Ang II type 1 (AT1) receptor

In vitro, irbesartan (20 μM, 3 h) decreases Th22 cell chemotaxis[1]. In vitro, irbesartan (0 μM, 20 μM, 40 μM, and 60 μM) inhibits the development of Th22 cells[1]. In vitro, TECs' proinflammatory response associated to Th22 cells is inhibited by irbesartan (20 μM)[1].

In Ang II-infused rats, irbesartan (oral gavage; 50 mg/kg/d; once daily) lowers serum IL-22 levels and Th22 lymphocytosis[1]. Renoprotective benefits of irbesartan (oral gavage; 50 mg/kg/d; once daily) are evident[1]. In hypertension-induced rats, irbesartan (oral gavage; 50 mg/kg/d; once daily) reduces kidney fibrosis and systemic inflammation[1]. In hypertensive renal injury mice, irbesartan hydrochloride (20 μM) for three hours can reduce Th22 cell recruitment and IL-22 release, possibly by blocking chemotaxis[1].

The ARBs irbesartan and telmisartan (10 micromol/L) potently enhanced PPARgamma-dependent 3T3-L1 adipocyte differentiation associated with a significant increase in mRNA expression of the adipogenic marker gene adipose protein 2 (aP2), as measured by quantitative real-time polymerase chain reaction (irbesartan: 3.3+/-0.1-fold induction; telmisartan: 3.1+/-0.3-fold induction; both P<0.01). Telmisartan showed a more pronounced induction of aP2 expression in lower, pharmacologically relevant concentrations compared with the other ARBs. The ARB losartan enhanced aP2 expression only at high concentrations (losartan 100 micromol/L: 3.6+/-0.3-fold induction; P<0.01), whereas eprosartan up to 100 micromol/L had no significant effects. In transcription reporter assays, irbesartan and telmisartan (10 micromol/L) markedly induced transcriptional activity of PPARgamma by 3.4+/-0.9-fold and 2.6+/-0.6-fold (P<0.05), respectively, compared with 5.2+/-1.1-fold stimulation by the PPARgamma ligand pioglitazone (10 micromol/L). Irbesartan and telmisartan also induced PPARgamma activity in an AT1R-deficient cell model (PC12W), demonstrating that these ARBs stimulate PPARgamma activity independent of their AT(1)R blocking actions [1].

Cell Viability Assay[1]
Cell Types: CD4+ T cells
Tested Concentrations: 0, 20, 40 and 60 μM
Incubation Duration: 48 h
Experimental Results: Exerted no obvious effect on viability of CD4+T cells.

Animal/Disease Models: C57BL/6 mice[1]
Doses: 50 mg/kg
Route of Administration: po (oral gavage); 50 mg/kg /d; one time/day
Experimental Results: Displayed low Th22 cells and IL-22, exerted similar inhibitory effect on Th1 cell proportion and displayed diminished IL-22 level in kidney. Prevented BP elevation markedly and diminished urinary albumin/creatinine ratio, BUN and Scr. Repressed the expression of IL-1β, IL-6, TNF-α, α-SMA, FN and Col I and diminished the extent of fibrosis.

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Animal/Disease Models: C57BL/6 mice[1]
Doses: 20 μM
Route of Administration: 20 μM; for 3 h
Experimental Results: Downregulated renal CCL20, CCL22 and CCL27 concentrations.

