PHARMACOKINETICS OF LOSARTAN, AN ANGIOTENSIN-II RECEPTOR ANTAGONIST, AND ITS ACTIVE METABOLITE EXP3174 IN HUMANS

The pharmacokinetics of the angiotensin II receptor antagonist losarta n potassium and its active carboxylic acid metabolite EXP3174 were cha racterized in 18 healthy male subjects after administration of intrave nous losartan, intravenous EXP3174, and oral losartan. In these subjec ts, the average plasma clearance of losartan was 610 ml/min, and the v olume of distribution was 34 L. Renal clearance (70 ml/min) accounted for 12% of plasma clearance. Terminal half-life was 2.1 hours. In cont rast, the average plasma clearance of EXP3174 was 47 ml/min, and its v olume of distribution was 10 L. Renal clearance was 26 ml/min, which a ccounted for 55% of plasma clearance; terminal half-life was 6.3 hours . After oral administration of losartan, peak concentrations of losart an were reached in 1 hour. Peak concentrations of EXP3174 were reached in 3 1/2 hours. The area under the plasma concentration-time curve of EXP3174 was about four times that of losartan. The oral bioavailabili ty of losartan tablets was 33%. The low bioavailability was mainly att ributable to first-pass metabolism. After intravenous or oral administ ration of losartan the conversion of losartan to the metabolite EXP317 4 was 14%.