N-DEMETHYLATION OF P-(N1-METHYLHYDRAZINO METHYL)-N-ISOPROPYL BENZAMIDE (PROCARBAZINE), A CYTOSTATICALLY ACTIVE METHYLHYDRAZINE DERIVATIVE, IN INTACT RAT AND IN ISOLATED PERFUSED RAT LIVER

The oxidative N-deniethylation of p-(N1-methylhydrazino methyl)-N-isopropyl benzamide (procarbazine, Natulan) and of its postulated metabolite monomethyl hydrazine (MMH) has been studied in the intact rat, as well as in the isolated perfused rat liver, by measuring the formation of 14CO2 from 14CH3-labeled substrates. The CO2 production rate from procarbazine was 1·83 and 1·18 μmoles/hr per 100 g body weight in vivo and in the isolated perfused rat liver respectively. In both systems, this rate was markedly lowered by SKF 525-A and enhanced 3·10 to 3·50-fold by the pretreatment with 3-methylcholanthrene and 2·5-fold by the pretreatment with phenobarbital. The demethylation rate of equimolar amounts of MMH was 0·7 μmoles/hr per 100 g body weight in vivo and 2·08 jumoles per hr per 100 g body weight in the isolated liver. In the isolated liver SKF 525-A and 3-methylcholanthrene treatment resulted in a 14 and 26 per cent decrease of the demethylation rate of MMH respectively. These results indicate that the main pathway of CO2 production from procarbazine involves the primary cleavage of the N1-C bond and not the intermediary formation of MMH. The response of the CO2 production rate to SKF 525-A and 3-methylcholanthrene suggests that the N1-C bond of procarbazine is split by a microsomal hydroxylase. © 1969.