Absorption, Distribution and Excretion
Irbesartan is 60-80% bioavailable with a Tmax of 1.5-2hours. Taking irbesartan with food does not affect the bioavailability. In one study, healthy subjects were given single or multiple oral doses of 150mg, 300mg, 600mg, and 900mg of irbesartan. A single 150mg dose resulted in an AUC of 9.7±3.0µg\•hr/mL, a Tmax of 1.5 hours, a half life of 16±7 hours, and a Cmax of 1.9±0.4µg/mL. A single 300mg dose resulted in an AUC of 20.0±5.2µg\•hr/mL, a Tmax of 1.5 hours, a half life of 14±7 hours, and a Cmax of 2.9±0.9µg/mL. A single 600mg dose resulted in an AUC of 32.6±11.9µg\•hr/mL, a Tmax of 1.5 hours, a half life of 14±8 hours, and a Cmax of 4.9±1.2µg/mL. A single 900mg dose resulted in an AUC of 44.8±20.0µg\•hr/mL, a Tmax of 1.5 hours, a half life of 17±7 hours, and a Cmax of 5.3±1.9µg/mL. Multiple 150mg doses resulted in an AUC of 9.3±3.0µg\•hr/mL, a Tmax of 1.5 hours, a half life of 11±4 hours, and a Cmax of 2.04±0.4µg/mL. Multiple 300mg doses resulted in an AUC of 19.8±5.8µg\•hr/mL, a Tmax of 2.0 hours, a half life of 11±5 hours, and a Cmax of 3.3±0.8µg/mL. Multiple 600mg doses resulted in an AUC of 31.9±9.7µg\•hr/mL, a Tmax of 1.5 hours, a half life of 15±7 hours, and a Cmax of 4.4±0.7µg/mL. Multiple 900mg doses resulted in an AUC of 34.2±9.3µg\•hr/mL, a Tmax of 1.8 hours, a half life of 14±6 hours, and a Cmax of 5.6±2.1µg/mL.
20% of a radiolabelled oral dose of irbesartan is recovered in urine, and the rest is recovered in the feces. <2% of the dose is recovered in urine as the unchanged drug.
The volume of distribution of irbesartan is 53-93L.
Total plasma clearance of irbesartan is 157-176mL/min while renal clearance is 3.0-3.5mL/min.
Irbesartan is an orally active agent that does not require biotransformation into an active form. The oral absorption of irbesartan is rapid and complete with an average absolute bioavailability of 60% to 80%. Following oral administration of Avapro, peak plasma concentrations of irbesartan are attained at 1.5 to 2 hours after dosing. Food does not affect the bioavailability of Avapro. Irbesartan exhibits linear pharmacokinetics over the therapeutic dose range. The terminal elimination half-life of irbesartan averaged 11 to 15 hours. Steady-state concentrations are achieved within 3 days. Limited accumulation of irbesartan (<20%) is observed in plasma upon repeated once-daily dosing.
Studies in animals indicate that radiolabeled irbesartan weakly crosses the blood-brain barrier and placenta.
Irbesartan is 90% bound to serum proteins (primarily albumin and a1-acid glycoprotein) with negligible binding to cellular components of blood. The average volume of distribution is 53 liters to 93 liters. Total plasma and renal clearances are in the range of 157 mL/min to 176 mL/min and 3.0 mL/min to 3.5 mL/min, respectively. With repetitive dosing, irbesartan accumulates to no clinically relevant extent.
It is not known whether irbesartan is excreted in human milk, but irbesartan or some metabolite of irbesartan is secreted at low concentration in the milk of lactating rats.

