THE EFFECT OF ESTRADIOL-17-BETA TREATMENT ON THE METABOLISM AND BILIARY-EXCRETION OF PHENYTOIN IN THE ISOLATED PERFUSED-RAT-LIVER AND INVIVO

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  • 1 January 1980
    • journal article
    • research article
    • Vol. 215  (1) , 71-76
Abstract
The metabolism and biliary excretion of [14C]phenytoin (DPH) was examined in female control rats and in rats pretreated with estradiol-17.beta. (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-p-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, but there was no significant decrease in the bile concentration or excretion rate of this metabolite. Bile flow average 50 and 35 .mu.l/min per 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 milliliter) and biliary excretion rate (micromoles/min per kg) 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.