus, in contrast to cibenzoline, the metabolite does not appear to be a true antiarrhythmic agent.