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Metabolism / Metabolites
Irbesaran is largely metabolized by glucuronidation and oxidation in the liver. The majority of metabolism occurs through the action of CYP2C9 with a negligible contribution from CYP3A4. Some hydroxylation also occurs in irbesartan metabolism. Irbesartan can be glucuronidated by UGT1A3 to the M8 metabolite, oxidized to the M3 metabolite, or hydroxylated by CYP2C9 to one of the M4, M5, or M7 metabolites. The M4, M5, and M7 metabolites are all hydroxylated to become the M1 metabolite, which is then oxidized to the M2 metabolite. The M4 metabolite can also be oxidized to the M6 metabolite before hydroxylation to the M2 metabolite. Finally, the minor metabolite SR 49498 is generated from irbesartan by an unknown mechanism.
Irbesartan is metabolized via glucuronide conjugation and oxidation. Following oral or intravenous administration of (14)C-labeled irbesartan, more than 80% of the circulating plasma radioactivity is attributable to unchanged irbesartan. The primary circulating metabolite is the inactive irbesartan glucuronide conjugate (approximately 6%). The remaining oxidative metabolites do not add appreciably to irbesartan's pharmacologic activity. Irbesartan and its metabolites are excreted by both biliary and renal routes. Following either oral or intravenous administration of (14)C-labeled irbesartan, about 20% of radioactivity is recovered in the urine and the remainder in the feces, as irbesartan or irbesartan glucuronide. In vitro studies of irbesartan oxidation by cytochrome P450 isoenzymes indicated irbesartan was oxidized primarily by 2C9; metabolism by 3A4 was negligible. Irbesartan was neither metabolized by, nor did it substantially induce or inhibit, isoenzymes commonly associated with drug metabolism (1A1, 1A2, 2A6, 2B6, 2D6, 2E1). There was no induction or inhibition of 3A4.
Irbesartan has known human metabolites that include M7, (1S,4S,5S,6R)-3-[5-[2-[4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]phenyl]phenyl]-5H-tetrazol-2-ium-2-yl]-2,4,5,6-tetrahydroxycyclohexane-1-carboxylic acid, M3, and 2-(3-hydroxybutyl)-3-({4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-1,3-diazaspiro[4.4]non-1-en-4-one.

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Biological Half-Life
The terminal elimination half life of irbesartan is 11-15 hours.
The terminal elimination half-life of irbesartan averaged 11 to 15 hours.

Toxicity Summary
IDENTIFICATION AND USE: Irbesartan crystals are formulated into oral tablets. Irbesartan is an angiotensin II type 1 (AT1) receptor antagonist. It is used alone or in combination with other classes of antihypertensive drugs in the management of hypertension. It is also used for the treatment of diabetic nephropathy in patients with type 2 diabetes and hypertension. HUMAN EXPOSURE AND TOXICITY: The most likely manifestations of irbesartan overdose include hypotension and tachycardia; bradycardia might also occur from overdose. The use of irbesartan in pregnancy is contraindicated. While use during the first trimester does not suggest a risk of major anomalies, use during the second and third trimester may cause teratogenicity and severe fetal and neonatal toxicity. Fetal toxic effects may include anuria, oligohydramnios, fetal hypocalvaria, intrauterine growth restriction, premature birth, and patent ductus arteriosus. Anuria-associated oligohydramnios may produce fetal limb contractures, craniofacial deformation, and pulmonary hypoplasia. Severe anuria and hypotension that are resistant to both pressor agents and volume expansion may occur in the newborn following in utero exposure to irbesartan. ANIMAL STUDIES: No evidence of carcinogenicity was observed when irbesartan was administered in rats or mice for up to 2 years. Also, the fertility or mating of male and female rats was unaffected by administration of irbesartan. When pregnant rats were treated with the drug from day 0 to day 20 of gestation, increased incidences of renal pelvic cavitation, hydroureter and/or absence of renal papilla were observed in fetuses at doses as low as 50 mg/kg/day. Subcutaneous edema was observed in fetuses at doses as low as 180 mg/kg/day. As these anomalies were not observed in rats in which drug exposure was limited to gestation days 6 to 15, they appear to reflect late gestational effects of the drug. In pregnant rabbits, oral doses of 30 mg irbesartan/kg/day were associated with maternal mortality and abortion. Surviving females receiving this dose had a slight increase in early resorptions and a corresponding decrease in live fetuses. Irbesartan was not mutagenic in a battery of in vitro tests (Ames microbial test, rat hepatocyte DNA repair test, V79 mammalian-cell forward gene-mutation assay). Irbesartan was also negative in several tests for induction of chromosomal aberrations (in vitro-human lymphocyte assay; in vivo-mouse micronucleus study).

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Hepatotoxicity
Irbesartan has been associated with a low rate of serum aminotransferase elevations (
Likelihood score: C (Probable rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because no information is available on the use of irbesartan during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Irbesartan is 90% protein bound in plasma, mainly to albumin and α₁-acid glycoprotein.

