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Linezolid

Linezolid is a synthetic antibiotic developed by a team at Pharmacia and Upjohn Company [1]. It is used for the treatment of serious infections caused by Gram-positive bacteria that are resistant to several other antibiotics. Linezolid is active against most Gram-positive bacteria that cause disease, including streptococci, vancomycin-resistant enterococci (VRE), and methicillin-resistant Staphylococcus aureus (MRSA). The main indications of linezolid are infections of the skin and soft tissues and pneumonia (particularly hospital-acquired pneumonia), although off-label use for a variety of other infections is becoming popular. As a protein synthesis inhibitor, it stops the growth of bacteria by disrupting their production of proteins. Although many antibiotics work this way, the exact mechanism of action of linezolid appears to be unique in that it blocks the initiation of protein production, and not one of the later steps . Bacterial resistance to linezolid has remained very low since it was first detected in 1999, although it may be increasing.

Therapeutic use

Treatment of vancomycin-resistant Enterococcus faecium , including cases with concurrent bacteremia; treatment of nosocomial pneumonia, complicated and uncomplicated skin and skin structure infections (including diabetic foot infections without concomitant osteomyelitis), and community-acquired pneumonia caused by susceptible strains of specific organisms.

Dosage and Administration

 

Toxicology

Pharmacokinetic

Bioavailability 100%
Protein binding 31%
Metabolism hepatic; CYP450 not involved

Metabolites are aminoethoxyacetic acid (A) and hydroxyethyl glycine (B).

Half-life 4.2-5.4
Cmax (mg/ml) 18
tmax (hrs) 1-2
Clearance 40 mL/min
Distribution volume Vd (l) 40-50
Excretion 65% nin renal; 30% renal

Absorption

Rapidly and extensively absorbed after oral dosing. Tmax is 1 to 2 h. Absolute bioavailability is approximately 100% (no dose adjustment needed from IV to oral). Food does not affect absorption; however, Tmax is delayed from 1.5 to 2.2 h and Cmax is decreased 17% when high-fat food is given.

Distribution

Readily distributed to well-perfused tissues; 31% protein bound. Vd at steady state is 40 to 50L.

Excretion

Approximately 65% nonrenal Cl. Approximately 30% of dose appears in urine as linezolid (40% as metabolite B, 10% as metabolite A). Renal Cl is 40 mL/min.

Metabolism

Primarily metabolized by oxidation of the morpholine ring. Metabolites are aminoethoxyacetic acid (A) and hydroxyethyl glycine (B).

Mechanism of Action

 


Medicinal Chemistry

 

CAS number: 165800-03-3   EINECS:

Molecular Formula: C16H20FN3O4

Average mass: 337.3461 Da

Monoisotopic mass: 337.143799 Da

Systematic name: N-({(5S)-3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide

SMILES: CC(=O)NC[C@H]1CN(C(=O)O1)C2=CC(=C(C=C2)N3CCOCC3)F

Std. 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

ACD/LogP: 0.301.05 # of Rule of 5 Violations: 0
ACD/LogD (pH 5.5): -0.15 ACD/LogD (pH 7.4): 0.29
ACD/BCF (pH 5.5): 1.00 ACD/BCF (pH 7.4): 1.00
ACD/KOC (pH 5.5): 12.16 ACD/KOC (pH 7.4): 33.99
#H bond acceptors: 7 #H bond donors: 1
#Freely Rotating Bonds: 4 Polar Surface Area: 71.11 2
Index of Refraction: 1.554 Molar Refractivity: 83.00.3 cm3
Molar Volume: 259.03.0 cm3 Polarizability: 32.90.5 10-24cm3
Surface Tension: 47.73.0 dyne/cm Density: 1.30.1 g/cm3
Flash Point: 307.930.1 C Enthalpy of Vaporization: 87.53.0 kJ/mol
Boiling Point: 585.550.0 C at 760 mmHg Vapour Pressure: 0.01.6 mmHg at 25C

 


 

 


1. Brickner SJ "Oxazolidinone antibacterial agents". Current Pharmaceutical Design 2 (2): 17594, (1996).

2. Swaney SM, Aoki H, Ganoza MC, Shinabarger DL "The Oxazolidinone Linezolid Inhibits Initiation of Protein Synthesis in Bacteria". Antimicrobial Agents and Chemotherapy 1998, 42 (12): 32515.

 

 

 

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