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targets (4) transporters (3)
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Identification
Name Oseltamivir
Accession Number DB00198 (APRD01148)
Type small molecule
Groups approved
Description

An acetamido cyclohexene that is a structural homolog of sialic acid and inhibits neuraminidase. [PubChem]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
Oseltamivir phosphate
Salts Not Available
Brand names
Name Company
Tamiflu
Brand mixtures Not Available
Categories
  • Antiviral Agents
  • Enzyme Inhibitors
CAS number 204255-11-8
Weight Average: 312.4045
Monoisotopic: 312.204907394
Chemical Formula C16H28N2O4
InChI Key InChIKey=VSZGPKBBMSAYNT-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
Plain Text
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
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Carboxylic Acids and Derivatives
  • Cyclohexenes and Derivatives
Substructures
  • Carboxylic Acids and Derivatives
  • Alkanes and Alkenes
  • Acetates
  • Amino Ketones
  • Aliphatic and Aryl Amines
  • Ethers
  • Carboxamides and Derivatives
  • Cyclohexenes and Derivatives
Pharmacology
Indication Oseltamivir (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.
Pharmacodynamics Oseltamivir 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 action Oseltamivir 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.
Absorption Readily absorbed from the gastrointestinal tract after oral administration with a bioavailability of 75%.
Volume of distribution
  • 23 to 26 L
Protein binding Oseltamivir 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 elimination Absorbed 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 life 1 to 3 hours in most subjects after oral administration.
Clearance Not Available
Toxicity At 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
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Hoffmann la roche inc
Packagers
Dosage forms
Form Route Strength
Capsule Oral
Capsule Oral 75 mg
Powder, for suspension Oral
Powder, for suspension Oral 12 mg/mL
Prices
Unit description Cost Unit
Tamiflu 10 30 mg capsule Box 101.54 USD box
Tamiflu 10 45 mg capsule Box 101.54 USD box
Tamiflu 10 75 mg capsule Disp Pack 101.54 USD disp
Tamiflu 12 mg/ml Suspension 51.0 USD bottle
Tamiflu 30 mg gel capsule 9.76 USD gel capsule
Tamiflu 45 mg gel capsule 9.76 USD gel capsule
Tamiflu 75 mg gel capsule 9.76 USD gel capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Country Patent Number Approved Expires (estimated)
United States 5763483 1997-06-27 2017-06-27
United States 5866601 1996-02-02 2016-02-02
Canada 2188835 2006-08-08 2016-02-26
Properties
State solid
Experimental Properties
Property Value Source
water solubility Soluble Not Available
logP 1 Not Available
Predicted Properties
Property Value Source
water solubility 6.86e-01 g/l ALOGPS
logP 1.3 ALOGPS
logP 1.16 ChemAxon
logS -2.7 ALOGPS
pKa (strongest acidic) 14.03 ChemAxon
pKa (strongest basic) 9.31 ChemAxon
physiological charge 1 ChemAxon
hydrogen acceptor count 4 ChemAxon
hydrogen donor count 2 ChemAxon
polar surface area 90.65 ChemAxon
rotatable bond count 8 ChemAxon
refractivity 84.2 ChemAxon
polarizability 34.65 ChemAxon
References
Synthesis Reference Not Available
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
Resource Link
KEGG Drug D00900 Link_out
KEGG Compound C08093 Link_out
PubChem Compound 65028 Link_out
PubChem Substance 46507602 Link_out
ChemSpider 58540 Link_out
BindingDB 5025 Link_out
ChEBI 7798 Link_out
ChEMBL 7798 Link_out
Therapeutic Targets Database DAP000714 Link_out
PharmGKB PA450721 Link_out
Drug Product Database 2245549 Link_out
RxList http://www.rxlist.com/cgi/generic3/oseltamiv.htm Link_out
Drugs.com http://www.drugs.com/oseltamivir.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Oseltamivir Link_out
ATC Codes
  • J05AH02
AHFS Codes
  • 08:18.28
PDB Entries Not Available
FDA label show (67.2 KB)
MSDS show (107 KB)
Interactions
Drug Interactions Not Available
Food Interactions
  • Take without regard to meals. Food may improve gastric tolerance.
Targets

1. Neuraminidase

Pharmacological action: yes
Actions: inhibitor

Catalyzes the removal of terminal sialic acid residues from viral and cellular glycoconjugates. Cleaves off the terminal sialic acids on the glycosylated HA during virus budding to facilitate virus release. Additionally helps virus spread through the circulation by further removing sialic acids from the cell surface. These cleavages prevent self-aggregation and ensure the efficient spread of the progeny virus from cell to cell. Otherwise, infection would be limited to one round of replication. Described as a receptor-destroying enzyme because it cleaves a terminal sialic acid from the cellular receptors. May facilitate viral invasion of the upper airways by cleaving the sialic acid moities on the mucin of the airway epithelial cells. Likely to plays a role in the budding process through its association with lipid rafts during intracellular transport. May additionally display a raft-association independent effect on budding. Plays a role in the determination of host range restriction on replication and virulence. Sialidase activity in late endosome/lysosome traffic seems to enhance virus replication

Organism class: viral
UniProt ID: P11485 Link_out
Gene: NA
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: yes
Actions: other

Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs. Hydrolyzes aromatic and aliphatic esters, but has no catalytic activity toward amides or a fatty acyl CoA ester

Organism class: human
UniProt ID: P23141 Link_out
Gene: CES1
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: unknown
Actions: inhibitor

Catalyzes the removal of sialic acid (N-acetylneuramic acid) moities from glycoproteins and glycolipids. To be active, it is strictly dependent on its presence in the multienzyme complex. Appears to have a preference for alpha 2-3 and alpha 2-6 sialyl linkage

Organism class: human
UniProt ID: Q99519 Link_out
Gene: NEU1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: unknown
Actions: inhibitor

Hydrolyzes sialylated compounds

Organism class: human
UniProt ID: Q9Y3R4 Link_out
Gene: NEU2
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

May be an organic anion pump relevant to cellular detoxification

UniProt ID: O15439 Link_out
Gene: ABCC4 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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. Oligopeptide transporter, small intestine isoform

Actions: substrate

Proton-coupled intake of oligopeptides of 2 to 4 amino acids with a preference for dipeptides. May constitute a major route for the absorption of protein digestion end-products

UniProt ID: P46059 Link_out
Gene: SLC15A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenadine. Transports benzylpenicillin (PCG), estrone- 3-sulfate (E1S), cimetidine (CMD), 2,4-dichloro-phenoxyacetate (2,4-D), p-amino-hippurate (PAH), acyclovir (ACV) and ochratoxin (OTA)

UniProt ID: Q8TCC7 Link_out
Gene: SLC22A8 Link_out
Protein Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19