The Metabolism, Decomposition and Pharmacokinetics of Anti-Tumour Imidazotetrazinones

Abstract

Mitozolomide [8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-3]-1,2,3,5-tetrazin-4(3H)-one], the lead compound in a series of imidazo [5,1-d]-1,2,3,5-tetrazin-4(3H)-ones, and CCRG 81045, its 3-methyl analogue, show promise as antitumour agents. Chemical, biochemical, and experimental antitumour data revealed certain similarities with antitumour chloroethylnitrosoureas and triazenoimidazoles. Studies were undertaken using mitozolomide and CCRG 81045 in an attempt to establish the pharmacological basis for their therapeutic action and to identify potential areas of improvement over existing agents. Reversed-phase high-performance liquid chromatographic methods were developed to facilitate these studies. The results of in vitro studies supported a decomposition mechanism via a monoalkyltriazene, the putative active intermediate, as the principal chemical fate of these compounds under physiological conditions. First-order kinetics, an exquisite pH dependence, and a relative catalysis in plasma were features of this decomposition. The pharmacokinetics of mitozolomide and CCRG 81045 in mice and of mitozolomide in humans were described using a simple one-compartment model, supported by monophasic elimination and volumes of distribution approximating total body water. Mitozolomide was administered clinically at doses up to 153 mg/m², where severe thrombocytopenia prevented further escalation. Mitozolomide pharmacokinetics were independent of dose, and good oral bioavailability was demonstrated. Elimination half-lives for CCRG 81045 in mice and for mitozolomide in mice and humans were in agreement with in vitro data, implicating the importance of chemical degradation in the in vivo fate of these agents. Between 10 and 24% of administered mitozolomide was excreted unchanged in the urine of mice, and there was some evidence of a metabolic contribution to elimination. The potential importance of local pH variations to the in vivo activity and the interpretation of in vitro cytotoxicity data are discussed. The pharmacokinetics of these two imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-ones suggest they may offer significant improvement over currently used drugs.