Binding of 5,5-Diphenylhydantoin and Its Major Metabolite to Human and Rat Plasma Proteins

Abstract

Equilibrium dialysis was used to determine the degree of plasma protein binding of both 5,5-diphenylhydantoin and its major metabolite, 5-(p-hydroxyphenyl)-5-phenylhydantoin, in man and in the rat. Binding studies show that diphenylhydantoin is extensively bound to human and rat plasma proteins and that the amount of diphenylhydantoin bound per gram protein, at equivalent free diphenylhydantoin concentrations, is greater in human plasma than in rat plasma. Since the rat has higher ( ≈ 1.6-fold) free diphenylhydantoin levels at equivalent total plasma drug levels, correlation of free diphenylhydantoin levels in these species with the in vivo incidence of drug-induced gingival hyperplasia was not possible. Dialysis studies show that the para-hydroxy metabolite is strongly plasma protein bound and that the amount of metabolite bound per gram protein, at equivalent free metabolite concentrations, is greater in rat plasma than in human plasma. Since a given total metabolite plasma concentration results in higher ( ≈ 1.4-fold) free levels in human plasma than in rat plasma, differences in plasma protein binding of the metabolite between these species in vivo may contribute to an explanation for the species selectivity of diphenylhydantoin-induced gingival hyperplasia.