TY - JOUR T1 - HYPOTENSIVE METABOLITE PRODUCTION AND SEQUENTIAL METABOLISM OF N,N-DIALLYLMELAMINE IN RATS, DOGS AND MAN JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 194 LP - 205 VL - 159 IS - 1 AU - G. R. Zins AU - D. E. Emmert AU - R. A. Walk Y1 - 1968/01/01 UR - http://jpet.aspetjournals.org/content/159/1/194.abstract N2 - The metabolism of C14-labeled N, N-diallylmelamine (DAM) was compared in rats, dogs and man to determine the basis for species differences in its vasodilator activity. Metabolites were isolated for quantification by Sephadex column and paper chromatography. Man, who is refractory to DAM, readily absorbed the compound from the gastrointestinal tract but failed to produce significant amounts of two out of at least 10 metabolites normally excreted by rats and dogs. The absence of vasodilator effects in man was explained by the fact that one of the deficient metabolites, which was N-hydroxylated para to the tertiary amine, accounted for essentially all of the pharmacologic activity in rats. The sequential metabolism of DAM was also studied in rats by administering C14-labeled metabolites isolated from the urine of animals treated with radioactive precursors. With knowledge of seven metabolite structures, four of which were identified in the present experiments, four metabolic pathways were established. They were N-oxidation and N-methylation of the triazine ring, N-deallylation and bishydroxylation at the double bond in the side chain. Combinations of two of these pathways ultimately were involved in the formation of some of the excretion products. SKF 525A markedly inhibited side chain hydroxylation of DAM and deallylation of the N-oxidized metabolite and moderately inhibited deallylation of DAM and its ring N-methylation, but failed to influence N-oxidation of the triazine ring. © 1968 by The Williams & Wilkins Company ER -