Beta-oxidation of valproic acid. I. Effects of fasting and glucose in humans

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 less than 0.0001) were associated with lower unbound plasma VPA fractions (median 17%, p less than 0.0001). Unbound plasma VPA concentrations were notably lower in the glucose-infused state due to significantly higher (median 41%, p less than 0.0001) metabolic clearance, beta-oxidative metabolite formation clearance, representing the largest urinary dose fraction recovered, was significantly higher (median 60%, p less than 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.