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Identification
NameIrbesartan
Accession NumberDB01029  (APRD00413)
Typesmall molecule
Groupsapproved, investigational
Description

Irbesartan is an angiotensin receptor blocker (ARB) used mainly for the treatment of hypertension. It competes with angiotensin II for binding at the AT1 receptor subtype. Unlike ACE inhibitors, ARBs do not have the adverse effect of dry cough. The use of ARBs is pending revision due to findings from several clinical trials suggesting that this class of drugs may be associated with a small increased risk of cancer.

Structure
Thumb
Synonyms
SynonymLanguageCode
IrbesartanNot AvailableINN, USAN
SaltsNot Available
Brand names
NameCompany
AvaproNot Available
IrbesarranNot Available
LrbesartanNot Available
Brand mixtures
Brand NameIngredients
Avalide 150/12.5 mgHydrochlorothiazide + Irbesartan
Avalide 300/12.5 mgHydrochlorothiazide + Irbesartan
Categories
CAS number138402-11-6
WeightAverage: 428.5294
Monoisotopic: 428.232459548
Chemical FormulaC25H28N6O
InChI KeyInChIKey=YOSHYTLCDANDAN-UHFFFAOYSA-N
InChI
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)
IUPAC Name
2-butyl-3-({4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-1,3-diazaspiro[4.4]non-1-en-4-one
SMILES
CCCCC1=NC2(CCCC2)C(=O)N1CC1=CC=C(C=C1)C1=CC=CC=C1C1=NNN=N1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassAzoles
SubclassTetrazoles
Direct parentBiphenyltetrazoles and Derivatives
Alternative parentsBiphenyls and Derivatives; Imidazolinones; Tertiary Carboxylic Acid Amides; Tertiary Amines; Carboxylic Acids; Carboxamidines; Polyamines
Substituentsbiphenyl; imidazolinone; benzene; tertiary carboxylic acid amide; tertiary amine; carboxamide group; amidine; carboxylic acid amidine; carboxylic acid; carboxylic acid derivative; polyamine; amine; organonitrogen compound
Classification descriptionThis compound belongs to the biphenyltetrazoles and derivatives. These are organic compounds containing a biphenyl attached to a tetrazole. A carbon atom of the biphenyl moiety is boned to a carbon or the nitrogen atom of the tetrazole moiety.
Pharmacology
IndicationFor the treatment of hypertension, as well as diabetic nephropathy with an elevated serum creatinine and proteinuria (>300 mg/day) in patients with type 2 diabetes and hypertension. Irbesartan is also used as a second line agent in the treatment of congestive heart failure.
PharmacodynamicsAngiotensin II, the principal pressor agent of the renin-angiotensin system, is responsible for effects such as vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Irbesartan is a specific competitive antagonist of AT1 receptors with a much greater affinity (more than 8500-fold) for the AT1 receptor than for the AT2 receptor and no agonist activity. Irbesartan's inhibition of angiotensin II binding to the AT1 receptor leads to multiple effects including vasodilation, a reduction in the secretion of vasopressin, and reduction in the production and secretion of aldosterone. The resulting effect is a decrease in blood pressure.
Mechanism of actionIrbesartan is a nonpeptide tetrazole derivative and an angiotensin II antagonist that selectively blocks the binding of angiotensin II to the AT1 receptor. In the renin-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 is also 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. The action of ARBs is different from ACE inhibitors, which block the conversion of angiotensin I to angiotensin II, meaning that the production of angiotensin II is not completely inhibited, as the hormone can be formed via other enzymes. Also, unlike ACE inhibitors, irbesartan and other ARBs do not interfere with response to bradykinins and substance P, which allows for the absence of adverse effects that are present in ACE inhibitors (eg. dry cough).
AbsorptionRapid and complete with an average absolute bioavailability of 60-80%. Food has no affect on bioavailability.
Volume of distribution
  • 53 to 93 L
Protein binding90% bound to serum proteins (primarily albumin and a1-acid glycoprotein) with negligible binding to cellular components of blood.
Metabolism

Hepatic. Irbesartan is metabolized via glucuronide conjugation and oxidation. In vitro studies of irbesartan oxidation by cytochrome P450 isoenzymes indicated irbesartan was oxidized primarily by 2C9; metabolism by 3A4 was negligible.

