Pharmacokinetics of CPU0213, a novel endothelin receptor antagonist, after intravenous administration in mice

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-1/2 alpha) were 3.6, 4.2, 1.1 min and the elimination half-lives (T-1/2 alpha) were 39.4, 70.3, 61.9 min. There was a linear increase in C-0 proportional to dose, and the same as AUC(0-t) and AUC(0-infinity) AUC(0-t) and AUC(0-infinity) 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.