The metabolism of doubly labeled estradiol 3-benzoate and 16 alpha-hydroxyestrone diacetate (author's transl)

Abstract

The metabolic fates of intravenously administered doubly labeled synthetic estrogens- (6, 7-3H, 7′-14C) estradiol 3-benzoate in dogs or in albinotic rabbits, and (6, 7-3H, 3-oAc-1′-14C) 16a-hydroxyestrone diacetate and (6, 7-3H, 16-oAc-1′-14C) 16a-hydroxyestrone diacetate in dogs-were studied with or without biliary fistulas. This study afforded an evaluation of the loss of side chains (esters) and possible changes in steroid structures.(1) The metabolism of (6, 7-3H, 7′-14C) estradiol 3-benzoate in female dogs/The radioactivities were excreted as a percentage of the amounts injected, and the standard deviations were as follows : 11.9±1.1% of 3H and 40.5±3.5% of 14C in the urine of intact dogs, and 6.3±0.3% of 3H and 27.5±2.3% of 14C in the urine and 16.0±0.5% of 3H and 1.05±0.05% of 14C in the bile of dogs with biliary fistulas 7 h. after the administration. The dominant conjugates in the urine were sulfates. Hippuric acid, benzoic acid, 17-epiestradiol sulfate and estrone sulfate were identified in the urine. The dominant conjugates in the bile were glucosiduronates and sulfates. Estradiol 3-glucosiduronate, estrone 3-glucosiduronate, 17-epiestradiol sulfate and estrone sulfate were identified. These results indicate the immediate elimination of the 3-benzoyl group from estradiol 3-benzoate following the injection. They also indicate that hippuric acid (partially benzoic acid) is excreted mostly in the urine, and that an enterohepatic circulation of the hydrolyzed steroid occurs to some extent. The excretion of the benzoyl group into the urine reached a maximum at 1-2 h., and the estrogen metabolites were excreted with maximum excretions at 0.5-1 h. Glucosiduronates of estrogens were seen in the bile but were not detectable in the urine of either the intact dogs or the biliary fistula dogs. The concentrations of estradiol 3-benzoate in the blood were investigated in the intact dogs. 3H was excreted gradually into the urine, and 3C was excreted at a high ratio from 1 h. to 4 h. later. In this study it was clarified that the cleavage of the side chain quickly occurred after the injection, and that the binding of the benzoyl group may have some effects on the enterohepatic circulation of estrogen and on the conjugated form of metabolites.(2) The metabolism of (6, 7-3H, 7'-14C) estradiol 3-benzoate in female rabbits/The radioactivities were excreted for 7 h., given as a percentage of the injected dose, and the standard deviations were as follows : 17.5±0.5% of 3H and 42.0±2.0% of 14C in the urine of intact rabbits, and 13.0±1.5% of 3H and 28.5±1.6% of 14C in the urine and 2.5±0.9% of 3H and 0.64±0.15% of 14C in the bile of rabbits with biliary fistulas.In the intact rabbits, 51.2% of 3H and 39.5% of 14C in the urine, and 1.5% of 3H and 0.75% of 14C in the feces were recovered for 7 d. after the injection.The chief metabolites were hippuric acid, benzoic acid and estradio1-17a-glucuronoside-NAG in the urine. The amounts of 3H and 14C were very small in the bile and in the feces. These results indicate that estradiol 3-benzoate is hydrolyzed immediately, and that the dissociated steroid is probably not involved in an enterohepatic circulation in the rabbits as much as in the dogs. The extent of the enterohepatic circulation of this estrogen was small in comparison with estradiol in rabbits. The enterohepatic circulation of the ester with the benzoyl group was different from that of the original compound.