Abstract

The pharmacokinetics and plasma concentration-effect relationship for the nonpeptide angiotensin II (Ang II) receptor antagonist losartan potassium (losartan) have been determined with conscious and anesthetized dogs. The p.o. bioavailability of single doses of 5 to 20 mg/kg was low, 23 to 33%, and independent of the dose. Absorption was rapid, with peak plasma levels observed within 1 hr, and the Cmax and area under the concentration vs. time curve to infinity were proportional to the dose, P < .05. The elimination half-life, 108 to 153 min, was longer than that observed after a single i.v. dose, 41 min, and may reflect both continuous absorption and enterohepatic recirculation because the major route of excretion was via the bile. Single i.v. doses were eliminated rapidly, with a systemic plasma clearance of 22.2 ml/min/kg. When corrected for the blood:plasma distribution ratio, 0.66 to 0.72, the systemic clearance approximates hepatic blood flow, suggesting that clearance is primarily via hepatic metabolism and biliary excretion. Losartan was not distributed extensively to tissues; apparent volume of distribution at steady-state of 0.30 liters/kg and was highly but not extensively bound to plasma proteins; 2.7 to 2.9% unbound (free). The plasma concentration vs. blockade of exogenous Ang II-induced vasopressor response was also determined after a single 3-mg/kg i.v. dose of losartan with a sigmoidal Emax model. Blockade of the pressor response was rapid, 89% at 5 min, and declined to 11% at 240 min postdose. The relationship between concentration and effect was highly significant (r = 0.922, P < .01), with an IC50 (total) of 96 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)