N-demethylation of the antineoplastic agent hexamethylmelamine by rats and man.

Abstract

Summary The metabolism and physiological distribution of hexamethylmelamine (HMM), an effective human anticancer chemotherapeutic agent, was studied in cancer patients and in rats. Administration of HMM-methyl- 14 C to two patientst p.o. was followed by the prompt appearance of respiratory 14 CO 2 within 1 hr, accumulating to 9% of administered dose in 6 hr. After 72 hr, 29% of the radioactivity was recovered in the urine, and 0.5% was recovered in the feces. In rats, p.o. and i.p. administration of HMM- 14 C led to the recovery of 13 and 30%, respectively, of the dose as 14 CO 2 in 24 hr. After 72 hr, 58% of the p.o. dose of radioactivity was recovered, 16% as 14 CO 2 , 38% in the urine, and 4% in the feces; while in the same interval, 80% of the i.p. dose was recovered, 33% as 14 CO 2 , 42% in the urine, and 5% in the feces. No unmetabolized HMM was detected in urine; instead four distinct compounds could be chromatographically separated. The major urinary metabolites in patients and rats exhibited identical chromatographic and spectroscopic properties. Use of gas chromatography and mass spectrometry led to the identification of the major urinary metabolites as N 2 , N 4 , N 6 -trimethylmelamine, N 2 , N 4 -dimethylmelamine, monomethylmelamine, and melamine. Thus, N -demethylation appears to be of major significance in the metabolism of HMM in man and in rats. HMM and its metabolites did not demonstrate significant alkylating activity, as evidenced by their failure to react with 4-( p -nitrobenzyl)pyridine.