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Identification
NameOseltamivir
Accession NumberDB00198  (APRD01148)
Typesmall molecule
Groupsapproved
Description

An acetamido cyclohexene that is a structural homolog of sialic acid and inhibits neuraminidase. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
(−)-oseltamivirNot AvailableNot Available
Salts
Name/CAS Structure Properties
Oseltamivir phosphate
Thumb Not applicable DBSALT000881
Brand names
NameCompany
TamifluNot Available
Brand mixturesNot Available
Categories
CAS number204255-11-8
WeightAverage: 312.4045
Monoisotopic: 312.204907394
Chemical FormulaC16H28N2O4
InChI KeyVSZGPKBBMSAYNT-RRFJBIMHSA-N
InChI
InChI=1S/C16H28N2O4/c1-5-12(6-2)22-14-9-11(16(20)21-7-3)8-13(17)15(14)18-10(4)19/h9,12-15H,5-8,17H2,1-4H3,(H,18,19)/t13-,14+,15+/m0/s1
IUPAC Name
ethyl (3R,4R,5S)-5-amino-4-acetamido-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylate
SMILES
CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassOrganic Acids and Derivatives
ClassCarboxylic Acids and Derivatives
SubclassAmino Acids, Peptides, and Analogues
Direct parentGamma Amino Acids and Derivatives
Alternative parentsSecondary Carboxylic Acid Amides; Carboxylic Acid Esters; Ethers; Polyamines; Carboxylic Acids; Enolates; Monoalkylamines
Substituentscarboxylic acid ester; secondary carboxylic acid amide; carboxamide group; enolate; carboxylic acid; ether; polyamine; primary amine; primary aliphatic amine; amine; organonitrogen compound
Classification descriptionThis compound belongs to the gamma amino acids and derivatives. These are amino acids having a (-NH2) group attached to the gamma carbon atom.
Pharmacology
IndicationOseltamivir (Tamiflu) is for the treatment of uncomplicated acute illness due to influenza infection in patients 1 year and older who have been symptomatic for no more than 2 days. It is also used for the prophylaxis of influenza in adult patients and adolescents 13 years and older.
PharmacodynamicsOseltamivir is an antiviral drug, a neuraminidase inhibitor used in the treatment and prophylaxis of both influenza A and influenza B. Oseltamivir is a prodrug (usually administered as phosphate), it is hydrolysed hepatically to the active metabolite, the free carboxylate of oseltamivir (GS4071). Like zanamivir, oseltamivir acts as a transition-state analogue inhibitor of influenza neuraminidase.
Mechanism of actionOseltamivir is an ethyl ester prodrug requiring ester hydrolysis for conversion to the active form, oseltamivir carboxylate. The proposed mechanism of action of oseltamivir is inhibition of influenza virus neuraminidase with the possibility of alteration of virus particle aggregation and release.
AbsorptionReadily absorbed from the gastrointestinal tract after oral administration with a bioavailability of 75%.
Volume of distribution
  • 23 to 26 L
Protein bindingOseltamivir carboxylate: low (3%), Oseltamivir free base: 42%.
Metabolism

Extensively converted to oseltamivir carboxylate by esterases located predominantly in the liver. Neither oseltamivir nor oseltamivir carboxylate is a substrate for, or inhibitor of, cytochrome P450 isoforms. At least 75% of an oral dose reaches the systemic circulation as oseltamivir carboxylate.

