Pharmacokinetics of CPU0213, a novel endothelin receptor antagonist, after intravenous administration in mice.
OBJECTIVE
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 (T1/2 alpha ) were 3.6, 4.2, 1.1 min and the elimination half-lives (T1/2beta) 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-infinity);. AUC(0-t) and AUC(0-infinity) were 4.511, 13.070, 23.666 g x min x L(-1 ) and 4.596, 13.679, 24.115 g x min x L(-1), respectively. The intravenous LD50 was 315.5 mg/kg.


CONCLUSIONS
First order rate pharmacokinetics were observed for CPU0213 within the range of doses used, and the acute toxicity of CPU0213 is mild.
Research Division of Pharmacology. China Pharmaceutical University, Nanjing 210009, China.
Li
L
Guan
Yu
Y
Feng
Min
M
Ji
De-zai
DZ
Dai
D000818:Animals; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D065128:Endothelin Receptor Antagonists; D005260:Female; D006207:Half-Life; D007275:Injections, Intravenous; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D015394:Molecular Structure; D011720:Pyrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D017466:Receptors, Endothelin / Q000008:administration & dosage; D014662:Vasoconstrictor Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity
C513821:CPU0213; D065128:Endothelin Receptor Antagonists; D011720:Pyrazoles; D017466:Receptors, Endothelin; D014662:Vasoconstrictor Agents