Wong P C, Christ D D, Wong Y N, Lam G N
Section of Preclinical Pharmacology, DuPont Merck Pharmaceutical Company, Wilmington, Del, USA.
Pharmacology. 1996 Jan;52(1):25-9. doi: 10.1159/000139357.
The pharmacokinetics and pharmacodynamics of EXP3174 (2-n-butyl-4-chloro-1-[(2'-(1H-tetrazole-5-yl)biphenyl-4- yl-)methyl]imidazole-5-carboxylic acid), an angiotensin II receptor antagonist, were studied in conscious rats. Elimination half-life, systemic clearance, and apparent volume of distribution of EXP3174 at a dose of 10 mg/kg i.v. were 2.9 h, 1.8 ml/min/kg, and 0.25 l/kg, respectively. Inhibition of the angiotensin II pressor response correlated with the log of the steady state plasma EXP3174 concentration in a sigmoidal fashion with an IC50 of about 200 ng/ml. When corrected for plasma protein binding, the IC50 (free) for EXP3174 was 0.4 ng/ml (0.9 nmol/l). This study indicates a predictable plasma concentration-effect relationship of EXP3174 in rats which would be helpful in designing more rational dosing schemes for pharmacodynamic studies.
在清醒大鼠中研究了血管紧张素II受体拮抗剂EXP3174（2-正丁基-4-氯-1-[(2'-（1H-四氮唑-5-基）联苯-4-基）甲基]咪唑-5-羧酸）的药代动力学和药效学。静脉注射剂量为10mg/kg时，EXP3174的消除半衰期、全身清除率和表观分布容积分别为2.9小时、1.8ml/分钟/千克和0.25升/千克。血管紧张素II升压反应的抑制与稳态血浆EXP3174浓度的对数呈S形相关，IC50约为200ng/ml。经血浆蛋白结合校正后，EXP3174的IC50（游离）为0.4ng/ml（0.9nmol/l）。本研究表明EXP3174在大鼠中具有可预测的血浆浓度-效应关系，这将有助于为药效学研究设计更合理的给药方案。
