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Metabolism of 2(R,S)-1,2-bis(nicotinamido)propane, a new agent with anti-vasospasm activity, in rats and rabbits.

1. The metabolic fate of the new Anti-vasospasm Substance (AVS), 2(R,S)-1,2-bis(nicotinamido)propane (CAS 79455-30-4), was studied using 14C-labelled drug in rats and rabbits by thinlayer chromatography, mass spectrometry and nuclear magnetic resonance. 2. More than 75% of the radioactivity was observed in the urine when 14C-AVS was given intravenously to rabbits and rats, showing that the major route of excretion of AVS and its metabolites is via the kidney. 3. Marked species differences were observed in the metabolism of AVS in rats and rabbits. In rabbits, the major metabolites were 6- or 6'-monopyridone (23.5% of dose), and there were a few minor metabolites such as the mono N- or N1-oxide of two pyridine rings. In rats, however, only approximately 5% of the radioactivity was due to metabolites, mainly the N-oxide. 4. Formation of AVS monopyridone by rabbit liver cytosol was much higher than in rats, and was markedly inhibited by the aldehyde oxidase inhibitor, menadione. The difference between rats and rabbits in oxidase activity giving the AVS monopyridone metabolite correlated well with that measured by the general assay method for aldehyde oxidase. These results suggest that the species difference in AVS metabolism between rats and rabbits is mainly due to the difference in aldehyde oxidase activity, which is involved in formation of the monopyridone.