Metabolism of cibenzoline in dogs
The disposition of /sup 14/C-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.
- Research Organization:
- Hoffmann-La Roche Inc., Nutley, NJ
- OSTI ID:
- 6762746
- Report Number(s):
- CONF-8604222-; TRN: 87-010462
- Journal Information:
- Fed. Proc., Fed. Am. Soc. Exp. Biol.; (United States), Vol. 45:4; Conference: 70. annual meeting of the Federation of American Society for Experimental Biology, St. Louis, MO, USA, 13 Apr 1986
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
IMIDAZOLES
METABOLISM
PURIFICATION
CARBON 14 COMPOUNDS
DOGS
DOSE-RESPONSE RELATIONSHIPS
METABOLITES
THIN-LAYER CHROMATOGRAPHY
TRACER TECHNIQUES
URINE
ANIMALS
AZOLES
BIOLOGICAL MATERIALS
BIOLOGICAL WASTES
BODY FLUIDS
CHROMATOGRAPHY
HETEROCYCLIC COMPOUNDS
ISOTOPE APPLICATIONS
LABELLED COMPOUNDS
MAMMALS
MATERIALS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
SEPARATION PROCESSES
VERTEBRATES
WASTES
550501* - Metabolism- Tracer Techniques