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Identification
NameLinezolid
Accession NumberDB00601  (APRD01073, DB08769)
Typesmall molecule
Groupsapproved, investigational
Description

Linezolid is a synthetic antibiotic, the first of the oxazolidinone class, used for the treatment of infections caused by multi-resistant bacteria including streptococcus and methicillin-resistant Staphylococcus aureus (MRSA). The drug works by inhibiting the initiation of bacterial protein synthesis.

Structure
Thumb
Synonyms
SynonymLanguageCode
LinezolidGermanINN
LinezolidSpanishINN
LinezolideFrenchINN
LinezolidumLatinINN
SaltsNot Available
Brand names
NameCompany
AntizolidVerisfield
LinoseptOrion
LinozidOrion
LizbidAbbott
LizemoxMolekule
LizolidGlenmark
XolidCorona
ZenixHemofarm
ZizolidBiofarma
ZodlinFDC
ZolinidTeva
ZyvoxPfizer
ZyvoxamPfizer
ZyvoxidPfizer
Brand mixturesNot Available
CategoriesNot Available
CAS number165800-03-3
WeightAverage: 337.3461
Monoisotopic: 337.143784348
Chemical FormulaC16H20FN3O4
InChI KeyInChIKey=TYZROVQLWOKYKF-ZDUSSCGKSA-N
InChI
InChI=1S/C16H20FN3O4/c1-11(21)18-9-13-10-20(16(22)24-13)12-2-3-15(14(17)8-12)19-4-6-23-7-5-19/h2-3,8,13H,4-7,9-10H2,1H3,(H,18,21)/t13-/m0/s1
IUPAC Name
N-{[(5S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide
SMILES
CC(=O)NC[C@H]1CN(C(=O)O1)C1=CC(F)=C(C=C1)N1CCOCC1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassOxazinanes
SubclassMorpholines
Direct parentPhenylmorpholines
Alternative parentsFluorobenzenes; Oxazolidinediones; Aryl Fluorides; Secondary Carboxylic Acid Amides; Carbamic Acids and Derivatives; Tertiary Amines; Polyamines; Enolates; Ethers; Carboxylic Acids; Organofluorides
Substituentsoxazolidinedione; fluorobenzene; aryl fluoride; aryl halide; benzene; tertiary amine; secondary carboxylic acid amide; carboxamide group; carbamic acid derivative; polyamine; carboxylic acid derivative; enolate; ether; carboxylic acid; organohalogen; organofluoride; amine; organonitrogen compound
Classification descriptionThis compound belongs to the phenylmorpholines. These are aromatic compounds containing a morpholine ring and a benzene ring linked to each other through a CC or a CN bond.
Pharmacology
IndicationFor the treatment of bacterial infections caused by susceptible strains of vancomycin resistant Enterococcus faecium, Staphylococcal aureus (methicillin resistant and susceptible strains), Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae.
PharmacodynamicsLinezolid is a synthetic antibacterial agent of a new class of antibiotics, the oxazolidinones, which has clinical utility in the treatment of infections caused by aerobic Gram-positive bacteria. The in vitro spectrum of activity of linezolid also includes certain Gram-negative bacteria and anaerobic bacteria. Susceptible organisms include methicillin- and vancomycin-resistant staphylococci, vancomycin-resistant enterococci, penicillin-resistant pneumococci and anaerobes. Oxazolidinones inhibit protein synthesis by binding at the P site at the ribosomal 50S subunit. Resistance to other protein synthesis inhibitors does not affect oxazolidinone activity, however rare development of oxazolidinone resistance cases, associated with 23S rRNA alterations during treatment have been reported. Linezolid inhibits bacterial protein synthesis through a mechanism of action different from that of other antibacterial agents; therefore, cross-resistance between linezolid and other classes of antibiotics is unlikely.
Mechanism of actionLinezolid is a synthetic antibacterial agent of the oxazolidinone class of antibiotics. It has in vitro activity against aerobic Gram positive bacteria, certain Gram negative bacteria and anaerobic microorganisms. It selectively inhibits bacterial protein synthesis through binding to sites on the bacterial ribosome and prevents the formation of a functional 70S-initiation complex. Specifically, linezolid binds to a site on the bacterial 23S ribosomal RNA of the 50S subunit and prevents the formation of a functional 70S initiation complex, which is an essential component of the bacterial translation process. The results of time-kill studies have shown linezolid to be bacteriostatic against enterococci and staphylococci. For streptococci, linezolid was found to be bactericidal for the majority of strains. Linezolid is also a reversible, nonselective inhibitor of monoamine oxidase. Therefore, linezolid has the potential for interaction with adrenergic and serotonergic agents.
AbsorptionLinezolid is rapidly and extensively absorbed after oral dosing. Maximum plasma concentrations are reached approximately 1 to 2 hours after dosing, and the absolute bioavailability is approximately 100%.
Volume of distribution
  • 40 to 50 L [healthy adult volunteers]
Protein binding31%
Metabolism

