Clinical Pharmacology of the Angiotensin Receptor Antagonists

Domenic A. Sica, MD, Division of Clinical Pharmacology and Hypertension, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA.

In This Article

Metabolism And Active Metabolites

Metabolic conversion of an AT1-RA can be viewed in two different ways. First, it may be a step required in order to produce an active metabolite, such as is the case with losartan and candesartan cilexitil. Alternatively, metabolic conversion may simply be a factor in the disposition of a compound, with the metabolites being physiologically inactive. This is the case with irbesartan. Losartan, an active substrate molecule, is converted to its more active metabolite, E-3174,31-33 whereas candesartan cilexitil, a prodrug, is hydrolyzed to the active compound candesartan in the course of absorption from the gastrointestinal tract.[34]

The metabolic conversion of candesartan cilexitil seems not to be influenced to any degree by disease states, genetic variation in metabolism, or chronic dosing.[34] Questions have been raised, however, concerning the metabolic profile of losartan. In rare cases, certain enzyme variants may serve to decrease conversion of this agent to its active metabolite. To date, fewer than 1% of the population of patients exposed to therapy with losartan have this abnormal genetic profile for the metabolism of losartan. Thus, it is unlikely that a metabolic polymorphism for losartan breakdown will ever be found in a clinically important number of patients.