Pharmacokinetic Profiles of AT1 Receptor Antagonists

While all AT1 receptor antagonists share the same mechanism of action, they differ in their pharmacoki-netic profiles. Losartan is well absorbed following oral administration and undergoes significant first-pass liver metabolism to an active metabolite, EXP3174. This metabolite is a long-acting (6-8 hours) noncompetitive antagonist at the AT1 receptor that contributes to the pharmacological effects of losartan. Production of the long-acting metabolite accounts for the sustained anti-hypertensive properties of losartan following chronic therapy, which would otherwise eventually be overwhelmed by removal of the negative feedback system (inhibition of renin release) for angiotensin II production. Following oral administration, 6% of losartan is excreted unchanged in the urine.

Valsartan has a higher affinity for the ATI receptor than losartan, does not have an active metabolite, and has a slightly longer duration of action than losartan. Irbesartan exhibits high bioavailability and high affinity for the AT1 receptor, does not have an active metabolite, and has a considerably longer duration of action than losartan. Candesartan cilexetil has an active metabolite with a long duration of action, is a prodrug, and exhibits an ATI receptor affinity 80 times that of losartan. Telmisartan is the longest-acting ATI receptor antagonist and has no active metabolites. In contrast, eprosartan has the shortest half-life of the ATI receptor antagonists and has been suggested to exhibit selective blockade of some effects of angiotensin II more than others.

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