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-β-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 (>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.