Preliminary Studies on the Metabolism and Pharmacokinetics of the Dialkylphenyltriazenes

Abstract

The metabolism and pharmacokinetics of a series of dialkylphenyltriazenes have been examined with a view to selecting an appropriate clinical alternative to DTIC. A number of these compounds have shown activity against a mouse PC6 plasmacytoma. However, it has previously been demonstrated for pentamethylmelamine (PMM) and DTIC, agents which, like the dialkylphenyltriazenes, are believed to require metabolic activation, that such antitumour activity does not adequately reflect the clinical situation because of marked species differences in oxidative N-demethylation. In an examination of the pharmacokinetics of 1-p-carboxamidophenyl-3,3-dimethyltriazene (CB 10-286) this compound was found to be more rapidly metabolised in the mouse (plasma t 1/2 ß = 3.7mins) than in the rat (t1/2ß = 16.9mins), and resulted in the generation of some four-fold higher levels of the monomethyltriazene, which is the putative active metabolite. However, by pretreating rats with oral sodium phenobarbitone it was possible to mimic the mouse pharmacokinetics in the rat. Despite marked antitumour activity of 1- p-carboxyphenyl-3,3-dimethyltriazene (CB 10–277) this compound failed to undergo any N-demethylation in vitro, in contrast to the carboxyamido derivative. Furthermore, there was no apparent formation of a monomethyl metabolite in vivo. The apparent lack of oxidative N-demethylation of this particular triazene brings into question the hypothesis that such metabolism is a prerequisite of antitumour activity for this class of compounds.