Investigations of the Metabolism of N-alkyl agents with Antineoplastic Activity

Abstract

The metabolism and the pharmacokinetics of the antitumour agents, HMM (2,4,6-Tris(dimethylamino]-1,3,5-triazine) and NMF (N-methylformamide) was investigated. An attempt was made to discover a pharmacokinetic or metabolic explanation for the pharmacological activities and toxicities of these compounds. HMM was studied in-vitro and the disposition of NMF was investigated in-vivo. The kinetic properties of the metabolism of HMM was compared with those of a series of derivatives of HMM and with those of AP (1-phenyl-2,3-dimethylamino-pyrazolon-5). The rate of N-demethylation of HMM and N-desmethyl derivatives, seemed to be related to their lipophilicities and also to their antitumour activity. HEM (2,4,6-Tris[diethylamino]-1,3,5-triazine) was readily dealkylated. However, even though it is more lipophilic than HMM, it is devoid of antitumour activity. TetraMM (2,4-Bis[methylamino] -6-dimethylamino-1,3,5-triazine) and TriMM (2,4,6-Tris[metylamino]-1,3,5-triazine) are demethylated at a rate slower than that for HMM and PMM (2, 4-Bis[dimethylamino] -6-methylamino-1,3,5-triazine), which may partly explain the long plasma elimination half-lives of the HMM metabolites, TetraMM and TriMM, compared to those of HMM and PMM. The fate of N-alkylformamides in-vivo was studied by determining the plasma disposition and urinary excretion of these compounds in mice and patients. From the resulting plasma concentration-time profiles, pharmacokinetic parameters were evaluated which showed that NMF exhibited good oral bioavailability in both mice and patients. After administration to mice of equimolar doses of two closely related derivatives of NMF, DMF (N,N-dimethylformamide) and NEF (N-ethylformamide), the area under the plasma concentration-time curves for these agents were significantly lower than that for NMF. These results suggest that the marginal antitumour acitvity of DMF and NEF compared to the dramatic activity of NMF, may have a pharmacokinetic basis. A comparison of the urinary excretion of 14C-methyllabelled NMF (14C-NMF) with that of unlabelled NMF indicates that only 26.4% of drug was excreted unchanged and 50% as an unidentified metabolite of NMF, probably a conjugate of a hydroxylated derivative of NMF. The plasma disposition of NMF and DMF in mice, within 24 hours after administration, could not be described by a linear pharmacokinetic model and appeared to be dependent on the dose administered. However, after 60 hours after administration of 14C-NMF, radioactivity was eliminated from the plasma with a half-life of 71.1 hours.