Dose-dependent kinetics of diethylstilbestrol in the rat.

Diethylstilbestrol (DES) acts as a transplacental carcinogen with organotropic properties. The question is raised whether the pharmacokinetics of DES contribute to this effect. [3H] DES was administered to female Wistar rats orally, intravenously, and introperitoneally at doses ranging from 0.025 to 25 mg/kg. Radioactivity associated with erythrocytes and plasma proteins was measured and the pattern of unconjugated metabolites and glucuronides after column and thin-layer chromatography in blood determined. The different routes of administration resulted in different metabolite patterns. After iv injection, unconjugated, unpolar metabolites predomininated; after ip injection, glucuronides of unpolar metabolites; and after oral administration, unconjugated polar metabolites. The different compositions of the glucuronide fractions remained constant with time. The composition of the unconjugated metabolites changed with time after oral administration but not after iv injection. Blood levels of metabolites did not increase proportionally with dose. Overproportional increase was most prominent with the highest dose used. The observed effects are explained with intestinal metabolism and a liver first-pass effect.