Route of eliminationAbsorbed oseltamivir is primarily (>90%) eliminated by conversion to oseltamivir carboxylate. Oseltamivir carboxylate is not further metabolized and is eliminated in the urine. Oseltamivir carboxylate is eliminated entirely (>99%) by renal excretion.
Half life1 to 3 hours in most subjects after oral administration.
ClearanceNot Available
ToxicityAt present, there has been no experience with overdose. Single doses of up to 1000 mg of oseltamivir have been associated with nausea and/or vomiting. Mean LD (intravenous, mouse) = 100 mg/kg.
Affected organisms
  • Influenza Virus
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9156
Blood Brain Barrier - 0.9535
Caco-2 permeable - 0.702
P-glycoprotein substrate Substrate 0.5919
P-glycoprotein inhibitor I Non-inhibitor 0.5415
P-glycoprotein inhibitor II Non-inhibitor 0.9771
Renal organic cation transporter Non-inhibitor 0.9429
CYP450 2C9 substrate Non-substrate 0.9083
CYP450 2D6 substrate Non-substrate 0.8276
CYP450 3A4 substrate Substrate 0.5283
CYP450 1A2 substrate Non-inhibitor 0.8367
CYP450 2C9 substrate Non-inhibitor 0.8774
CYP450 2D6 substrate Non-inhibitor 0.9174
CYP450 2C19 substrate Non-inhibitor 0.6677
CYP450 3A4 substrate Non-inhibitor 0.8364
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8682
Ames test Non AMES toxic 0.6907
Carcinogenicity Non-carcinogens 0.8863
Biodegradation Not ready biodegradable 0.6191
Rat acute toxicity 2.2695 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9826
hERG inhibition (predictor II) Non-inhibitor 0.9464
Pharmacoeconomics
Manufacturers
  • Hoffmann la roche inc
Packagers
Dosage forms
FormRouteStrength
CapsuleOral
CapsuleOral75 mg
Powder, for suspensionOral
Powder, for suspensionOral12 mg/mL
Prices
Unit descriptionCostUnit
Tamiflu 10 30 mg capsule Box101.54USDbox
Tamiflu 10 45 mg capsule Box101.54USDbox
Tamiflu 10 75 mg capsule Disp Pack101.54USDdisp
Tamiflu 12 mg/ml Suspension51.0USDbottle
Tamiflu 30 mg gel capsule9.76USDgel capsule
Tamiflu 45 mg gel capsule9.76USDgel capsule
Tamiflu 75 mg gel capsule9.76USDgel capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States57634831997-06-272017-06-27
United States58666011996-02-022016-02-02
Canada21888352006-08-082016-02-26
Properties
Statesolid
Experimental Properties
PropertyValueSource
water solubilitySolubleNot Available
logP1Not Available
Predicted Properties
PropertyValueSource
water solubility6.86e-01 g/lALOGPS
logP1.3ALOGPS
logP1.16ChemAxon
logS-2.7ALOGPS
pKa (strongest acidic)14.03ChemAxon
pKa (strongest basic)9.31ChemAxon
physiological charge1ChemAxon
hydrogen acceptor count4ChemAxon
hydrogen donor count2ChemAxon
polar surface area90.65ChemAxon
rotatable bond count8ChemAxon
refractivity84.2ChemAxon
polarizability34.65ChemAxon
number of rings1ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

DrugSyn.org

US5763483
General Reference
  1. Chokephaibulkit K, Uiprasertkul M, Puthavathana P, Chearskul P, Auewarakul P, Dowell SF, Vanprapar N: A child with avian influenza A (H5N1) infection. Pediatr Infect Dis J. 2005 Feb;24(2):162-6. Pubmed
  2. de Jong MD, Tran TT, Truong HK, Vo MH, Smith GJ, Nguyen VC, Bach VC, Phan TQ, Do QH, Guan Y, Peiris JS, Tran TH, Farrar J: Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med. 2005 Dec 22;353(25):2667-72. Pubmed
  3. Kiso M, Mitamura K, Sakai-Tagawa Y, Shiraishi K, Kawakami C, Kimura K, Hayden FG, Sugaya N, Kawaoka Y: Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Lancet. 2004 Aug 28-Sep 3;364(9436):759-65. Pubmed
  4. Ward P, Small I, Smith J, Suter P, Dutkowski R: Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic. J Antimicrob Chemother. 2005 Feb;55 Suppl 1:i5-i21. Pubmed
External Links
ResourceLink
KEGG DrugD00900
KEGG CompoundC08093
PubChem Compound65028
PubChem Substance46507602
ChemSpider58540
BindingDB5025
ChEBI7798
ChEMBLCHEMBL1229
Therapeutic Targets DatabaseDAP000714
PharmGKBPA450721
Drug Product Database2245549
RxListhttp://www.rxlist.com/cgi/generic3/oseltamiv.htm
Drugs.comhttp://www.drugs.com/oseltamivir.html
WikipediaOseltamivir
ATC CodesJ05AH02
AHFS Codes
  • 08:18.28
PDB EntriesNot Available
FDA labelshow(67.2 KB)
MSDSshow(107 KB)
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

1. Neuraminidase

Kind: protein

Organism: Influenza A virus (strain A/Chile/1/1983 H1N1)

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Neuraminidase P11485 Details

References:

  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. McKimm-Breschkin J, Trivedi T, Hampson A, Hay A, Klimov A, Tashiro M, Hayden F, Zambon M: Neuraminidase sequence analysis and susceptibilities of influenza virus clinical isolates to zanamivir and oseltamivir. Antimicrob Agents Chemother. 2003 Jul;47(7):2264-72. Pubmed
  4. Du QS, Wang SQ, Chou KC: Analogue inhibitors by modifying oseltamivir based on the crystal neuraminidase structure for treating drug-resistant H5N1 virus. Biochem Biophys Res Commun. 2007 Oct 19;362(2):525-31. Epub 2007 Aug 13. Pubmed
  5. Wang MZ, Tai CY, Mendel DB: Mechanism by which mutations at his274 alter sensitivity of influenza a virus n1 neuraminidase to oseltamivir carboxylate and zanamivir. Antimicrob Agents Chemother. 2002 Dec;46(12):3809-16. Pubmed

