Description

Cardiovascular Disease

Description

Irbesartan (Avapro, SR-47436, BMS-186295) is a highly potent and specific angiotensin II type 1 (AT1) receptor antagonist with IC50 of 1.3 nM.

Targets

IC₅₀

In Vitro

Irbesartan competes with angiotensin II (AII) for binding at the AT1 receptor subtype and antagonizes AII-induced contraction in rabbit aorta ring with IC50 of 4 nM. Irbesartan has no affinity for AT2 receptors. ^[1] Irbesartan (10 μM) blocks angiotensin II induced increase in α_v, β₁, β₃, and β₅ integrins, osteopontin, and α-actinin mRNA and protein levels in rat cardiac fibroblasts, leading to the decrease of cell attachment to extracellular matrix (ECM) proteins. ^[2] Irbesartan treatment markedly induces the expression of the adipogenic marker gene adipose protein 2 (aP2) in 3T3-L1 cells in a concentration-dependent manner with EC50 of 3.5 μM and 3.3-fold induction at the concentration of 10 μM. Irbesartan (10 μM) markedly induces transcriptional activity of the peroxisome proliferator–activated receptor-γ (PPARγ) by 3.4-fold independent of its AT1 receptor blocking action. ^[3] Pretreatment with Irbesartan (~10 μM) decreases angiotensin II-induced apoptosis in rat vascular smooth muscle cells by blocking angiotensin II internalization in a concentrationdependent manner. ^[4]

In Vivo

Oral administration of Irbesartan (1 mg/kg) reduces angiotensin II (AII)-induced hypertension, equipotent with losartan in conscious normotensive rats, markedly more active than losartan (10 mg/kg) in normotensive cynomolgus monkeys. ^[1] Administration of Irbesartan (7 mg/kg/day) significantly prevents skeletal muscle apoptosis and muscle atrophy in rats with monocrotaline-induced congestive heart failure (CHF), which is involved with the decrease of TNFα level and attributed to AT1 receptor blocking. ^[5]

Clinical Trials

A Phase I study to evaluate pharmacokinetics and safety after oral administration of Irbesartan and Atorvastatin in combination as HCP0912 in healthy male subjects has been completed.

Features

Irbesartan is a longer acting AT1 receptor antagonist than losartan and valsartan.

Angiotensin II Binding Study on Rat Liver Membranes

The plasma membranes of livers are purified from male Sprague-Dawley rats, and diluted in the incubation buffer (20 mM Tris-HCI, 10 mM MgCI₂, 2 g/L RSA, 145 mg/L bacitracin, pH 7.5). Aliquots of membrane suspension (20-330 μg protein/assay) are incubated for 1 hour at 25 °C with [¹²⁵I]angiotensin II (AII) and various concentrations of Irbesartan in 200 μL of incubation buffer. The incubation is stopped by rapid filtration through a Whatman GF/B filter followed by three consecutive washing sin 5 mL of cold incubation buffer (the GF/B filters are preincubated for 1 hour in the incubation buffer). The radioactivity bound to the filter is counted in a γ counter. Specific binding is defined as the difference between total binding and the binding in the presence of 1 μM unlabeled angiotensin II (AII). The concentration of Irbesartan producing 50% inhibition (IC50) of radioligand binding is determined from competition curve.

Animal Models

Male Sprague-Dawley rats and female cynomolgus monkeys (Macaca fascicularis) injected (iv) with angiotensin II (AII)

Formulation

Dissolved in water by neutralization with a stoichiometric equivalent of KOH, or dissolved in saline by neutralization with a stoichiometric equivalent of L-arginine

Doses

1 mg/kg

Administration

Oral gavage