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Pharmacodynamics: Mechanism of Action: Antihypertensive action: Losartan is an angiotensin II receptor (type AT1) antagonist that blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively and competitively blocking the binding of angiotensin II to the AT1 receptor found in many tissues, including vascular smooth muscle.
Pharmacokinetics: Onset of action: 6 hours.
Distribution: Vd: Losartan: 34 L; E-3174: 12 L; does not cross blood brain barrier.
Protein binding, plasma: High.
Metabolism: Hepatic (14%) via CYP2C9 and 3A4 to active metabolite, E-3174 (40 times more potent than losartan); extensive first-pass effect.
Bioavailability: 25% to 33%; AUC of E-3174 is four times greater than that of losartan.
Half-life elimination: Losartan: 1.5-2 hours; E-3174: 6-9 hours.
Time to peak, serum: Losartan: 1 hour; E-3174: 3-4 hours.
Excretion: Urine (4% as unchanged drug, 6% as active metabolite).
Clearance: Plasma: Losartan: 600 ml/minute; active metabolite: 50 ml/minute.
