Pharmacology: Mechanism of Action: Irbesartan is a nonpeptide angiotensin II antagonist that selectively blocks the binding of angiotensin II to the AT1, receptor. In the rennin-angiotensin system, angiotensin I is converted by angiotensin-converting enzyme (ACE) to form angiotensin II. Angiotensin II stimulates the adrenal cortex to synthesize and secrete Aldosterone, which decreases the excretion of sodium and increases the excretion of potassium. Angiotensin II also acts as a vasoconstrictor in vascular smooth muscle. Irbesartan, by blocking the binding of angiotensin II to the AT1 receptor, promotes vasodilation and decreases the effects of Aldosterone. The negative feedback regulation of angiotensin II on renin secretion also is inhibited, but the resulting rise in plasma renin concentrations and consequent rise in angiotensin II plasma concentrations do not counteract the blood pressure-lowering effect that occurs.
Pharmacokinetics: Absorption: Rapid and complete; average absolute bioavailability ranges from 60 to 80%. Food does not affect the bioavailability of Irbesartan.
Distribution: Volume of distribution (VolD)-53 to 93 liters. Irbesartan crosses the blood-brain barrier and placenta in low concentrations.
Protein binding: High (90%), primarily to albumin and alpha1-acid glycoprotein.
Biotransformation: Irbesartan is metabolized by glucuronide conjugation and oxidation. Following oral of radiolabeled Irbesartan, more than 80% of the circulating plasma radioactivity is attributed to unchanged Irbesartan. The primary metabolite is the inactive Irbesartan glucuronide conjugate and accounts for approximately 6% of circulating metabolites. The remaining oxidative metabolites are considered to be inactive. In vitro studies indicate that Irbesartan is oxidized primarily by the cytochrome P450 2C9 isoenzyme.
Half life: Elimination: 11 to 15 hours.
Time to peak concentration: 1.5 to 2 hours.
Elimination: Renal: Approximately 20%.
Fecal (biliary): Approximately 80%.
In dialysis: Irbesartan is not removable by hemodialysis.