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Identification
NameValsartan
Accession NumberDB00177  (APRD00133)
Typesmall molecule
Groupsapproved, investigational
Description

Valsartan is an angiotensin-receptor blocker (ARB) that may be used to treat a variety of cardiac conditions including hypertension, diabetic nephropathy and heart failure. Valsartan lowers blood pressure by antagonizing the renin-angiotensin-aldosterone system (RAAS); it competes with angiotensin II for binding to the type-1 angiotensin II receptor (AT1) subtype and prevents the blood pressure increasing effects of angiotensin II. Unlike angiotensin-converting enzyme (ACE) inhibitors, ARBs do not have the adverse effect of dry cough. Valsartan may be used to treat hypertension, isolated systolic hypertension, left ventricular hypertrophy and diabetic nephropathy. It may also be used as an alternative agent for the treatment of heart failure, systolic dysfunction, myocardial infarction and coronary artery disease.

Structure
Thumb
SynonymsNot Available
SaltsNot Available
Brand names
NameCompany
DiovanNovartis
Brand mixturesNot Available
Categories
CAS number137862-53-4
WeightAverage: 435.5188
Monoisotopic: 435.227039819
Chemical FormulaC24H29N5O3
InChI KeyACWBQPMHZXGDFX-QFIPXVFZSA-N
InChI
InChI=1S/C24H29N5O3/c1-4-5-10-21(30)29(22(16(2)3)24(31)32)15-17-11-13-18(14-12-17)19-8-6-7-9-20(19)23-25-27-28-26-23/h6-9,11-14,16,22H,4-5,10,15H2,1-3H3,(H,31,32)(H,25,26,27,28)/t22-/m0/s1
IUPAC Name
(2S)-3-methyl-2-[N-({4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)pentanamido]butanoic acid
SMILES
CCCCC(=O)N(CC1=CC=C(C=C1)C1=CC=CC=C1C1=NNN=N1)[C@@H](C(C)C)C(O)=O
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassAzoles
SubclassTetrazoles
Direct parentBiphenyltetrazoles and Derivatives
Alternative parentsN-acyl-alpha Amino Acids; Biphenyls and Derivatives; Tertiary Carboxylic Acid Amides; Tertiary Amines; Enolates; Carboxylic Acids; Polyamines
Substituentsn-acyl-alpha-amino acid; n-acyl-alpha amino acid or derivative; biphenyl; alpha-amino acid or derivative; benzene; tertiary carboxylic acid amide; carboxamide group; tertiary amine; carboxylic acid; polyamine; enolate; carboxylic acid derivative; 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
IndicationMay be used as a first line agent to treat uncomplicated hypertension, isolated systolic hypertension and left ventricular hypertrophy. May be used as a first line agent to delay progression of diabetic nephropathy. Losartan may be also used as a second line agent in the treatment of congestive heart failure, systolic dysfunction, myocardial infarction and coronary artery disease in those intolerant of ACE inhibitors.
PharmacodynamicsValsartan belongs to a class of antihypertensive agents called angiotensin II receptor blockers (ARBs). Valsartan is a specific and selective type-1 angiotensin II receptor (AT1) antagonist which blocks the blood pressure increasing effects angiotensin II via the renin-angiotensin-aldosterone system (RAAS). RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from granular cells of the juxtaglomerular apparatus in the kidneys. Renin cleaves circulating angiotensinogen to angiotensin I, which is cleaved by angiotensin converting enzyme (ACE) to angiotensin II. Angiotensin II increases blood pressure by increasing total peripheral resistance, increasing sodium and water reabsorption in the kidneys via aldosterone secretion, and altering cardiovascular structure. Angiotensin II binds to two receptors: AT1 and type-2 angiotensin II receptor (AT2). AT1 is a G-protein coupled receptor (GPCR) that mediates the vasoconstrictive and aldosterone-secreting effects of angiotensin II. Studies performed in recent years suggest that AT2 antagonizes AT1-mediated effects and directly affects long-term blood pressure control by inducing vasorelaxation and increasing urinary sodium excretion. Angiotensin receptor blockers (ARBs) are non-peptide competitive inhibitors of AT1. ARBs block the ability of angiotensin II to stimulate pressor and cell proliferative effects. Unlike ACE inhibitors, ARBs do not affect bradykinin-induced vasodilation. The overall effect of ARBs is a decrease in blood pressure.
Mechanism of actionValsartan is an ARB that selectively inhibits the binding of angiotensin II to AT1, which is found in many tissues such as vascular smooth muscle and the adrenal glands. This effectively inhibits the AT1-mediated vasoconstrictive and aldosterone-secreting effects of angiotensin II and results in a decrease in vascular resistance and blood pressure. Valsartan is selective for AT1 and has virtually no affinity for AT2. Inhibition of aldosterone secretion may inhibit sodium and water reabsorption in the kidneys while decreasing potassium excretion. The primary metabolite of valsartan, valeryl 4-hydroxy valsartan, has no pharmacological activity.
AbsorptionAbsolute bioavailability = 23% with high variability
Volume of distribution
  • 17 L (low tissue distribution)
Protein binding94 - 97% bound to serum proteins, primarily serum albumin
Metabolism

Valsartan is excreted largely as unchanged drug (80%) and is minimally metabolized in humans. The primary circulating metabolite, 4-OH-valsartan, is pharmacologically inactive and produced CYP2C9. 4-OH-valsartan accounts for approximately 9% of the circulating dose of valsartan. Although valsartan is metabolized by CYP2C9, CYP-mediated drug-drug interactions between valsartan and other drugs is unlikely.

