Increased microsomal irreversible binding of phenytoin by valproic acid.

Phenytoin is known to be metabolized to form p-hydroxyphenyl-phenyl-hydantoin, possibly via the arene oxide intermediate. The reactive arene oxide may bind to macromolecules irreversibly and cause toxicity. In this study, valproic acid was found to increase the irreversible binding of phenytoin to rat liver microsomes at high concentrations. The effect was similar to that of TCPO and could be reversed by adding glutathione. Valproic acid may increase the hepatotoxicity of phenytoin.