PLASMA-PROTEIN BINDING AND METABOLIC-CLEARANCE OF PHENYTOIN IN RAT

Abstract

Effects of certain changes in plasma protein binding on the disposition of phenytoin after i.v. administration in the rat were examined. Treatment of rats with sulfisoxazole and oleic acid significantly reduced plasma protein binding of phenytoin. Displacement of phenytoin from plasma proteins by sulfisoxazole had no significant effect on elimination of phenytoin, whereas comparable displacement by oleic acid produced an increase in the apparent volume of distribution and a marked decrease in metabolic clearance of the drug. A similar difference in metabolic clearance was noted when phenytoin elimination was determined as a function of the intrinsic ability of the rat to bind phenytoin in the plasma. Rats showing relatively high plasma protein binding of phenytoin cleared the drug much more rapidly than rats showing relatively low plasma protein binding of phenytoin. Assuming that an endogenous inhibitor is responsible for decreased plasma protein binding and decreased metabolic clearance of phenytoin in rats with an intrinsically reduced ability to bind phenytoin in plasma, this inhibitor is evidently similar to oleic acid in its effects.