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Identification of phase-I and phase-II metabolites of fluphenazine in rat bile. Intact glucuronide and sulfate conjugates

CJ Jackson, JW Hubbard, G McKay, JK Cooper, EM Hawes and KK Midha

College of Pharmacy, University of Saskatchewan, Saskatoon, Canada.

In rat bile following ip administration of fluphenazine (FLU) dihydrochloride (20 mg/kg body weight), phase-I metabolites 7- hydroxyfluphenazine (7-HOFLU) and FLU sulfoxide (FLUSO), together with unmetabolized FLU, were isolated and identified by HPLC and fast atom bombardment spectrometry (FAB/MS) and also by comparison with authentic compounds. Two intact glucuronide conjugates of FLU were isolated and identified as phase-II metabolites: 7-hydroxyfluphenazine ring glucuronide (glucuronic acid linked to the aromatic hydroxyl group of 7- hydroxyfluphenazine), and FLU glucuronide (glucuronide linked to the aliphatic group of the side chain of FLU) by HPLC and FAB/MS in comparison with authentic compounds. Further confirmed by FAB/MS were several sulfate conjugates of FLU that were isolated and identified indirectly as phase-II sulfate metabolites: FLU sulfate, 7- hydroxyfluphenazine sulfate and/or 7-hydroxyfluphenazine ring sulfate, and FLU sulfoxide sulfate by HPLC and FAB/MS; their aglycones were identified after sulfatase hydrolysis as FLU, 7-HOFLU and FLUSO. A further phase-II metabolite, for which no authentic standard was available, was tentatively identified as a monoglucuronide of dihydroxy derivative of FLU. To our knowledge, this report provides the first direct evidence of the presence of intact phase-II metabolites of FLU in rat bile.

Volume 19, Issue 1, pp. 188-193, 01/01/1991
Copyright © 1991 by American Society for Pharmacology and Experimental Therapeutics






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Copyright © 1991 by the American Society for Pharmacology and Experimental Therapeutics.