SubstrateEnzymesProduct
Valsartan
4-HydroxyvalsartanDetails
Route of elimination83% of absorbed valsartan is excreted in feces and 13% is excreted in urine, primarily as unchanged drug
Half lifeThe initial phase t1/2 α is < 1 hour while the terminal phase t1/2 β is 5-9 hours.
Clearance
  • 2 L/h [IV administration]
  • 4.5 L/h [heart Failure patients receiving oral administration 40 to 160 mg twice a day]
ToxicityNot Available
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Valsartan Action PathwayDrug actionSMP00165
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9956
Blood Brain Barrier - 0.8032
Caco-2 permeable - 0.6912
P-glycoprotein substrate Substrate 0.685
P-glycoprotein inhibitor I Non-inhibitor 0.5548
P-glycoprotein inhibitor II Non-inhibitor 0.5966
Renal organic cation transporter Non-inhibitor 0.8646
CYP450 2C9 substrate Non-substrate 0.7722
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Non-substrate 0.5073
CYP450 1A2 substrate Non-inhibitor 0.8707
CYP450 2C9 substrate Non-inhibitor 0.5398
CYP450 2D6 substrate Non-inhibitor 0.8816
CYP450 2C19 substrate Inhibitor 0.5539
CYP450 3A4 substrate Non-inhibitor 0.5521
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.5618
Ames test Non AMES toxic 0.6384
Carcinogenicity Non-carcinogens 0.645
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 2.6518 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9766
hERG inhibition (predictor II) Non-inhibitor 0.7388
Pharmacoeconomics
Manufacturers
  • Novartis pharmaceuticals corp
  • Novartis Corporation
Packagers
Dosage forms
FormRouteStrength
TabletOral160 mg
TabletOral320 mg
TabletOral40 mg
TabletOral80 mg
Prices
Unit descriptionCostUnit
Diovan hct 320-25 mg tablet4.63USDtablet
Diovan hct 320-12.5 mg tablet4.1USDtablet
Diovan hct 160-25 mg tablet3.66USDtablet
Diovan hct 160-12.5 mg tablet3.27USDtablet
Diovan 320 mg tablet3.17USDtablet
Diovan hct 80-12.5 mg tablet3.0USDtablet
Diovan 160 mg tablet2.42USDtablet
Diovan 80 mg tablet2.33USDtablet
Diovan 40 mg tablet2.32USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States62941971997-12-182017-12-18
United States53995781995-03-212012-03-21
Canada22591482009-09-292017-06-18
Canada20364271998-12-292011-02-15
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point116-117 °CNot Available
logP5.8Not Available
Predicted Properties
PropertyValueSource
water solubility2.34e-02 g/lALOGPS
logP3.68ALOGPS
logP5.27ChemAxon
logS-4.3ALOGPS
pKa (strongest acidic)4.37ChemAxon
pKa (strongest basic)-0.11ChemAxon
physiological charge-1ChemAxon
hydrogen acceptor count6ChemAxon
hydrogen donor count2ChemAxon
polar surface area112.07ChemAxon
rotatable bond count10ChemAxon
refractivity134.77ChemAxon
polarizability47.27ChemAxon
number of rings3ChemAxon
bioavailability1ChemAxon
rule of fiveNoChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Zvi Harel, Igor Rukhman, “Process for the preparation of valsartan.” U.S. Patent US20050010053, issued January 13, 2005.

