Oral Bioavailability and Disposition Characteristics of Irbesartan, an Angiotensin Antagonist, in Healthy Volunteers

Abstract

Absolute oral bioavailability and disposition characteristics of irbesartan, an angiotensin II receptor antagonist, were investigated in 18 healthy young male volunteers. Subjects received [14C] irbesartan as a 30-minute intravenous infusion (50 mg), [14C] irbesartan orally as a solution (50 mg or 150 mg), or irbesartan capsule (50 mg). Irbesartan was rapidly and almost completely absorbed after oral administration, and exhibited a mean absolute oral bioavailability of 60% to 80%. Mean total body clearance was approximately 157 mL/min, and renal clearance was 3.0 mL/min. Volume of distribution at steady state was 53 L to 93 L, and terminal elimination half-life was approximately 13 to 16 hours. Hepatic extraction ratio was low (0.2). There were no major circulating metabolites, and approximately 80% of total plasma radioactivity was attributable to unchanged irbesartan. Regardless of route of administration, approximately 20% of dose was recovered in urine and the remainder in feces.

Clinical pharmacokinetics of angiotensin II (AT1) receptor blockers in hypertension

“…6 bioavailability is in the range of 60-80% (Table 6a). 14,15,32,126,127 Food does not influence neither the absorption nor bioavailability of the drug. 6,14,15,32,126,127 Peak plasma levels of irbesartan are achieved at 1.3-3 h after oral dosing.…”

“…6,14,15,32,126,127 Peak plasma levels of irbesartan are achieved at 1.3-3 h after oral dosing. 6,32,41,61,110,[126][127][128][129] Irbesartan displays linear doserelated pharmacokinetics over the dose range of 50-600 mg. 6,14,15,110 The drug is 90% bound, mainly to albumin (binding to alpha 1-acid glycoprotein = 22%). 6,14,15 Steady-state plasma levels are reached in 3 days after daily dosing, and no clinically important accumulation (Ͻ20%) occurs (Table 6b).…”

“…6,14,15,110,129 The Vd of irbesartan is between 53 L and 93 L, and it has a Cl T of 157-177 mL/min (Table 6b). 14,15,126 Irbesartan has a long plasma elimination t . (11-18 h).…”

“…(11-18 h). 6,14,15,32,41,61,110,[126][127][128] The hepatic extraction ratio of irbesartan is low (0.2), 126 and the drug is partially metabolised (6% of the dose) by oxidation (by cytochrome CYP2C9) and glucuronidation to form eight inactive metabolites. 14,15,130 The metabolites account for only 9% of the circulating drug, 5-10% in urine and 6% in faeces.…”

“…14,15,131 Most of the administered dose (80%) is excreted in faeces via bile (Table 7), and the remainder in urine. 6,14,15,126 Losartan: Losartan is pharmacologically active, but its major metabolite EXP3174 (10-40 times more potent than losartan) is responsible for most of its pharmacological activity (see above), 2,3,14,15,133 and long duration of action. 2,3,133 After oral administration, losartan is rapidly absorbed, and undergoes substantial first-pass metabolism by cytochrome P450 enzymes.…”