Acta Pharmacologica Sinica 2006 March; 27 (3): 367-371; doi: 10.1111/j.1745-7254.2006.00288.x

Aim: To determine the pharmacokinetics associated with acute toxic doses of CPU0213, a novel endothelin receptor antagonist in mice after a single intravenous administration.

Methods: Concentrations in serum and the pharmacokinetic parameters of CPU0213 were assayed by high pressure liquid chromatography (HPLC) following a single intravenous bolus of CPU0213 at concentrations of 25, 50, and 100 mg/kg in mice. The intravenous acute toxicity of CPU0213 was also assessed in mice.

Results: A simple, sensitive and selective HPLC method was developed for quantitative determination of CPU0213 in mouse serum. The concentration-time data conform to a 2-compartment model after iv administration of CPU0213 at concentrations of 25, 50, 100 mg/kg. The corresponding distribution half-lives (T_1/2α) were 3.6, 4.2, 1.1 min and the elimination half-lives (T_1/2β) were 39.4, 70.3, 61.9 min. There was a linear increase in C₀ proportional to dose, and the same as AUC_0-t and AUC_0-∞;. AUC_0-t and AUC_0-∞; were 4.511, 13.070, 23.666 g·min·L^-1 and 4.596, 13.679, 24.115 g·min·L^-1, respectively. The intravenous LD₅₀ was 315.5 mg/kg.

Conclusion: First order rate pharmacokinetics were observed for CPU0213 within the range of doses used, and the acute toxicity of CPU0213 is mild.

Keywords: CPU0213; high pressure liquid chromatography; mice; pharmacokinetics; acute toxicity