Pharmacokinetics and tissue distribution of the imidazoacridinone C1311 in tumour-bearing mice

Abstract

C1311 is the most active member of a new series of rationally designed anti-cancer agents, the imidazoacridinones, which has shown promising pre-clinical anti-tumour activity in vitro and in vivo against a variety of human colon cancers and is a strong candidate for clinical trials. Data are not available on the pharmacokinetic properties of this compound; therefore, the main aim of this project was to study the plasma 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 distribution 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, 100 and (the maximum tolerated dose, (MTD) 150 mg kg⁻¹ i.p. Plasma, tissue and tumour levels were monitored over a 24-h period using high-performance liquid chromatography (HPLC) with fluorescence detection. The distribution of C1311 in murine and human whole blood was studied using both HPLC and fluorescence microscopy. C1311 was quickly cleared from 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. Overall concentrations were ranked in the order of plasma ≪ liver < kidney < fat < small intestine < spleen. Tumour concentrations were similar to those measured in the liver and kidney, with AUCs being 186 (MAC15A) and 94.4 μg h ml⁻¹(HT-29). Plasma pharmacokinetics were linear at doses of 15–100 mg  kg⁻¹, 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 higher concentrations occurring in the cellular fraction than in plasma. Nucleated cells accounted for a large proportion of this localised drug. In conclusion, C1311 is quickly cleared from the plasma and rapidly distributed into the tissues, with tissue concentrations being far higher than plasma levels. The plasma pharmacokinetics are linear up to but not above doses of 100 mg kg⁻¹. Concentrations of C1311 are greater in the cellular fraction of the blood than in the plasma, with disproportionately high concentrations occurring in the nucleated fraction.