US20050010053
General Reference
  1. Bader, M. (2004). Renin-angiotensin-aldosterone system. In S. Offermanns, & W. Rosenthal (Eds.). Encyclopedic reference of molecular pharmacology (pp. 810-814). Berlin, Germany: Springer.
  2. Diovan. (2009). [Electronic version]. e-CPS. Retrieved December 28, 2009.
  3. Stanfield, C.L., & Germann, W.J. (2008). Principles of human physiology (3 rd ed.). San Francisco, CA: Pearson Education, Inc.
External Links
ResourceLink
KEGG DrugD00400
PubChem Compound60846
PubChem Substance46509000
ChemSpider54833
BindingDB50049186
ChEBI9927
ChEMBLCHEMBL1069
Therapeutic Targets DatabaseDAP000363
PharmGKBPA451848
IUPHAR3937
Guide to Pharmacology3937
Drug Product Database2244781
RxListhttp://www.rxlist.com/cgi/generic/valsartan.htm
Drugs.comhttp://www.drugs.com/cdi/valsartan.html
WikipediaValsartan
ATC CodesC09CA03
AHFS Codes
  • 24:32.08
PDB EntriesNot Available
FDA labelshow(237 KB)
MSDSshow(36.2 KB)
Interactions
Drug Interactions
Drug
AmifostineAdditive hypotensive effects may occur. At chemotherapeutic doses of Amifostine, Valsartan should be withheld for 24 hours prior to Amifostine administration. Use caution at lower doses of Amifostine.
AmilorideIncreased risk of hyperkalemia
EltrombopagEltrombopag may increase the therapeutic and/or toxic effects of Valsartan. Increased Valsartan serum concentrations may be caused by inhibition of hepatic uptake and decreased metabolism. Consider dose modification, alternate therapy or monitor for changes in the therapeutic and toxic effects of Valsartan if Eltrombopag is initiated, discontinued or dose changed.
LithiumValsartan may increase serum lithium concentrations. Monitor serum lithium levels during concomitant therapy to avoid lithium toxicity.
PotassiumIncreased risk of hyperkalemia
RituximabAdditive hypotensive effects may occur. Increased risk of hypotension. Consider withholding Valsartan for 12 hours prior to administration of Rituximab.
TobramycinIncreased risk of nephrotoxicity
TrandolaprilThe angiotensin II receptor blocker, Valsartan, may increase the adverse effects of Trandolapril.
TreprostinilAdditive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
TriamtereneIncreased risk of hyperkalemia
Food InteractionsNot Available

Targets

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. Azizi M, Menard J, Bissery A, Guyenne TT, Bura-Riviere A, Vaidyanathan S, Camisasca RP: Pharmacologic demonstration of the synergistic effects of a combination of the renin inhibitor aliskiren and the AT1 receptor antagonist valsartan on the angiotensin II-renin feedback interruption. J Am Soc Nephrol. 2004 Dec;15(12):3126-33. Pubmed
  3. Criscione L, de Gasparo M, Buhlmayer P, Whitebread S, Ramjoue HP, Wood J: Pharmacological profile of valsartan: a potent, orally active, nonpeptide antagonist of the angiotensin II AT1-receptor subtype. Br J Pharmacol. 1993 Oct;110(2):761-71. Pubmed
  4. Shargorodsky M, Leibovitz E, Lubimov L, Gavish D, Zimlichman R: Prolonged treatment with the AT1 receptor blocker, valsartan, increases small and large artery compliance in uncomplicated essential hypertension. Am J Hypertens. 2002 Dec;15(12):1087-91. Pubmed
  5. de Gasparo M, Whitebread S: Binding of valsartan to mammalian angiotensin AT1 receptors. Regul Pept. 1995 Nov 10;59(3):303-11. Pubmed
  6. Siragy HM, El-Kersh MA, De Gasparo M, Webb RL, Carey RM: Differences in AT2 -receptor stimulation between AT1 -receptor blockers valsartan and losartan quantified by renal interstitial fluid cGMP. J Hypertens. 2002 Jun;20(6):1157-63. Pubmed

Enzymes

1. 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. Nakashima A, Kawashita H, Masuda N, Saxer C, Niina M, Nagae Y, Iwasaki K: Identification of cytochrome P450 forms involved in the 4-hydroxylation of valsartan, a potent and specific angiotensin II receptor antagonist, in human liver microsomes. Xenobiotica. 2005 Jun;35(6):589-602. Pubmed
  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
  4. Lexicomp

Carriers

1. Serum albumin

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Serum albumin P02768 Details

References:

  1. Diovan. (2009). [Electronic version]. e-CPS. Retrieved September 15, 2011.

Transporters

1. Solute carrier organic anion transporter family member 1B3

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Solute carrier organic anion transporter family member 1B3 Q9NPD5 Details

References:

  1. Poirier A, Cascais AC, Funk C, Lave T: Prediction of pharmacokinetic profile of valsartan in human based on in vitro uptake transport data. J Pharmacokinet Pharmacodyn. 2009 Dec;36(6):585-611. Epub 2009 Nov 20. Pubmed
  2. Poirier A, Cascais AC, Funk C, Lave T: Prediction of pharmacokinetic profile of valsartan in humans based on in vitro uptake-transport data. Chem Biodivers. 2009 Nov;6(11):1975-87. Pubmed

2. Solute carrier organic anion transporter family member 1B1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Solute carrier organic anion transporter family member 1B1 Q9Y6L6 Details

References:

  1. Poirier A, Cascais AC, Funk C, Lave T: Prediction of pharmacokinetic profile of valsartan in human based on in vitro uptake transport data. J Pharmacokinet Pharmacodyn. 2009 Dec;36(6):585-611. Epub 2009 Nov 20. Pubmed
  2. Poirier A, Cascais AC, Funk C, Lave T: Prediction of pharmacokinetic profile of valsartan in humans based on in vitro uptake-transport data. Chem Biodivers. 2009 Nov;6(11):1975-87. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:08