2. Liver carboxylesterase 1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: other

Components

Name UniProt ID Details
Liver carboxylesterase 1 P23141 Details

References:

  1. Shi D, Yang J, Yang D, LeCluyse EL, Black C, You L, Akhlaghi F, Yan B: Anti-influenza prodrug oseltamivir is activated by carboxylesterase human carboxylesterase 1, and the activation is inhibited by antiplatelet agent clopidogrel. J Pharmacol Exp Ther. 2006 Dec;319(3):1477-84. Epub 2006 Sep 11. Pubmed
  2. Wattanagoon Y, Stepniewska K, Lindegardh N, Pukrittayakamee S, Silachamroon U, Piyaphanee W, Singtoroj T, Hanpithakpong W, Davies G, Tarning J, Pongtavornpinyo W, Fukuda C, Singhasivanon P, Day NP, White NJ: Pharmacokinetics of high-dose oseltamivir in healthy volunteers. Antimicrob Agents Chemother. 2009 Mar;53(3):945-52. Epub 2008 Dec 22. Pubmed
  3. Zhu HJ, Markowitz JS: Activation of the antiviral prodrug oseltamivir is impaired by two newly identified carboxylesterase 1 variants. Drug Metab Dispos. 2009 Feb;37(2):264-7. Epub 2008 Nov 20. Pubmed

3. Sialidase-1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Sialidase-1 Q99519 Details

References:

  1. Chavas LM, Kato R, Suzuki N, von Itzstein M, Mann MC, Thomson RJ, Dyason JC, McKimm-Breschkin J, Fusi P, Tringali C, Venerando B, Tettamanti G, Monti E, Wakatsuki S: Complexity in influenza virus targeted drug design: interaction with human sialidases. J Med Chem. 2010 Apr 8;53(7):2998-3002. Pubmed

4. Sialidase-2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Sialidase-2 Q9Y3R4 Details

References:

  1. Chavas LM, Kato R, Suzuki N, von Itzstein M, Mann MC, Thomson RJ, Dyason JC, McKimm-Breschkin J, Fusi P, Tringali C, Venerando B, Tettamanti G, Monti E, Wakatsuki S: Complexity in influenza virus targeted drug design: interaction with human sialidases. J Med Chem. 2010 Apr 8;53(7):2998-3002. Pubmed

Transporters

1. Multidrug resistance-associated protein 4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Multidrug resistance-associated protein 4 O15439 Details

References:

  1. Ose A, Ito M, Kusuhara H, Yamatsugu K, Kanai M, Shibasaki M, Hosokawa M, Schuetz JD, Sugiyama Y: Limited brain distribution of [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxyl ate phosphate (Ro 64-0802), a pharmacologically active form of oseltamivir, by active efflux across the blood-brain barrier mediated by organic anion transporter 3 (Oat3/Slc22a8) and multidrug resistance-associated protein 4 (Mrp4/Abcc4). Drug Metab Dispos. 2009 Feb;37(2):315-21. Epub 2008 Nov 24. Pubmed

2. Solute carrier family 15 member 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Solute carrier family 15 member 1 P46059 Details

References:

  1. Ogihara T, Kano T, Wagatsuma T, Wada S, Yabuuchi H, Enomoto S, Morimoto K, Shirasaka Y, Kobayashi S, Tamai I: Oseltamivir (tamiflu) is a substrate of peptide transporter 1. Drug Metab Dispos. 2009 Aug;37(8):1676-81. Epub 2009 May 13. Pubmed

3. Solute carrier family 22 member 8

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Solute carrier family 22 member 8 Q8TCC7 Details

References:

  1. Ose A, Ito M, Kusuhara H, Yamatsugu K, Kanai M, Shibasaki M, Hosokawa M, Schuetz JD, Sugiyama Y: Limited brain distribution of [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxyl ate phosphate (Ro 64-0802), a pharmacologically active form of oseltamivir, by active efflux across the blood-brain barrier mediated by organic anion transporter 3 (Oat3/Slc22a8) and multidrug resistance-associated protein 4 (Mrp4/Abcc4). Drug Metab Dispos. 2009 Feb;37(2):315-21. Epub 2008 Nov 24. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on October 08, 2013 14:25