β-Oxidation of Valproic Acid..

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Abstract
The effect of fasting and glucose-infusion on valproate (VPA) disposition was investigated to determine the involvement of endogenous fatty acid (FA) .beta.-oxidation in the metabolism of VPA. Fifteen healthy volunteers received multiple oral doses of VPA to achieve steady state under both conditions. Depressed plasma FA concentrations in the glucose-infused state (median 51%, p < 0.0001) were associated with lower unbound plasma VPA fractions (median 17%, p < 0.0001). Unbound plasma VPA concentrations were notably lower in the glucose-infused state due to significantly higher (median 41%, p < 0.0001) metabolic clearance. .beta.-oxidative metabolite formation clearance, representing the largest urinary dose fraction recovered, was significantly higher (median 60%, p < 0.004) in the glucose-infused state. This finding is consistent with competition between endogenous FA and VPA for the enzymes of .beta.-oxidation modulated by conditions which affect FA mobilization to the site of catabolism.

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