SubstrateEnzymesProduct
Irbesartan
SR 49498Details
Irbesartan
Irbesartan derivative M4Details
Irbesartan
Irbesartan derivative M5Details
Irbesartan
Irbesartan derivative M7Details
Irbesartan
    Irbesartan derivative M3Details
    Irbesartan
    Irbesartan derivative M8Details
    Irbesartan derivative M4
    Irbesartan derivative M1Details
    Irbesartan derivative M1
      Irbesartan derivative M2Details
      Irbesartan derivative M7
      Irbesartan derivative M1Details
      Irbesartan derivative M5
      Irbesartan derivative M1Details
      Irbesartan derivative M4
        Irbesartan derivative M6Details
        Irbesartan derivative M6
          Irbesartan derivative M2Details
          Route of eliminationIrbesartan is metabolized via glucuronide conjugation and oxidation. Irbesartan and its metabolites are excreted by both biliary and renal routes. Irbesartan is excreted in the milk of lactating rats.
          Half life11-15 hours
          Clearance
          • 157-176 mL/min
          ToxicityHypotension and tachycardia; bradycardia might also occur from overdose, LD50=mg/kg(orally in rat)
          Affected organisms
          • Humans and other mammals
          Pathways
          PathwayCategorySMPDB ID
          Irbesartan Action PathwayDrug actionSMP00161
          SNP Mediated EffectsNot Available
          SNP Mediated Adverse Drug ReactionsNot Available
          ADMET
          Predicted ADMET features
          Property Value Probability
          Human Intestinal Absorption + 1.0
          Blood Brain Barrier + 0.9271
          Caco-2 permeable - 0.5679
          P-glycoprotein substrate Substrate 0.7046
          P-glycoprotein inhibitor I Inhibitor 0.639
          P-glycoprotein inhibitor II Non-inhibitor 0.6458
          Renal organic cation transporter Non-inhibitor 0.5091
          CYP450 2C9 substrate Non-substrate 0.6401
          CYP450 2D6 substrate Non-substrate 0.9115
          CYP450 3A4 substrate Substrate 0.5749
          CYP450 1A2 substrate Non-inhibitor 0.6782
          CYP450 2C9 substrate Inhibitor 0.5928
          CYP450 2D6 substrate Non-inhibitor 0.7584
          CYP450 2C19 substrate Inhibitor 0.6619
          CYP450 3A4 substrate Inhibitor 0.796
          CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.6192
          Ames test Non AMES toxic 0.5238
          Carcinogenicity Non-carcinogens 0.7492
          Biodegradation Not ready biodegradable 1.0
          Rat acute toxicity 2.7762 LD50, mol/kg Not applicable
          hERG inhibition (predictor I) Weak inhibitor 0.9171
          hERG inhibition (predictor II) Non-inhibitor 0.7728
          Pharmacoeconomics
          Manufacturers
          • Sanofi aventis us llc
          Packagers
          Dosage forms
          FormRouteStrength
          TabletOral
          Prices
          Unit descriptionCostUnit
          Avalide 300-25 mg tablet3.92USDtablet
          Avalide 300-12.5 mg tablet3.63USDtablet
          Avalide 150-12.5 mg tablet3.33USDtablet
          Avapro 300 mg tablet2.64USDtablet
          Avapro 150 mg tablet2.33USDtablet
          Avapro 75 mg tablet2.21USDtablet
          DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
          Patents
          CountryPatent NumberApprovedExpires (estimated)
          United States59943481995-12-072015-12-07
          United States52703171994-09-302011-09-30
          Canada21777722007-04-102016-05-30
          Canada20579131997-07-082011-03-20
          Properties
          Statesolid
          Experimental Properties
          PropertyValueSource
          melting point180-181 °CNot Available
          logP6Not Available
          Predicted Properties
          PropertyValueSource
          water solubility8.84e-03 g/lALOGPS
          logP4.51ALOGPS
          logP5.5ChemAxon
          logS-4.7ALOGPS
          pKa (strongest acidic)7.4ChemAxon
          pKa (strongest basic)4.12ChemAxon
          physiological charge0ChemAxon
          hydrogen acceptor count5ChemAxon
          hydrogen donor count1ChemAxon
          polar surface area87.13ChemAxon
          rotatable bond count7ChemAxon
          refractivity136.72ChemAxon
          polarizability47.59ChemAxon
          number of rings5ChemAxon
          bioavailability1ChemAxon
          rule of fiveNoChemAxon
          Ghose filterNoChemAxon
          Veber's ruleNoChemAxon
          MDDR-like ruleYesChemAxon
          Spectra
          SpectraNot Available
          References
          Synthesis Reference

          Gennady Nisnevich, “Novel synthesis of irbesartan.” U.S. Patent US20040192713, issued September 30, 2004.

