Pharmacokinetics of aryldihydro-s-triazines with antifolate activity I: metabolism and excretion by rats

The metabolism and excretion of three aryldihydro-striazines were studied using rats. The compounds investigated were 4,6-diarnino-l,2-dihydro-2,2-dimethy-lp-hle nyl-s-triazine (I),t he prototype of the series; 4,6-diamino-1-(3,4-dichlorophenyl)-1,2-dihydro-2,2-dimethyl-s-triazine (11); and N-( m -tolyl)- p -(4,6-diamino-l,2-dihydro-2,2-dimethyl- s -triazin-1-yl)hydrocinnamide (III). All three compounds were excreted rapidly. Urinary excretion was favored by a lower molecular weight, and biliary excretion was favored by a higher molecular weight. The overall elimination rates of I and III were similar, I being excreted predominantly in urine and III (considerably metabolized) in bile. The overall elimination rate of II, excreted mainly in urine, was lower than for the other two triazines. A large percentage (and probably all) of the dose of I and 11 was unmetabolized. Metabolism of III does not appear to involve the phenyldihydrotriazine moiety. This broad view of the metabolism and excretion of the three triazines gives no particular insight into why II, although a more potent inhibitor of dihydrofolate reductase and of L-1210 tumor cell cultures, has been found to compare very poorly with III in its in uiuo antineoplastic activity in rats.