Azilsartan Medoxomil

Angiotensin II is formed from angiotensin I through a reaction catalysed by angiotensin-converting enzyme (ACE, also called kinase II). It is the main pressor substance of the renin-angiotensin system, and its effects include vasoconstriction, stimulation of aldosterone synthesis and release, cardiac stimulation, and renal reabsorption of sodium. Azilsartan works against the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking its binding to the AT1 receptor in tissues such as vascular smooth muscle and the adrenal gland, so its action does not depend on the pathway by which angiotensin II is made. Many tissues also carry an AT2 receptor, but this receptor is not known to play a part in cardiovascular homeostasis, and azilsartan binds the AT1 receptor with more than 10,000 times the affinity it shows for AT2. Blockade of the renin-angiotensin system with ACE inhibitors, which prevent the biosynthesis of angiotensin II from angiotensin I, is a widely used approach to treating hypertension, but ACE inhibitors also block the breakdown of bradykinin, since this reaction too is catalysed by ACE. Azilsartan does not inhibit ACE, so it should not be expected to alter bradykinin levels, though whether this distinction matters clinically is still unclear. Azilsartan does not bind or block any other receptors or ion channels known to be important for cardiovascular regulation. Blocking the angiotensin II receptor removes angiotensin II's negative feedback on renin secretion, and although this raises plasma renin activity and circulating angiotensin II, the rise is not enough to offset azilsartan's effect on blood pressure.

Azilsartan inhibits the pressor response to an angiotensin II infusion in a dose-related way: a single dose equivalent to 32 mg of azilsartan medoxomil cut the maximal pressor effect by about 90% at peak and by about 60% at 24 hours. In healthy subjects given single and repeated doses of azilsartan, plasma angiotensin I and II levels and plasma renin activity rose while plasma aldosterone fell, without any clinically meaningful change in serum potassium or sodium.

On absorption, azilsartan medoxomil is hydrolysed in the gastrointestinal tract to its active form, azilsartan, during the absorption process itself, so the parent compound is not detected in plasma after an oral dose. Exposure to azilsartan rises in proportion to dose across the azilsartan medoxomil range of 20 mg to 320 mg, whether given as a single dose or repeated dosing, and its estimated absolute bioavailability is around 60%. After an oral dose of azilsartan medoxomil, azilsartan reaches peak plasma concentration (Cmax) within 1.5 to 3 hours, and food does not change its bioavailability.

As for distribution, azilsartan has a volume of distribution of roughly 16 L and is bound to human plasma proteins, chiefly albumin, to a very high degree (over 99%); this binding stays constant even at plasma concentrations well above those seen with recommended doses. In rats, only a minimal amount of azilsartan-related radioactivity crossed the blood-brain barrier, while in pregnant rats azilsartan did cross the placental barrier and reached the fetus.

Regarding metabolism and elimination, azilsartan is broken down into two main metabolites: an O-dealkylation product, M-II, which is the major metabolite found in plasma, and a decarboxylation product, M-I, which is the minor one. Human systemic exposure to M-II and M-I is roughly 50% and less than 1%, respectively, of the exposure to azilsartan itself, and neither metabolite adds to azilsartan's pharmacological activity. The enzyme mainly responsible for metabolising azilsartan is CYP2C9.