Linezolid is primarily metabolized by oxidation of the morpholine ring, which results in two inactive ring-opened carboxylic acid metabolites: the aminoethoxyacetic acid metabolite (A), and the hydroxyethyl glycine metabolite

SubstrateEnzymesProduct
Linezolid
    aminoethoxyacetic acidDetails
    Linezolid
      Hydroxyethyl glycineDetails
      Route of eliminationNot Available
      Half life4.5-5.5 hours
      ClearanceNot Available
      ToxicityClinical signs of acute toxicity lead to decreased activity, ataxia, vomiting and tremors.
      Affected organisms
      • Gram negative and gram positive bacteria
      PathwaysNot Available
      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 + 0.9363
      Caco-2 permeable + 0.8866
      P-glycoprotein substrate Substrate 0.5881
      P-glycoprotein inhibitor I Inhibitor 0.7599
      P-glycoprotein inhibitor II Non-inhibitor 0.6478
      Renal organic cation transporter Non-inhibitor 0.7469
      CYP450 2C9 substrate Non-substrate 0.7898
      CYP450 2D6 substrate Non-substrate 0.9116
      CYP450 3A4 substrate Substrate 0.5904
      CYP450 1A2 substrate Non-inhibitor 0.7811
      CYP450 2C9 substrate Non-inhibitor 0.8174
      CYP450 2D6 substrate Non-inhibitor 0.8112
      CYP450 2C19 substrate Non-inhibitor 0.5664
      CYP450 3A4 substrate Non-inhibitor 0.7563
      CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.5544
      Ames test Non AMES toxic 0.6839
      Carcinogenicity Non-carcinogens 0.8916
      Biodegradation Not ready biodegradable 0.9895
      Rat acute toxicity 2.4938 LD50, mol/kg Not applicable
      hERG inhibition (predictor I) Weak inhibitor 0.7883
      hERG inhibition (predictor II) Inhibitor 0.6297
      Pharmacoeconomics
      Manufacturers
      • Pharmacia and upjohn co
      Packagers
      Dosage forms
      FormRouteStrength
      SolutionIntravenous
      TabletOral
      Prices
      Unit descriptionCostUnit
      Zyvox 600 mg tablet93.81USDtablet
      Zyvox 200 mg/100 ml iv soln0.6USDml
      DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
      Patents
      CountryPatent NumberApprovedExpires (estimated)
      United States65145292001-09-152021-09-15
      United States56887921994-11-182014-11-18
      Canada21685602001-08-142014-08-16
      Properties
      Statesolid
      Experimental Properties
      PropertyValueSource
      water solubility3 mg/mLNot Available
      logP0.9Not Available
      Predicted Properties
      PropertyValueSource
      water solubility1.44e+00 g/lALOGPS
      logP0.61ALOGPS
      logP0.64ChemAxon
      logS-2.4ALOGPS
      pKa (strongest acidic)14.45ChemAxon
      pKa (strongest basic)-0.66ChemAxon
      physiological charge0ChemAxon
      hydrogen acceptor count5ChemAxon
      hydrogen donor count1ChemAxon
      polar surface area71.11ChemAxon
      rotatable bond count4ChemAxon
      refractivity84.47ChemAxon
      polarizability34.06ChemAxon
      number of rings3ChemAxon
      bioavailability1ChemAxon
      rule of fiveYesChemAxon
      Ghose filterYesChemAxon
      Veber's ruleNoChemAxon
      MDDR-like ruleNoChemAxon
      Spectra
      SpectraNot Available
      References
      Synthesis Reference

