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Pharmacology: Pharmacodynamics: Losartan and its principal active metabolite block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor found in many tissues, (e.g., vascular smooth muscle, adrenal gland).
The active metabolite is 10 to 40 times more potent by weight than losartan and appears to be a reversible, non-competitive inhibitor of the AT1 receptor.
Neither losartan nor its active metabolite inhibits ACE (kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin); nor do they bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Pharmacokinetics: Losartan is readily absorbed from the gastrointestinal tract following oral administration, but undergoes substantial first-pass metabolism resulting in a systemic bioavailability of about 33%. It is metabolised to an active carboxylic acid metabolite E-3174 (EXP-3174), which has greater pharmacological activity than losartan; some inactive metabolites are also formed. Metabolism is primarily by cytochrome P450 isoenzymes CYP2C9 and CYP3A4. Peak plasma concentrations of losartan and E-3174 occur about 1 hour and 3 to 4 hours, respectively, after an oral dose.
Both losartan and E-3174 are more than 98% bound to plasma proteins. Losartan is excreted in the urine, and in the faeces via bile, as unchanged drug and metabolites. Following oral dosing about 4% of the dose is excreted unchanged in urine and about 6% is excreted in urine as the active metabolite. The terminal elimination half-lives of losartan and E-3174 are about 1.5 to 2.5 hours and 3 to 9 hours, respectively.