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Interactions
Do not coadminister aliskiren with Avapro in patients with diabetes. Avoid use of aliskiren with AVAPRO in patients with renal impairment (GFR <60 mL/min).
Dual blockade of the renin-angiotensin system (RAS) with angiotensin-receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes in patients on Avapro and other agents that affect the RAS.
Concomitant use of potassium-sparing diuretics, potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium.
Possible decreased irbesartan metabolism when irbesartan is used concomitantly with tolbutamide.
For more Interactions (Complete) data for Irbesartan (6 total), please visit the HSDB record page.

[1]. Schupp M, et al. Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptor-gamma activity. Circulation. 2004 May 4;109(17):2054-7. Epub 2004 Apr 26.
[2]. Ruiz E, et al. Importance of intracellular angiotensin II in vascular smooth muscle cell apoptosis: inhibition by the angiotensin AT1 receptor antagonist irbesartan. Eur J Pharmacol. 2007 Jul 19;567(3):231-9. Epub 2007 Apr 6.
[3]. Yong Zhong, et al. Irbesartan may relieve renal injury by suppressing Th22 cells chemotaxis and infiltration in Ang II-induced hypertension. Int Immunopharmacol

Therapeutic Uses
Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents
Avapro (irbesartan) is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents. /Included in US product label/
Avapro is indicated for the treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria (>300 mg/day) in patients with type 2 diabetes and hypertension. In this population, Avapro reduces the rate of progression of nephropathy as measured by the occurrence of doubling of serum creatinine or end-stage renal disease (need for dialysis or renal transplantation). /Included in US product label/
Angiotensin II receptor antagonists /including irbesartan/ have been used in the management of congestive heart failure. /NOT included in US product label/

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Drug Warnings
/BOXED WARNING/ WARNING: FETAL TOXICITY. When pregnancy is detected, discontinue Avapro as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Avapro as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimesters of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Avapro, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
Neonates with a history of in utero exposure to Avapro: If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.
FDA Pregnancy Risk Category: D /POSITIVE EVIDENCE OF RISK. Studies in humans, or investigational or post-marketing data, have demonstrated fetal risk. Nevertheless, potential benefits from the use of the drug may outweigh the potential risk. For example, the drug may be acceptable if needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective./
For more Drug Warnings (Complete) data for Irbesartan (16 total), please visit the HSDB record page.

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Pharmacodynamics
Irbesartan is an angiotensin receptor blocker used to treat hypertension and diabetic nephropathy. It has a long duration of action as it is usually taken once daily and a wide therapeutic index as doses may be as low as 150mg daily but doses of 900mg/day were well tolerated in healthy human subjects.

C25H28N6O

428.53

428.232

C, 70.07; H, 6.59; N, 19.61; O, 3.73

138402-11-6

Irbesartan-d4;1216883-23-6;Irbesartan hydrochloride;329055-23-4;Irbesartan-d6;Irbesartan-d6-1;2375621-21-7

3749

White to off-white solid

1.3±0.1 g/cm3

648.6±65.0 °C at 760 mmHg

180-181°C

346.0±34.3 °C

0.0±1.9 mmHg at 25°C

1.690

4.51

1

5

7

32

682

0

O=C1C2(C([H])([H])C([H])([H])C([H])([H])C2([H])[H])N=C(C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H])N1C([H])([H])C1C([H])=C([H])C(C2=C([H])C([H])=C([H])C([H])=C2C2N=NN([H])N=2)=C([H])C=1[H]

YOSHYTLCDANDAN-UHFFFAOYSA-N

InChI=1S/C25H28N6O/c1-2-3-10-22-26-25(15-6-7-16-25)24(32)31(22)17-18-11-13-19(14-12-18)20-8-4-5-9-21(20)23-27-29-30-28-23/h4-5,8-9,11-14H,2-3,6-7,10,15-17H2,1H3,(H,27,28,29,30)

2-butyl-3-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one

2934.99.03.00

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.83 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.83 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.83 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 30% PEG400+0.5% Tween80+5% Propylene glycol : 30 mg/mL

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 (Please use freshly prepared in vivo formulations for optimal results.)