      DrugSyn.org

      US5688792
      General Reference
      1. Link
      2. Park IN, Hong SB, Oh YM, Kim MN, Lim CM, Lee SD, Koh Y, Kim WS, Kim DS, Kim WD, Shim TS: Efficacy and tolerability of daily-half dose linezolid in patients with intractable multidrug-resistant tuberculosis. J Antimicrob Chemother. 2006 Sep;58(3):701-4. Epub 2006 Jul 19. Pubmed
      External Links
      ResourceLink
      KEGG DrugD00947
      KEGG CompoundC08146
      PubChem Compound441401
      PubChem Substance46504452
      ChemSpider390139
      BindingDB50116067
      Therapeutic Targets DatabaseDAP000398
      PharmGKBPA450233
      HETZLD
      Drug Product Database2243684
      RxListhttp://www.rxlist.com/cgi/generic3/linezolid.htm
      Drugs.comhttp://www.drugs.com/cdi/linezolid.html
      PDRhealthhttp://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/zyv1556.shtml
      WikipediaLinezolid
      ATC CodesJ01XX08
      AHFS Codes
      • 08:12.28.24
      PDB EntriesNot Available
      FDA labelshow(106 KB)
      MSDSshow(43.7 KB)
      Interactions
      Drug Interactions
      Drug
      BezafibrateMAO Inhibitors may enhance the adverse/toxic effect of Bezafibrate. Avoid concomitant use of bezafibrate with monoamine oxidase inhibitors (MAOIs) like linezolid.
      BrimonidineMAO Inhibitors like linezolid may enhance the hypertensive effect of Alpha2-Agonists (Ophthalmic). The concomitant use of monoamine oxidase inhibitors and ophthalmic alpha2 agonists is contraindicated.
      BuprenorphineBuprenorphine may enhance the adverse/toxic effect of MAO Inhibitors like linezolid. When possible, avoid use of buprenorphine in patients who have used a monoamine oxidase inhibitor within the past 14 days due to possible severe adverse effects.
      CitalopramCombination associated with possible serotoninergic syndrome
      DesvenlafaxineIncreased risk of serotonin syndrome. Ensure adequate washout period between therapies to avoid toxicity. Concurrent therapy should be avoided.
      DobutaminePossible increase of arterial pressure
      DopaminePossible increase of arterial pressure
      EphedraPossible increase of arterial pressure
      EphedrinePossible increase of arterial pressure
      EpinephrinePossible increase of arterial pressure
      EscitalopramCombination associated with possible serotoninergic syndrome
      FenoterolPossible increase of arterial pressure
      FluoxetineLinezolide, a MAO inhibitor, may increase the serotonergic effect of fluoxetine, a SSRI. Increased for of serotonin syndrome. Concomitant therapy should be avoided.
      FluvoxamineCombination associated with possible serotoninergic syndrome
      IsoprenalinePossible increase of arterial pressure
      MephenterminePossible increase of arterial pressure
      MetaraminolPossible increase of arterial pressure
      MethoxaminePossible increase of arterial pressure
      NefazodoneCombination associated with possible serotoninergic syndrome
      NorepinephrinePossible increase of arterial pressure
      OrciprenalinePossible increase of arterial pressure
      ParoxetineCombination associated with possible serotoninergic syndrome
      PhenylephrinePossible increase of arterial pressure
      PhenylpropanolaminePossible increase of arterial pressure
      PirbuterolPossible increase of arterial pressure
      ProcaterolPossible increase of arterial pressure
      PseudoephedrinePossible increase of arterial pressure
      SalbutamolPossible increase of arterial pressure
      SertralineCombination associated with possible serotoninergic syndrome
      TerbutalinePossible increase of arterial pressure
      TetrabenazineTetrabenazine may increase the adverse/toxic effects of Linezolid. Concomitant therapy is contraindicated.
      TolcaponeTolcapone and Linezolid decrease the metabolism of endogenous catecholamines. Concomitant therapy may result in increased catecholamine effects. Consider alternate therapy or use cautiously and monitor for increased catecholamine effects.
      TramadolTramadol increases the risk of serotonin syndrome and seizure induction by the MAO inhibitor, Linezolid.
      TranylcypromineThe MAO inhibitor, Tranylcypromine, may increase the adverse effects of Linezolid. These agents should not be administered within 14 days of each other.
      TrazodoneIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
      TrimipramineIncreased risk of serotonin syndrome. Ensure adequate washout period between therapies to avoid toxicity. Avoid combination or monitor for symptoms of serotonin syndrome and/or hypertensive crisis.
      VenlafaxineIncreased risk of serotonin syndrome. Ensure adequate washout period between therapies to avoid toxicity. Concurrent therapy should be avoided.
      VilazodoneMAO Inhibitors may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. Avoid combination.
      ZolmitriptanThe MAO inhibitor, linezolid, may increase the serum concentration of zolmitriptan by decreasing its metabolism. Concomitant therapy and use of zolmitriptan within two weeks of discontinuing linezolid are contraindicated.
      Food Interactions
      • Take without regard to meals.

