Studies on phenolic steroids in human subjects. XIV. Fate of a nitrogen mustard of estradiol-17beta.

ABSTRACT

Estracyt, a conjugate of estradiol-17beta (E2) and a nitrogen mustard, is a compound which recently has been found to be of value in the treatment of cancer of the prostate. The present study concerned itself with the fate of labeled Estracyt administered 1) either as a mixture of 3H-Estracyt, labeled in the estrogen moiety, and 14C-E2 or 2) as doubly labeled Estracyt with 3H in the E2 and 14C in the carbamate part. These studies were performed in the human and baboon, with biliary excretion studies being performed in the latter. In the human studies with singly labeled Estracyt, it was shown that about 10-15% of the compound is hydrolyzed in such a fashion as to yield E2, which is then metabolized and conjugated similarly to the 14C-labeled E2; and that the excretory pattern in the urine of the released E2, including the CCD pattern, did not differ materially from that of the 14C-E2, though it was excreted at about 1/3 the rate of the 14C-E2. The remainder of the injected Estracyt was not accounted for. No intact Estracyt was found in the urine. When doubly labeled Estracyt was administered to human subjects, it was shown that the excretion of the 14C (carbamate moiety) was much lower than that of the 3H (E2 moiety), indicating that hydrolysis of the molecule did, in fact, take place, but that the excretion of the 14C, as well as the rest of Estracyt, must follow a route other than the urine. The most likely route is the biliary excretion of either intact Estracyt and/or its metabolites and conjugates without any significant enterohepatic circulation, with the bulk ultimately being excreted in the stools. The studies in the baboon mirrored those in the human. We were able, however, to demonstrate substantial excretion of singly and doubly labeled Estracyt in the bile, indicating that this may be the major route by which the compound is excreted in the baboon and, by analogy, in the human.