Pre-clinical pharmacokinetics of the acridine antitumour candidate AC04 and its 1-oxo-metabolite plasma profile

1. This work aimed to investigate plasma pharmacokinetics and tissue distribution of a new acridine derivative 5-acridin-9-ylmethylene-3-(4-methyl-benzyl)-thiazolidine-2,4-dione (AC04) and its 1-oxo-AC04 metabolite disposition in Wistar rats.

2. After a single AC04 1.5?mg/kg intravenous (i.v.) bolus dose, blood samples were taken up to 120?h. Plasma samples were deproteinization, and AC04 and metabolite were quantified by validated liquid chromatography in tandem with mass spectrometry method. Protein binding was determined by ultrafiltration. AC04 tissue disposition was evaluated after i.v. bolus dose.

3. Individual AC04 concentration–time profiles were best fitted by a two-compartment model showing CL_tot of 3.4?±?3.4?L/h/kg, Vd_SS of 137.9?±?91.4?L/kg, AUC_0–∞ of 788?±?483 ng·h/mL and a t_1/2 of 45.5?±?31.5?h. Protein binding was 98.1?±?1.6%. AC04 showed higher penetration into the lung, spleen and liver, with AUC_0–96 of 798,443, 263,211 and 303,722 ng·h/mL, respectively. The 1-oxo-AC04 metabolite represented 10% of AC04 plasma concentration, showing a t_1/2 of 23.2?±?10.4?h.

4. These results suggest that, despite the small free plasma fraction, AC04 penetrates extensively reaching high concentrations in most tissues residing for a long time, which is important for its activity on solid tumours. All results combined indicate that AC04 is potentially a good antitumour candidate.