In vivo metabolism of the antitumor imidazoacridinone C1311 in the mouse and in vitro comparison with humans

C1311 has emerged as the lead compound from a novel group of anticancer age nts, the imidazoacridinones, and will be entering clinical trials shortly. Previous murine pharmacokinetic studies have shown C1311 to be rapidly and extensively distributed into tissues including tumor. This study has identi fied two major metabolites of C1311 and describes their pharmacokinetics in mice. M1 is a glucuronide of the parent compound with high concentrations in both plasma and liver. Calculated area under the plasma concentration ve rsus time curve values were 6-fold and 2-fold greater, respectively, than C 1311, Based on these studies, we propose M2 to be a nonfluorescent oxidatio n product because electrospray ionization-mass spectroscopy/mass spectrosco py analysis gave a molecular ion at m/z 367, 16 U greater than the parent c ompound. It formed rapidly in liver preparations in vitro, both murine and human, by a cytosolic process in the presence of NADPH and in vivo was dete cted in liver tissues at concentrations equivalent to those of C1311 but wa s not detectable in plasma. Preliminary in vitro toxicity studies showed M2 to be as potent as C1311 against MAC15A tumor cells. Over the first 24 h, 39% of the administered dose is eliminated via the bile (28%) mostly as C13 11 or the kidneys (11%) as the glucuronide (M1). This study has given valua ble information as to the likely metabolic pathway to occur in humans, and the cytotoxic metabolite M2 may play a role in the antitumor activity or to xicity of C1311 in the clinic.