Impaired biliary elimination of β-glucuronidase-resistant 'glucuronides' of valproic acid after intravenous administration in the rat. Evidence for oxidative metabolism of the resistant isomers

Abstract

A major metabolite of valproic acid (VPA) is its glucuronic acid conjugate (VPA-G). The disposition of VPA-G was compared with that of its intramolecularly rearranged, β-glucuronidase-resistant isomers (collectively called VPA-G-R) after iv bolus administration to pentobarbitone-anesthetized rats. VPA-G was eliminated from blood more rapidly than VPA-G-R. After administration of dose A (predominantly VPA-G) and dose B (predominantly VPA-G-R) to rats with catheterized bladders and bile ducts, total conjugated VPA in blood declined from 110μg of VPA/ml at 2 min to 1.1 μg/ml at 1 and 3 hr, respectively. A role for systemic hydrolysis of VPA-G was demonstrated by blood concentrations of free VPA..