Oxidation and glucuronidation of valproic acid in male rats--influence of phenobarbital, 3-methylcholanthrene, beta-naphthoflavone and clofibrate.
The influence of phenobarbital, clofibrate, 3-methylcholanthrene and beta-naphthoflavone on omega- and beta-oxidation as well as on glucuronidation of valproic acid (n-dipropylacetic acid) was evaluated in male Sprague-Dawley rats by determination of urinary excretion of its metabolites by GC-MS after administration of 100 mg/kg. In controls 12% of the dose was excreted within 24 hours, primarily as glucuronides; metabolites formed by oxidation amounted to about 4%. Phenobarbital treatment led to stimulation of 4-hydroxyvalproic acid [(omega-1)-oxidation], 5-hydroxyvalproic acid and n-propylglutaric acid (omega-oxidation) excretion. Clofibrate enhanced the excretion of 4-hydroxyvalproic acid and 3-keto-valproic acid, a product of peroxisomal beta-oxidation. beta-Naphthoflavone slightly increased the excretion of 5-hydroxyvalproic acid. The most specific effect was found for 3-methylcholanthrene, which was effective in stimulating the formation of 3-hydroxyvalproic acid which might be formed by (omega-2)-oxidation. The addition of fatty acids (olive oil in which 3-methylcholanthrene and beta-naphthoflavone were suspended) led to increased excretion of 3-keto-valproic, 4-hydroxyvalproic and n-propylglutaric acid. The excretion of 3-hydroxyvalproic acid was completely suppressed by olive oil. Such specific effects were not observed for glucuronidation of valproic acid and its metabolites, although stimulation was attained after phenobarbital, clofibrate and 3-methylcholanthrene treatment, because of instability of glucuronide conjugates. Stimulation of valproic acid metabolism was also shown by increased plasma clearance after treatment with phenobarbital. In contrast, clofibrate given once 1 hr before valproic acid inhibited excretion of valproic acid, possibly by competition during renal tubular secretion. Determination of valproic acid metabolites in urine provides a useful tool for evaluation of inducer specificity of short chain fatty acid metabolism and differentiation between microsomal and peroxisomal enzyme activity.
D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology*; D002994:Clofibrate / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology*; D005965:Glucuronates / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D014635:Valproic Acid / Q000378:metabolism*; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D005419:Flavonoids; D005965:Glucuronates; D008748:Methylcholanthrene; D019324:beta-Naphthoflavone; D014635:Valproic Acid; D002994:Clofibrate; D010634:Phenobarbital