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.
Guan
Li
L
Research Division of Pharmacology. China Pharmaceutical University, Nanjing 210009, China.
Feng
Yu
Y
Ji
Min
M
Dai
De-zai
DZ
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