Ant¡tumor Activity and Pharmacokinetics in Mice of 8-Carbamoyl-3-methyl- imidazo[5,l-on-l,2,3,5-tetrazin-4(37/)-one (CCRG 81045; M & B 39831), a Novel Drug with Potential as an Alternative to Dacarbazine1

A number of 3-alkyl analogues of the experimental antitumor drug mitozolomide [8-carbamoyl-3-(2-chloroethyl)imidazo|5,l-235% against the P388 and 1,1210 leukemias, respectively. In the female C57BL x DBA/2 F( mouse the 10% lethal dose was 125 mg/kg daily for 5 days. CCRG 81045 was found to undergo mild alkaline hydrolysis and ring fission to form the linear triazene 5-(3-methyltriazen-l-yl)imidazole-4-carboxamide, which is the putative metabolite formed upon metabolic activation of the antitumor drug dacarbazine |5-(3,3-diniethyltriazen-l-yl)imidazole-4-carboxainide). The half-life of CCRG 81045 at 37°Cin 0.2 M phosphate buffer (pH 7.4) was 1.24 h, whereas that of 5-(3-methyltriazen-l-yl)imidazole-4-carboxamide at 25°Cwas reported to be 8 min (F. H. Shealy and C. A. kraut li. J. Med. Chem., 9:34-37,1966). The half-life of CCRG 81045 in human plasma in vitro at 37°Cwas 0.42 h. Pharmacokinetic experiments con ducted in BALB/c mice produced plasma profiles of CCRG 81045, administered i.p. or p.o., which showed a rapid absorption phase, elimi nation half-lives of 1.13 h (i.p.) and 1.29 h (p.o.), and a bioavailability of 0.98.