Identification of phase-I and phase-II metabolites of fluphenazine in rat bile. Intact glucuronide and sulfate conjugates.
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.
Jackson
C J
CJ
College of Pharmacy, University of Saskatchewan, Saskatoon, Canada.
Hubbard
J W
JW
McKay
G
G
Cooper
J K
JK
Hawes
E M
EM
Midha
K K
KK
D000818:Animals; D001646:Bile / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005476:Fluphenazine / Q000378:metabolism*; D005965:Glucuronates / Q000378:metabolism; D005966:Glucuronidase; D006868:Hydrolysis; D007202:Indicators and Reagents; D051381:Rats; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013429:Sulfatases; D013431:Sulfates / Q000378:metabolism
D005965:Glucuronates; D007202:Indicators and Reagents; D013431:Sulfates; D013429:Sulfatases; D005966:Glucuronidase; D005476:Fluphenazine