Pre-clinical pharmacokinetics of the acridine antitumour candidate AC04 and its 1-oxo-metabolite plasma profile.
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. 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. 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. 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.
Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Maiara Cássia
MC
Pigatto
Flávia De Toni
Fde T
Uchôa
Bruna
B
Torres
Sandra
S
Haas
Maria
M
do Carmo Alves de Lima
Suely Lins
SL
Galdino
Ivan da
Id
Rocha Pitta
Norberto
N
Peporine Lopes
Teresa
T
Dalla Costa
D000166:Acridines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D008297:Male; D009369:Neoplasms / Q000188:drug therapy; D051381:Rats; D045162:Thiazolidinediones / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014018:Tissue Distribution
C568945:5-acridin-9-ylmethylene-3-(4-methyl-benzyl)-thiazolidine-2,4-dione; D000166:Acridines; D000970:Antineoplastic Agents; D045162:Thiazolidinediones