Metabolism of carcinogenic and non-carcinogenic N-nitroso-N-methylaminopyridines. II. Investigations in vivo.

A comparative study of in vivo metabolism of isomeric N-nitroso-N-methylaminopyridines (NMPY) by analysis of urinary metabolites showed remarkable qualitative and quantitative differences in metabolic pathways. After oral application of the carcinogenic and mutagenic 2-NMPY to BD VI rats only 2-hydroxypyridine and 2-aminopyridine were excreted in urine. 2-Hydroxypyridine most probably is formed after activation of the parent compound by alpha-C-hydroxylation, demethylation and hydrolysis of the putative pyridine-2-diazonium intermediate. Evidence is presented that 2-amino-pyridine is generated by the same pathway after reductive cleavage of pyridine-azobonds formed by coupling of the diazonium intermediate to various nucleophiles. No metabolites derived from deactivating pathways and no unchanged 2-NMPY were detected in urine. After oral application of non-carcinogenic 4-NMPY, only the parent compound, its N-oxide and a ring hydroxylated metabolite with intact N-nitroso structure were found, together with 4-aminopyridine. Formation of the latter is thought to result from demethylation of the denitrosation product 4-methylaminopyridine. In contrast to metabolism of carcinogenic 2-NMPY, no 4-hydroxypyridine, indicative for activation of 4-NMPY to a diazonium intermediate, was detectable in urine.