Inhibitory Effect of Valproic Acid on Metabolic Clearance of Carbamazepine Epoxide

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In order to clarify the inhibitory effect of valproic acid (VPA) on the metabolic clearance of carbamazepine-10,11-epoxide (EPO), an active metabolite of carbamazepine, in rat, the disposition of EPO from plasma and the in vitro hydration of EPO were measured in the presence of VPA, in addition to estimating the effect of the antiepileptic on uridine 5'-diphosphoglucuronyltransferase (UDPGT) activity. It was found that the elimination of EPO from plasma was hardly affected by the pretreatment of VPA (100 mg/kg/d for 7 d). However, the elimination was significantly delayed by VPA at steady-state concentration, maintained by the repeated oral administration of the drug, with a 38% decrease in total clearance and a 52% increase in the fraction of EPO eliminated unchanged in urine. The in vitro hydration of EPO was inhibited competitively by VPA at the concentrations comparable to the in vivo levels. The UDPGT activity of hepatic microsomes was also partly inhibited by VPA. These results suggest that VPA at steady state interferes with the metabolic clearance of EPO, by inhibiting the hydration of EPO and glucuronidation of carbamazepine-trans-diol, a hydrated metabolite.
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