Metabolism, tissue distribution, and elimination kinetics of phenytoin in the frog

The elimination, tissue distribution, and biotransformation of phenytoin (PHT) were studied in the leopard frog (Rana pipiens). Elimination of PHT proceeded by concentration-dependent kinetics. At lymph concentrations above 3 μg/ml, elimination proceeded at a constant rate (0.43 μg/ml/hr). At concentrations below 3 μg/ml, PHT was eliminated at a constant half-life (4.8 hr). Tissue/plasma ratios of PHT levels were greater than unity for all tissues except lymph and stomach contents. Highest levels were found in bile, kidney, pancreas, and brain. Major metabolites of PHT were p-HPPH [5-(p-hydroxyphenyl)-5-phenylhydantoin] and its glucuronic acid conjugate. Minor metabolites were m-HPPH [5-(m-hydroxyphenyl)-5-phenylhydantoin], the dihydrodiol [5-(3,4-dihydroxy-1,5-cyclohexadien-1-yl)-5-phenylhydantoin], the catechol [5-(3,4-dihydroxyphenyl)-5-phenylhydantoin], and an O-methylcatechol metabolite. It is concluded that the metabolism, tissue distribution, and elimination of PHT in the frog are similar to those in many mammals, including man.