Hepatic presystemic elimination of diethylstilbestrol by rats and effect of pretreatment with inducers of UDP-glucuronosyltransferase.

In order to determine if the synthetic estrogen diethylstilbestrol (DES) undergoes hepatic presystemic elimination, male Sprague-Dawley rats were administered [3H]DES (0.005, 0.05, 0.5 mg/kg) into either the ileocolic (portal administration) or femoral (systemic administration) vein. Plasma and bile samples were collected and the concentrations of both DES and DES glucuronide fractions were determined. The concentration of the DES fraction was lower and the proportion of glucuronides was higher after portal than after systemic administration of all three doses. Comparison of the areas under the curve (AUC) of plasma concentration versus time for the DES fraction indicates that the liver diminishes this fraction by 50-70%. Biliary excretion of DES also showed route-dependent differences, in that it was higher for 10-20 min after portal than after systemic administration. To determine if these effects could be enhanced by induction of UDP-glucuronosyltransferase, rats were pretreated for 4 d with phenobarbital, 3-methylcholanthrene, or pregnenolone-16 alpha-carbonitrile and then administered DES (0.5 mg/kg) by the portal or systemic route. 3-Methylcholanthrene and pregnenolone-16 alpha-carbonitrile enhanced the plasma disappearance of the DES fraction to a greater extent after portal than systemic administration and thus further increased the apparent hepatic presystemic elimination. This effect does not appear to involve increased glucuronidation or biliary excretion. These data provide evidence that hepatic presystemic elimination of DES occurs in rats, and this effect can be enhanced by some microsomal enzyme inducers.