Effect of Phenobarbital on the Ethynyl Estradiol-Induced Cholestasis in the Rat

Abstract

Bile flow and bile salt excretion rates were determined in 4 groups of female rats to study whether phenobarbital was able to prevent or reverse ethynyl estradiol-induced cholestasis. Liver weight increased after 7 days of ethynyl estradiol administration. A further increment was reported when ethynyl estradiol and phenobarbital were administered together. The ethynyl estradiol reduced bile flow and bile salt excretion rate but phenobarbital returned the bile flow to control values when given either before or after estrogen administration. Modifications of bile salt excretion rate were different depending on the sequence of phenobarbital administration. When given after ethynyl estradiol the bile salt excretion rate returned to control values. When phenobarbital was given before ethynyl estradiol and for 7 days bile salt excretion rates rose 1.5 times the rate of excretion of control rats. Phenobarbital alone increased bile flow more than when given with ethynyl estradiol. Phenobarbital increased bile flow 6 hours after a single intraperitoneal dose reaching maximum stimulation after 14 hours. Actinomycin D and cycloheximide inhibited the stimulation of bile flow by phenobarbital. Ethynyl estradiol decreased bile flow several hours after a single intraperitoneal dose (.5 mg). Maximum inhibition was obtained 18 hours after the injection returning to control values 36 hours after ethynyl estradiol administration. The lag period observed suggested that either ethynyl estradiol required various steps to inhibit bile flow or that it was acting on the system necessary to maintain bile flow and whose half-life was several hours.