The effect of diethylstilbestrol treatment on the metabolism and biliary excretion of [¹⁴C]phenytoin in the isolated perfused rat liver

The metabolism and biliary excretion of [¹⁴C]phenytoin (DPH) were examined in isolated perfused livers taken from Sprague-Dawley rats pretreated with 0.01, 0.05, 0.1, 0.5, and 1.0 mg/day diethylstilbestrol (DES) sc for 6 days. No difference was seen in the rate of disappearance of DPH from the perfusate or in the perfusate levels of its hydroxylated metabolite, 5-phenyl-5-para-hydroxyphenylhydantoin (HPPH). The biliary excretion of HPPH-glucuronide, however, was significantly depressed in livers from DES-treated rats and resulted in a significant increase in the amount of HPPH-glucuronide appearing in the perfusate. A linear relationship existed between the percentage decrease in biliary excretion of HPPH-glucuronide and the log of the pretreatment dose of DES. Bile flow was significantly depressed at all pretreatment doses of DES such that bile flow was 53.7 and 10.9% of bile flow in controls after 0.01 and 1.0 mg/day DES, respecively. The low bile flow appeared to limit secretion of HPPH-glucuronide in the bile since the maximal concentration of HPPH-glucuronide in bile was greater in livers from DES-treated rats than controls and no significant differences were found in the maximal bile/perfusate concentration ratios of HPPH-glucuronide.