Disposition of β-glucuronidase-resistant 'glucuronides' of valproic acid after intrabiliary administration in the rat: Intact absorption, fecal excretion and intestinal hydrolysis

Abstract

The major metabolite of valproic acid (VPA) is its β-glucuronidase-susceptible glucuronide conjugate (VPA-G). At slightly alkaline pH such as in bile, VPA-G undergoes intramolecular rearrangement into at least six β-glucuronidase-reistant isomers (VPA-G-R). The in vivo disposition of VPA-G-R was compared with those of VPA-G and VPA, each at 100 mg of VPA per kg, after intrabiliary administration to surgically prepared rats fasted during the experiments. Administered VPA was rapidly and completely absorbed into blood (peak 30 μg of VPA per ml at 0-2 hr). Administered VPA-G was predominantly hydrolyzed (β-glucuronidase) in the intestine and liberated VPA absorbed into blood (peak 5 μg of VPA p..