THE PHARMACOKINETICS AND PHARMACODYNAMICS OF THE ANGIOTENSIN-II RECEPTOR ANTAGONIST LOSARTAN POTASSIUM (DUP 753 MK 954) IN THE DOG/

The pharmacokinetics and plasma concentration-effect relationship for the nonpeptide angiotensin II (Ang II) receptor antagonist losartan po tassium (losartan) have been determined with conscious and anesthetize d 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, wit h peak plasma levels observed within 1 hr, and the C-max and area unde r the concentration vs. time curve to infinity were proportional to th e 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 eli minated rapidly, with a systemic plasma clearance of 22.2 ml/min/kg. W hen corrected for the blood:plasma distribution ratio, 0.66 to 0.72, t he 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 o f distribution at steady-state of 0.30 liters/kg and was highly but no t extensively bound to plasma proteins; 2.7 to 2.9% unbound (free). Th e plasma concentration vs. blockade of exogenous Ang II-induced vasopr essor response was also determined after a single 3-mg/kg i.v. dose of losartan with a sigmoidal E(max) model. Blockade of the presser respo nse was rapid, 89% at 5 min, and declined to 11% at 240 min postdose. The relationship between concentration and effect was highly significa nt (r = 0.922, P < .01), with an IC50 (total) of 96 ng/ml. When correc ted for plasma protein binding, the IC50 (free) was approximately 3 ng /ml or 6 nM, a value coincident with the IC50 for the blockade by losa rtan of Ang II binding in vitro in the absence of albumin, 5 nM. These studies have described the disposition of losartan in the dog, and sh ould allow more rational design and interpretation of studies of this agent in this animal model.