C1311 has emerged as the lead compound from a novel group of
anticancer agents, 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 identified 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 versus time curve values were 6-fold and 2-fold greater, respectively, than
C1311. Based on these studies, we propose M2 to be a nonfluorescent oxidation product because electrospray ionization-mass spectroscopy/mass spectroscopy analysis gave a molecular ion at m/z 367, 16 U greater than the parent compound. 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 detected in liver tissues at concentrations equivalent to those of
C1311 but was 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
C1311 or the kidneys (11%) as the
glucuronide (M1). This study has given valuable 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 toxicity of
C1311 in the clinic.