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.
|Number of pages||10|
|Journal||Toxicology and Applied Pharmacology|
|State||Published - May 1981|
Bibliographical noteFunding Information:
i This work was supported by BRSG RR 05374, Public Health Service Grant HD 13250, and Grant 1 P30 CA 23154 from NIH to the Ephraim McDowell Community Cancer Network. * Preliminary reports of this work were presented at the Society of Toxicology Meetings in March 1980 (Abstract No. 39).
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