Abstract
The influence of phenobarbital, clofibrate, 3-methylcholanthrene and β-naphthoflavone on ω- and β-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 [(ω-l)-oxidation], 5-hydroxy-valproic acid and n-propylglutaric acid (ω-oxidation) excretion. Clofibrate enhanced the excretion of 4-ydroxyvalproic acid and 3-keto-valproic acid, a product of peroxisomal β-oxidation. β-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 (ω-2)-oxidation. The addition of fatty acids (olive oil in which 3-methylcholanthrene and β-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.
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