title: Biosynthesis and characterization of glucuronide metabolites of fluphenazine: 7-hydroxyfluphenazine glucuronide and fluphenazine glucuronide.
abstract: 1. To expedite direct studies on phase II metabolites of fluphenazine, pure fluphenazine or 7-hydroxyfluphenazine were incubated with a rabbit hepatic microsomal immobilized enzyme system. After purification and recrystallization a high yield (60%) of 7-hydroxy-beta-D-O-glucuronyl-fluphenazine was obtained. 2. The structure of this glucuronide was proven unambiguously by mass spectrometry (fast atom bombardment, daughter ion analysis, electron impact, chemical ionization) and 1H-n.m.r. and 13C-n.m.r. spectroscopy. The phenolic ether glucuronide was the sole product of the reaction. 3. There was no evidence of conjugation at the primary alcohol group of the side-chain of fluphenazine, or of the formation of quaternary ammonium-linked glucuronides with either of tertiary aliphatic nitrogen atoms of the side-chain. 4. Incubation of fluphenazine with the immobilized enzyme system gave a poor yield (less than 1%) of the aliphatic ether glucuronide as reaction product, consistent with a low susceptibility of the side-chain primary alcohol function of fluphenazine to glucuronidation.
authors.affiliation: College of Pharmacy, University of Saskatchewan, Saskatoon, Canada.
authors.forename: C J
authors.initials: CJ
authors.lastname: Jackson
authors.forename: J W
authors.initials: JW
authors.lastname: Hubbard
authors.forename: K K
authors.initials: KK
authors.lastname: Midha
mesh_terms: D000818:Animals; D002247:Carbon Isotopes; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D004800:Enzymes, Immobilized; D005476:Fluphenazine / Q000031:analogs & derivatives* / Q000378:metabolism*; D005965:Glucuronates / Q000378:metabolism*; D014453:Glucuronosyltransferase; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008862:Microsomes, Liver; D011817:Rabbits; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013057:Spectrum Analysis; D014297:Trimethylsilyl Compounds
chemical_list: D002247:Carbon Isotopes; D004800:Enzymes, Immobilized; D005965:Glucuronates; D014297:Trimethylsilyl Compounds; C070089:7-hydroxyfluphenazine glucuronide; D014453:Glucuronosyltransferase; D005476:Fluphenazine