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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
N-(((S)-3-(3-Fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl)methyl)acetamideNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
AntizolidVerisfield
LinoseptOrion
LinozidOrion
LizbidAbbott
LizemoxMolekule
LizolidGlenmark
XolidCorona
ZenixHemofarm
ZizolidBiofarma
ZodlinFDC
ZolinidTeva
ZyvoxPfizer
ZyvoxamPfizer
ZyvoxidPfizer
Brand mixturesNot Available
Categories
CAS number165800-03-3
WeightAverage: 337.3461
Monoisotopic: 337.143784348
Chemical FormulaC16H20FN3O4
InChI KeyTYZROVQLWOKYKF-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
Not Available
aminoethoxyacetic acidDetails
Linezolid
Not Available
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.

Targets

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

Enzymes

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

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