PHARMACOKINETICS AND TISSUE DISTRIBUTION OF THE IMIDAZOACRIDINONE C1311 IN TUMOR-BEARING MICE

C1311 is the most active member of a new series of rationally designed anti-cancer agents, the imidazoacridinones, which has shown promising preclinical anti-tumour activity in vitro and in vivo against a varie ty of human colon cancers and is a strong candidate for clinical trial s. Data are not available on the pharmacokinetic properties of this co mpound; therefore, the main aim of this project was to study the plasm a pharmacokinetics and tissue and tumour distribution of C1311 in mice and to assess, prior to potential clinical application, whether these pharmacokinetics were linear with respect to the dose. The distributi on of C1311 in whole blood was also studied. NMRI or NCR-Nu mice were used throughout the study. C1311 was given i.p. at doses of 15, 50, 10 0 and (the maximum tolerated dose, (MTD) 150 mg kg(-1) i.p. Plasma, ti ssue and tumour levels were monitored over a 24-h period using highper formance liquid chromatography (HPLC) with fluorescence detection. The distribution of C1311 in murine and human whole blood was studied usi ng both HPLC and fluorescence microscopy. C1311 was quickly cleared fr om the plasma (47-410 ml min kg(-1)) and rapidly distributed into the tissues at all doses. Tissue-to-plasma ratios were large, ranging from 8 in the liver (15 mg kg(-1)) to 600 (50 mg kg(-1)) in the spleen. Ov erall concentrations were ranked in the order of plasma much less than liver < kidney < fat < small intestine < spleen. Tumour concentration s were similar to those measured in the liver and kidney, with AUCs be ing 186 (MAC15A) and 94.4 mu g h ml(-1) (HT-29) Plasma pharmacokinetic s were linear at doses of 15-100 mg kg,but disproportionate increases were seen in plasma and tissue concentrations at doses above 100 mg kg (-1). C1311 distributed unevenly in both mouse and human blood, with h igher concentrations occurring in the cellular fraction than in plasma . Nucleated cells accounted for a large proportion of this localised d rug. In conclusion, C1311 is quickly cleared from the plasma and rapid ly distributed into the tissues, with tissue concentrations being far higher than plasma levels. The plasma pharmacokinetics are linear up t o but not above doses of 100 mg kg(-1). Concentrations of C1311 are gr eater in the cellular fraction of the blood than in the plasma, with d isproportionately high concentrations occurring in the nucleated fract ion.