Biliary excretion of diphenylhydantoin in the rat. Time-course studies

The role of biliary excretion in the dose-dependent elimination of diphenylhydantoin (DPH) was investigated in the rat. During 6 hr, following iv injection of 10 mg of (14-C)DPH per kg, 28% of the radioactivity was excreted in bile and following the higher dose of DPH reached a plateau and remained constant over a period of 6 hr, whereas, with the lower dose, the excretion was a first order process (half-life 165 plus or minus 34 (SE) min). When the major metabolite of DPH,5-(P-hydroxyphenyl)-5-phenylhydantoin (P-HPPH, 14-C-labeled), was administered 1 and 10 mg/kg iv), the rates of biliary excretion of total radioactivity were first order, with half-lives of 49 plus or minus 3 and 57 plus or minus 4 min, respectively. Therefore, the conjugation of p-HPPH and the transfer of the conjugate from liver cells into bile were not saturable with the two doses studied. The data are consistent with the assumption that the dose-dependent elimination of DPH is due to the saturable conversion of DPH to p-HPPH.