Discovery and Development of Angiotensin Receptor Blockers - Drug Comparison and Pharmacokinetics

Drug Comparison and Pharmacokinetics

ARBs have a large therapeutic index and therefore their (mostly low) oral bioavailability does not appear to be of clinical significance. As can be seen in table 1, these drugs are highly plasma protein-bound and therefore oral administration once a day should provide sufficient antihypertensive effects. Around 14% of orally ingested losartan is metabolized to its 5-carboxylic acid metabolite EXP 3174. As mentioned before, candesartan cilexetil and olmesartan medoxomil are inactive ester prodrugs that are completely hydrolyzed to their active forms by esterases during absorption from the gastrointestinal tract. These three metabolites are more potent AT₁ receptor antagonists than their prodrugs. The other ARBs do not have active metabolites.

All of the ARBs, except for telmisartan and olmesartan, are metabolized in some way by the cytochrome P450 (CYP) enzyme 2C9, that is found in the human liver. CYP2C9 is for example responsible for the metabolizing of losartan to EXP 3174 and the slow metabolizing of valsartan and candesartan to their inactive metabolites. Telmisartan is, on the other hand, in part metabolized by glucuronidation and olmesartan is excreted as the unchanged drug. Telmisartan is the only ARB that can cross the blood–brain barrier and can therefore inhibit centrally mediated effects of Ang II, contributing to even better blood pressure control.

All of the ARBs have the same mechanism of action and differences in their potency can be related to their different pharmacokinetic profiles. A few clinical head-to-head comparisons have been made and candesartan, irbesartan and telmisartan appear to be slightly more effective than losartan in lowering blood pressure. This difference may be related to different strengths of activity at the receptor level, such as duration and strength of receptor binding.