NONPEPTIDE ANGIOTENSIN-II RECEPTOR ANTAGONIST - PHARMACOKINETICS AND PHARMACODYNAMICS IN RATS OF EXP3174, AN ACTIVE METABOLITE OF LOSARTAN

The pharmacokinetics and pharmacodynamics of EXP3174 -5-yl)biphenyl-4- yl-)methyl]imidazole-5-carboxylic acid), an angiotensin II receptor an tagonist, were studied in conscious rats. Elimination half-life, syste mic clearance, and apparent volume of distribution of EXP3174 at a dos e of 10 mg/kg i.v. were 2.9 h, 1.8 ml/min/kg, and 0.25 1/kg, respectiv ely. Inhibition of the angiotensin II presser response correlated with the log of the steady state plasma EXP3174 concentration in a sigmoid al 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/1 ). This study indicates a predictable plasma concentration-effect rela tionship of EXP3174 in rats which would be helpful in designing more r ational dosing schemes for pharmacodynamic studies.