          US20040192713
          General Reference
          1. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I: Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001 Sep 20;345(12):851-60. Pubmed
          2. Adams MA, Trudeau L: Irbesartan: review of pharmacology and comparative properties. Can J Clin Pharmacol. 2000 Spring;7(1):22-31. Pubmed
          3. Croom KF, Curran MP, Goa KL, Perry CM: Irbesartan: a review of its use in hypertension and in the management of diabetic nephropathy. Drugs. 2004;64(9):999-1028. Pubmed
          External Links
          ResourceLink
          KEGG DrugD00523
          KEGG CompoundC07469
          PubChem Compound3749
          PubChem Substance46506575
          ChemSpider3618
          ChEBI5959
          ChEMBLCHEMBL1513
          Therapeutic Targets DatabaseDAP000364
          PharmGKBPA450084
          IUPHAR589
          Guide to Pharmacology589
          Drug Product Database2237924
          RxListhttp://www.rxlist.com/cgi/generic/irbesart.htm
          Drugs.comhttp://www.drugs.com/cdi/irbesartan.html
          WikipediaIrbesartan
          ATC CodesC09CA04
          AHFS Codes
          • 24:32.08
          PDB EntriesNot Available
          FDA labelshow(263 KB)
          MSDSshow(57.3 KB)
          Interactions
          Drug Interactions
          Drug
          AmilorideIncreased risk of hyperkalemia
          DrospirenoneIncreased risk of hyperkalemia
          LithiumThe ARB increases serum levels of lithium
          PotassiumIncreased risk of hyperkalemia
          SpironolactoneIncreased risk of hyperkalemia
          TobramycinIncreased risk of nephrotoxicity
          TrandolaprilThe angiotensin II receptor blocker, Irbesartan, may increase the adverse effects of Trandolapril.
          TreprostinilAdditive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
          TretinoinThe moderate CYP2C8 inhibitor, Irbesartan, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Irbesartan is initiated, discontinued to dose changed.
          TriamtereneIncreased risk of hyperkalemia
          Food Interactions
          • Take without regard to meals.

          1. Type-1 angiotensin II receptor

          Kind: protein

          Organism: Human

          Pharmacological action: yes

          Actions: antagonist

          Components

          Name UniProt ID Details
          Type-1 angiotensin II receptor P30556 Details

          References:

          1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
          2. Voigt JP, Bramlage P, Fink H: Hypophagic effect of the angiotensin AT1 receptor antagonist irbesartan in rats. Eur J Pharmacol. 2007 Jun 14;564(1-3):131-7. Epub 2007 Mar 3. Pubmed
          3. Waeber B, Burnier M: AT1-receptor antagonism in hypertension: what has been learned with irbesartan? Expert Rev Cardiovasc Ther. 2003 May;1(1):23-33. Pubmed
          4. Dol F, Martin G, Staels B, Mares AM, Cazaubon C, Nisato D, Bidouard JP, Janiak P, Schaeffer P, Herbert JM: Angiotensin AT1 receptor antagonist irbesartan decreases lesion size, chemokine expression, and macrophage accumulation in apolipoprotein E-deficient mice. J Cardiovasc Pharmacol. 2001 Sep;38(3):395-405. Pubmed
          5. Martin G, Dol F, Mares AM, Berezowski V, Staels B, Hum DW, Schaeffer P, Herbert JM: Lesion progression in apoE-deficient mice: implication of chemokines and effect of the AT1 angiotensin II receptor antagonist irbesartan. J Cardiovasc Pharmacol. 2004 Feb;43(2):191-9. Pubmed
          6. van den Meiracker AH, Admiraal PJ, Janssen JA, Kroodsma JM, de Ronde WA, Boomsma F, Sissmann J, Blankestijn PJ, Mulder PG, Man In ’t Veld AJ, et al.: Hemodynamic and biochemical effects of the AT1 receptor antagonist irbesartan in hypertension. Hypertension. 1995 Jan;25(1):22-9. Pubmed
          7. Carraway JW, Park S, McCune SA, Holycross BJ, Radin MJ: Comparison of irbesartan with captopril effects on cardiac hypertrophy and gene expression in heart failure-prone male SHHF/Mcc-fa(cp) rats. J Cardiovasc Pharmacol. 1999 Mar;33(3):451-60. Pubmed
          8. Hope S, Brecher P, Chobanian AV: Comparison of the effects of AT1 receptor blockade and angiotensin converting enzyme inhibition on atherosclerosis. Am J Hypertens. 1999 Jan;12(1 Pt 1):28-34. Pubmed
          9. Mazzolai L, Maillard M, Rossat J, Nussberger J, Brunner HR, Burnier M: Angiotensin II receptor blockade in normotensive subjects: A direct comparison of three AT1 receptor antagonists. Hypertension. 1999 Mar;33(3):850-5. Pubmed
          10. Morsing P, Adler G, Brandt-Eliasson U, Karp L, Ohlson K, Renberg L, Sjoquist PO, Abrahamsson T: Mechanistic differences of various AT1-receptor blockers in isolated vessels of different origin. Hypertension. 1999 Jun;33(6):1406-13. Pubmed
          11. Adams MA, Trudeau L: Irbesartan: review of pharmacology and comparative properties. Can J Clin Pharmacol. 2000 Spring;7(1):22-31. Pubmed
          12. Croom KF, Plosker GL: Irbesartan: a review of its use in hypertension and diabetic nephropathy. Drugs. 2008;68(11):1543-69. Pubmed
          13. Croom KF, Curran MP, Goa KL, Perry CM: Irbesartan: a review of its use in hypertension and in the management of diabetic nephropathy. Drugs. 2004;64(9):999-1028. Pubmed

