Nonpeptide angiotensin II receptor antagonist: pharmacokinetics and pharmacodynamics in rats of EXP3174, an active metabolite of losartan.
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.
Wong
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PC
Section of Preclinical Pharmacology, DuPont Merck Pharmaceutical Company, Wilmington, Del, USA.
Christ
D D
DD
Wong
Y N
YN
Lam
G N
GN
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D007093:Imidazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D007275:Injections, Intravenous; D007928:Lethal Dose 50; D019808:Losartan; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D007093:Imidazoles; D013777:Tetrazoles; C066026:losartan carboxylic acid; D019808:Losartan