The effect of estradiol-17β treatment on the metabolism and biliary excretion of phenytoin in the isolated perfused rat liver and in vivo

The metabolism and biliary excretion of [¹⁴C]phenytoin (DPH) was examined in female control rats and in rats pretreated with estradiol-17β (E₂) (1 mg/day s.c.) for 7 days. In the isolated perfused liver, the half-life of [¹⁴C]DPH in the perfusate was not altered by E₂ treatment, nor was the rate of appearance and disappearance of 5-[¹⁴C]phenyl-5-para-hydroxyphenylhydantoin (HPPH), the major metabolite of DPH. Cumulative secretion of the glucuronide conjugate of HPPH into the bile and bile flow were decreased 4- and 6-fold, respectively, in E₂-treated rats. Following administration of [¹⁴C]DPH (1 mg/kg i.v.) in vivo, the concentration of [¹⁴C]HPPH-glucuronide was significantly increased in the blood in E₂-treated rats, although there was no significant decrease in the bile concentration or excretion rate of this metabolite. Bile flow averaged 50 and 35 μl/min/kg in control and E₂-treated rats, respectively. Following administration of [¹⁴C]HPPH (60 mg/kg i.v.) in vivo, the rate of disappearance of [¹⁴C]HPPH from the blood was increased in E₂-treated rats. The concentration in bile (micromoles per milliter) and biliary excretion rate (micromoles per minute per kilogram) of [¹⁴C]HPPH-glucuronide were significantly decreased and the blood levels of this metabolite significantly increased in E₂-treated rats relative to controls. Maximal bile/blood concentration ratios of [¹⁴C]HPPH-glucuronide were 725 and 200 in control and E₂-treated rats, respectively, indicating a decreased ability of the liver to concentrate the glucuronide conjugate in the bile following estrogen treatment.