Abstract

The metabolic disposition of the methylnitroimidazole moiety of azathioprine, labeled with 14C in carbons 4 and 5 of this imidazole ring, was investigated in the dog. The administration of the radioactive drug (10 mg/kg p.o.) was followed, after absorption, by a rapid uptake of the radioactivity into the blood cells, with subsequent redistribution to the plasma. The total urinary excretion of 14C was 41.6% in 32 hours. Anion exchange and high-pressure liquid chromatography of the urine revealed a large number of 14C-containing metabolites. These included unmetabolized azathioprine, 1-methyl-4-nitro-5-(N-acetyl-S-cysteinyl)imidazole, 1-methyl-4-nitro-5-thioimidazole and several compounds with ultraviolet absorption spectra similar to 5-substituted amino-1-methyl-4-nitroimidazoles. The most prominent of these was a highly acidic metabolite which was found to be identical in chemical, chromatographic and spectral properties with N,N'-[5-(1-METHYL-4-NITRO)IMIDAZOLYL]CYSTINE. This metabolite as well as 1-methyl-4-nitro-5-(N-acetyl-S-cysteinyl)imidazole and 1-methyl-4-nitro-5-thioimidazole were also identified in the urine of a dog given 1-methyl-4-nitro-5-(S-glutathionyl)-imidazole (10 mg/kg i.v.) suggesting that the latter compound is an intermediate in the formation of these urinary metabolites. The profile of the methylnitroimidazole urinary metabolites in the dog was similar to that in man and different from that in the rat. A metabolic pathway for the formation of these metabolites in the dog is proposed.