title: Impaired biliary elimination of beta-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, beta-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 110 micrograms of VPA/ml at 2 min to 1.1 micrograms/ml at 1 and 3 hr, respectively. A role for systemic hydrolysis of VPA-G was demonstrated by blood concentrations of free VPA which increased until 30 min. A minor role for systemic hydrolysis of VPA-G-R may be possible but cannot be proved from the current data. Urinary excretion (57 and 56% of doses A and B, respectively, in 3 hr) was greater than biliary excretion (32 and 10% of the doses, respectively, in 3 hr). The lower biliary elimination of VPA-G-R may be caused in part by impaired transport from blood to hepatocytes and/or hepatocytes to bile, but a role for phase I metabolism of the VPA moiety of VPA-G-R was demonstrated by recovery of 4.4% of dose B as 4-hydroxy-VPA. This latter mechanism was less (or not) applicable to VPA-G since only 0.4% of dose A was recovered as 4-hydroxy-VPA. Other VPA metabolites measured were quantitatively less important. These results were consistent in rats where either or both of the urinary and biliary elimination routes were surgically blocked.
authors.forename: R G
authors.initials: RG
authors.lastname: Dickinson
authors.forename: R M
authors.initials: RM
authors.lastname: Kluck
authors.forename: B T
authors.initials: BT
authors.lastname: Wood
authors.forename: M J
authors.initials: MJ
authors.lastname: Eadie
authors.forename: W D
authors.initials: WD
authors.lastname: Hooper
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism*; D002849:Chromatography, Gas; D005966:Glucuronidase / Q000378:metabolism*; D007536:Isomerism; D008297:Male; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D014635:Valproic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism* / Q000652:urine
chemical_list: C041285:valproic acid glucuronide; D014635:Valproic Acid; D005966:Glucuronidase