Metabolism of cibenzoline in dogs

The disposition of 14C-cibenzoline in male dogs after oral administration of 13.8 mg/kg of cibenzoline base, 4,5-dihydro-2-(2,2-diphenylcyclopropyl)-1H-imidazole, was investigated. Unchanged drug was the major excreted component in 0-24 h urine from 3 dogs, ranging from 32.2-56.6% of the dose. A phenolic metabolite was purified by TLC after Glusulase hydrolysis and identified by NMR and MS as p-hydroxycibenzoline in rearranged form, rac-4-[5-phenyl(2,3,6,7-tetrahydro-5H-pyrrolo-[1,2-a]imidazol-5-yl)] phenol. The 0-24 h urine contained 4-5% of the dose as this compound. The conditions leading to rearrangement of synthetic p-hydroxycibenzoline, trans-rac-4-[2-(4,5-dihydro-1H-imidazol-2-yl)-phenylcyclopropyl] phenol, were investigated. These studies suggested that unrearranged p-hydroxycibenzoline was excreted and that rearrangement occurred predominantly during the purification procedure. Unchanged cibenzoline, purified from urine, was analyzed by ORD/CD and found to display slight optical activity, corresponding to an optical purity of 15%. Shape of the spectra and sign (minus) were those of reference S(-) cibenzoline. p-Hydroxycibenzoline and its rearranged analog were only slightly active in inhibiting ventricular arrhythmia in rats induced by i.v. infusion of aconitine