          2. Transcription factor AP-1

          Kind: protein

          Organism: Human

          Pharmacological action: unknown

          Actions: other/unknown

          Components

          Name UniProt ID Details
          Transcription factor AP-1 P05412 Details

          References:

          1. Zhu ZS, Wang JM, Chen SL: Mesenteric artery remodeling and effects of imidapril and irbesartan on it in spontaneously hypertensive rats. World J Gastroenterol. 2004 May 15;10(10):1471-5. Pubmed
          2. Cheng SM, Yang SP, Ho LJ, Tsao TP, Chang DM, Lai JH: Irbesartan inhibits human T-lymphocyte activation through downregulation of activator protein-1. Br J Pharmacol. 2004 Jul;142(6):933-42. Epub 2004 Jun 21. Pubmed

          1. Cytochrome P450 2C8

          Kind: protein

          Organism: Human

          Pharmacological action: unknown

          Actions: substrate inhibitor

          Components

          Name UniProt ID Details
          Cytochrome P450 2C8 P10632 Details

          References:

          1. Walsky RL, Gaman EA, Obach RS: Examination of 209 drugs for inhibition of cytochrome P450 2C8. J Clin Pharmacol. 2005 Jan;45(1):68-78. Pubmed
          2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

          2. Cytochrome P450 2C9

          Kind: protein

          Organism: Human

          Pharmacological action: unknown

          Actions: substrate inhibitor

          Components

          Name UniProt ID Details
          Cytochrome P450 2C9 P11712 Details

          References:

          1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
          2. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
          3. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

          3. UDP-glucuronosyltransferase 1-3

          Kind: protein

          Organism: Human

          Pharmacological action: unknown

          Actions: substrate

          Components

          Name UniProt ID Details
          UDP-glucuronosyltransferase 1-3 P35503 Details

          References:

          1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed

          4. Prostaglandin G/H synthase 1

          Kind: protein

          Organism: Human

          Pharmacological action: unknown

          Actions: substrate

          Components

          Name UniProt ID Details
          Prostaglandin G/H synthase 1 P23219 Details

          References:

          1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed

          5. Cytochrome P450 1A2

          Kind: protein

          Organism: Human

          Pharmacological action: unknown

          Actions: inhibitor

          Components

          Name UniProt ID Details
          Cytochrome P450 1A2 P05177 Details

          References:

          1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

          6. Cytochrome P450 2D6

          Kind: protein

          Organism: Human

          Pharmacological action: unknown

          Actions: inhibitor

          Components

          Name UniProt ID Details
          Cytochrome P450 2D6 P10635 Details

          References:

          1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

          7. Cytochrome P450 3A4

          Kind: protein

          Organism: Human

          Pharmacological action: unknown

          Actions: inhibitor

          Components

          Name UniProt ID Details
          Cytochrome P450 3A4 P08684 Details

          References:

          1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

          Comments
          Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:13