The metabolic fate and elimination of streptozotocin.

sterone or [16B-”H]betamethasone was given at a dose of 0.23pmol/kg body wt. by intraperitoneal or intravenous route, and bile samples were collected at 30min intervals. In some experiments the animals were pretreated with daily doses (100mg/kg body wt., intraperitoneally) of phenobarbital for 3 consecutive days. In the isolated-liver perfusion experiments tissue-culture medium 199 (100ml) containing goat erythrocytes (haematocrit 35%) and bovine serum albumin (2Sg/lOOml) was used as the perfusion medium. The flow rate was carefully regulated at 0.72ml/min per g of liver under a constant head (35cm) of the perfusate. An hour after the perfusion began, the radioactive steroid (0.13pmol) was added to the reservoir, and bile samples were collected at 30min intervals. Samples (0.2ml) of the perfusion medium were withdrawn from points just before and after the liver at various time-intervals (5min-5 h) for radioactivity determination, The pooled bile samples were extracted twice with 1.5 vol. of ethyl acetate for the separation of unconjugated steroids. Our results (Figs. 1 and 2) show that, both in the bile-fistulated animals and in the perfused liver, corticosterone is very rapidly excreted in the bile. In 5 h the cumulative biliary excretion (%+ s.E.M.) was found to be 85.4f3.8 and 92.5k1.4 of the dose respectively. The rates of excretion ( %+s.E.M.) of betamethasone in uiuo and in the isolated perfused liver weresimilar (44.Ok 1.3and41.6k4.0) but considerably lower than therates observed for corticosterone excretion (Figs. 1 and 2). This difference between corticosterone and betamethasone could not be attributed to the differences in their rates of uptake by the liver, as in the bile-fistulated animals the excretion patterns were the same whether the steroids were given by intraperitoneal or intravenous routes. Further, in the perfusion studies, [3H]corticosterone and [3H]betamethasone disappeared at about the same rate from the perfusion medium. Corticosterone is extensively metabolized by the liver and excreted in the bile primarily as conjugates (Eriksson & Gustafsson, 1971). Although the hepatic metabolism of betamethasone has not been investigated, it is known from studies in uitro that structural modification of the corticosteroid molecule decreases its rate of metabolism by the liver (Fotherby & James, 1972). That metabolism may be implicated in the smaller biliary excretion of betamethasone is indicated by our finding that pretreatment of rats with the hepatic enzyme inducer phenobarbital enhanced the biliary excretion of betamethasone, and this was not attributable to changes in the bile flow. The fractionation of the metabolites in the bile showed that, whereas only 2-3 % of the corticosterone metabolites in the bile was present as unconjugated steroids, the corresponding value for betamethasone was 11-17%.