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The Physiological Disposition of the Carcinostatic Imidazole-4 (or 5)-carboxamide, 5(or 4)-[3,3-bis(2-chloroethyl)-1-triazeno] (NSC 82196) (Imidazole Mustard) in Mice and Dogs

Solid Tumor Service, Medicine Branch, National Cancer Institute, NIH, Bethesda, Maryland 20014

Studies with imidazole mustard (NSC 82196)-¹⁴C were performed to elucidate the in vitro stability of this compound and its physiological disposition, absorption, excretion, and metabolism in mice and dogs, after p.o. and parenteral administration. In vitro at pH 1, the drug decomposes to an ionic transformation product in the dark at 37°; ultraviolet light-catalyzed decomposition, however, primarily yields 2-azahypoxanthine. In vivo studies show that there is no particular organ localization of radioactivity in mice after 24 hr. Plasma half-time in dogs is 2 hr after i.v. administration, but penetration of the blood-brain barrier is negligible. Gastrointestinal absorption after p.o. administration is poor and erratic. The primary route of excretion of absorbed drug is renal in both species, with greater than 60% excreted in urine by dogs within 6 hr after i.v. administration. Drug metabolism studies indicate that the drug is not excreted as intact NSC 82196, but that approximately 60% of urinary radioactivity is present as ionic transformation product. The chemical form of the bulk of the remaining radioactivity could not be identified, although a small amount of radioactive 2-azahypoxanthine was noted. While the precise mechanism of action of the drug remains unknown, it is possible that at least some of its antitumor activity rests on in vivo conversion to 5-diazoimidazole-4-carboxamide and nor nitrogen mustard with resultant antimetabolite and possibly alkylating activity.

¹ To whom reprint requests should be sent at Solid Tumor Service, Medicine Branch, National Cancer Institute, Bethesda, Md. 20014.

Received 2/ 3/69. Accepted 1/29/70.