      1. 23S rRNA

      Kind: nucleotide

      Organism: Enteric bacteria and other eubacteria

      Pharmacological action: yes

      Actions: inhibitor

      Components

      Name UniProt ID 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. Sinclair A, Arnold C, Woodford N: Rapid detection and estimation by pyrosequencing of 23S rRNA genes with a single nucleotide polymorphism conferring linezolid resistance in Enterococci. Antimicrob Agents Chemother. 2003 Nov;47(11):3620-2. Pubmed
      4. Meka VG, Pillai SK, Sakoulas G, Wennersten C, Venkataraman L, DeGirolami PC, Eliopoulos GM, Moellering RC Jr, Gold HS: Linezolid resistance in sequential Staphylococcus aureus isolates associated with a T2500A mutation in the 23S rRNA gene and loss of a single copy of rRNA. J Infect Dis. 2004 Jul 15;190(2):311-7. Epub 2004 Jun 9. Pubmed
      5. Zhu W, Tenover FC, Limor J, Lonsway D, Prince D, Dunne WM Jr, Patel JB: Use of pyrosequencing to identify point mutations in domain V of 23S rRNA genes of linezolid-resistant Staphylococcus aureus and Staphylococcus epidermidis. Eur J Clin Microbiol Infect Dis. 2007 Mar;26(3):161-5. Pubmed
      6. Colca JR, McDonald WG, Waldon DJ, Thomasco LM, Gadwood RC, Lund ET, Cavey GS, Mathews WR, Adams LD, Cecil ET, Pearson JD, Bock JH, Mott JE, Shinabarger DL, Xiong L, Mankin AS: Cross-linking in the living cell locates the site of action of oxazolidinone antibiotics. J Biol Chem. 2003 Jun 13;278(24):21972-9. Epub 2003 Apr 10. Pubmed
      7. Feng J, Lupien A, Gingras H, Wasserscheid J, Dewar K, Legare D, Ouellette M: Genome sequencing of linezolid-resistant Streptococcus pneumoniae mutants reveals novel mechanisms of resistance. Genome Res. 2009 Jul;19(7):1214-23. Epub 2009 Apr 6. Pubmed

      1. Amine oxidase [flavin-containing] A

      Kind: protein

      Organism: Human

      Pharmacological action: unknown

      Actions: inhibitor

      Components

      Name UniProt ID Details
      Amine oxidase [flavin-containing] A P21397 Details

      References:

      1. Stevens DL, Dotter B, Madaras-Kelly K: A review of linezolid: the first oxazolidinone antibiotic. Expert Rev Anti Infect Ther. 2004 Feb;2(1):51-9. Pubmed
      2. Taylor JJ, Wilson JW, Estes LL: Linezolid and serotonergic drug interactions: a retrospective survey. Clin Infect Dis. 2006 Jul 15;43(2):180-7. Epub 2006 Jun 9. Pubmed

      2. Amine oxidase [flavin-containing] B

      Kind: protein

      Organism: Human

      Pharmacological action: unknown

      Actions: inhibitor

      Components

      Name UniProt ID Details
      Amine oxidase [flavin-containing] B P27338 Details

      References:

      1. Stevens DL, Dotter B, Madaras-Kelly K: A review of linezolid: the first oxazolidinone antibiotic. Expert Rev Anti Infect Ther. 2004 Feb;2(1):51-9. Pubmed
      2. Taylor JJ, Wilson JW, Estes LL: Linezolid and serotonergic drug interactions: a retrospective survey. Clin Infect Dis. 2006 Jul 15;43(2):180-7. Epub 2006 Jun 9. Pubmed

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