Identification and Related Records
- 【Iupac name】
- 【Registry number】
- 165800-03-3 (CAS DataBase Reference)
- 【Molecular Formula】
- C16H20FN3O4 (Products with the same molecular formula)
- 【Molecular Weight】
- 【Canonical SMILES】
- 【Isomers smiles】
Chemical and Physical Properties
- White Solid
- 1.302 g/cm3
- 【Melting Point】
- 【Boiling Point】
- 585.5 oC at 760 mmHg
- 1.08E-13mmHg at 25°C
- 【Refractive Index】
- 【Flash Point】
- 307.9 oC
- White crystals from ethyl acetate and hexanes
- 【Storage temp】
- Store in original container in a cool dark place.
- 【Spectral properties】
- Specific optical rotation at 20 deg C for D (sodium) line = -9 deg (c = 0.919 in chloroform)
- 【Computed Properties】
- Molecular Weight:337.346103 [g/mol]
Rotatable Bond Count:4
Topological Polar Surface Area:71.1
Heavy Atom Count:24
Isotope Atom Count:0
Defined Atom Stereocenter Count:1
Undefined Atom Stereocenter Count:0
Defined Bond Stereocenter Count:0
Undefined Bond Stereocenter Count:0
Covalently-Bonded Unit Count:1
Feature 3D Acceptor Count:3
Feature 3D Donor Count:1
Feature 3D Cation Count:1
Feature 3D Ring Count:3
Effective Rotor Count:7
Conformer Sampling RMSD:0.8
CID Conformer Count:116
Safety and Handling
- 【Hazard Codes】
- Xn: Harmful;
- 【Risk Statements】
- 【Safety Statements 】
Safety Information of Acetamide,N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]- (CAS NO.165800-03-3):
Risk Statements: 20/21/22?
R20/21/22:Harmful by inhalation, in contact with skin and if swallowed.
Safety Statements: 36?
S36:Wear suitable protective clothing.
- Parenteral: Injection, for IV infusion: 2 mg/mL (200 and 600 mg) in sterile isotonic solution Zyvox Injection ( in flexible containers), (Pfizer).
Oral: For suspension: 100 mg/5 mL Zyvox, (Pfizer); Tablets, film-coated: 600 mg Zyvox, (Pfizer).
- 【Exposure Standards and Regulations】
- The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl linezolide, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.
? Acetamide,N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]- (CAS NO.165800-03-3), its Synonyms are Linezolid ; N-(((S)-3-(3-Fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl)methyl)acetamide ; Zivoxid ; Zyvox ; Acetamide, N-((3-(3-fluoro-4-(4-morpholinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl)-, (S)- .
- 【Octanol/Water Partition Coefficient】
- log Kow = 1.26 (est)
- 【Disposal Methods】
- SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.
Use and Manufacturing
Prototype of the oxazolidinone antimicrobials; inhibits bacterial mRNA translation.
Biomedical Effects and Toxicity
- 【Biological Activity】
- Oxazolidinone antibiotic. Inhibits bacterial protein synthesis prior to chain initiation. Displays potent antibacterial activity against a variety of multidrug-resistant gram-positive microbes in vitro and in vivo .
- 【Pharmacological Action】
- - Substances that prevent infectious agents or organisms from spreading or kill infectious agents in order to prevent the spread of infection.
- Compounds which inhibit the synthesis of proteins. They are usually ANTI-BACTERIAL AGENTS or toxins. Mechanism of the action of inhibition includes the interruption of peptide-chain elongation, the blocking the A site of ribosomes, the misreading of the genetic code or the prevention of the attachment of oligosaccharide side chains to glycoproteins.
- 【Therapeutic Uses】
Intravenous and oral linezolid is indicated in the treatment of nosocomial pneumonia caused by methicillin-susceptible and methicillin resistant Staphylococcus aureus or penicillin-susceptible strains of Streptococcus pneumonia. /Included in US product labeling/
Intravenous and oral linezolid is indicated in the treatment of vancomycin-resistant Enterococcus faecium infections. /Included in US product labeling/
Oral linezolid is indicated in the treatment of uncomplicated skin and soft tissue infections caused by methicillin-susceptible strains of Staphylococcus aureus or Streptococcus pyogenes. /Included in US product labeling/
Intravenous and oral linezolid is indicated in the treatment of complicated skin and soft tissue infections, including diabetic foot infections, without concomitant osteomyelitis, caused by Staphylococcus aureus (methicillin-susceptible and methicillin-resistant), Streptococcus pyogenes, or Streptococcus agalactiae. Patients with decubitus ulcers were not included in the clinical trials. /Included in US product labeling/
Intravenous and oral linezolid is indicated in the treatment of community acquired pneumonia caused by penicillin-susceptible strains of Streptococcus pneumonia or methicillin-susceptible strains of Staphylococcus aurenus. /Included in US product labeling/
Linezolid is an oxazolidinone antibiotic with excellent in vitro activity against a number of Gram-positive organisms including antibiotic-resistant isolates. The safety and pharmacokinetics of intravenously administered linezolid were evaluated in children and adolescents to examine the potential for developmental dependence on its disposition characteristics. Fifty-eight children (3 months to 16 years old) participated in this study; 44 received a single 1.5-mg/kg dose and 14 received a single 10-mg/kg dose of linezolid administered by intravenous infusion. Repeated blood samples (n = 10 in children > or = 12 months; n = 8 in children 3 to 12 months) were obtained during 24 hr after drug administration, and linezolid was quantitated from plasma by high performance liquid chromatography with mass spectrometry detection. Plasma concentration vs. time data were evaluated with a model independent approach. Linezolid was well-tolerated by all subjects. The disposition of linezolid appears to be age-dependent. A significant although weak correlation between age and total body clearance was observed. The mean (+ or - SD) values for elimination half-life, total clearance and apparent volume of distribution were 3.0 + or - 1.1 hr, 0.34 + or - 0.15 liter/h/kg and 0.73 + or - 0.18 liter/kg, respectively. Estimates of total body clearance and volume of distribution were significantly greater in children than historical values of adult data. As such maximum achievable linezolid plasma concentrations were slightly lower in children, and concentrations 12 hr after a single 10-mg/kg dose were below the MIC90 for selected pathogens with in vitro susceptibility to the drug. Based on these data a linezolid dose of 10 mg/kg given two to three times daily would appear appropriate for use in pediatric therapeutic clinical trials of this agent. [Kearns GL et al; Pediatr Infect Dis J 19 (12): 1178-84 (2000)]
- 【Biomedical Effects and Toxicity】
- Distributed to well-perfused tissues; volume of distribution slightly lower in women than men. VolD (steady state) - 40 to 50 L.
AUC is lower for pediatric patients compared with adults and a wider variability of linezolid AUC cross all pediatric age groups as compared with adults. Most pre-term neonates less than 7 days of age (gestational age less than 34 weeks) have larger AUC values than many full-term neonates and older infants.
Linezolid was rapidly absorbed after p.o. dosing with an p.o. bioavailability of > 95% in rat and dog, and > 70% in mouse. Twenty-eight-day i.v./p.o. toxicokinetic studies in rat (20-200 mg kg(-1) day(-1)) and dog (10-80 mg kg(-1) day(-1)) revealed neither a meaningful increase in clearance nor accumulation upon multiple dosing. Linezolid had limited protein binding (PubMed Abstract
In two randomized, double-blind, placebo-controlled, dose-escalating trials, subjects were exposed either to oral (375, 500 or 625 mg) or intravenous (500 or 625 mg) linezolid or placebo twice daily. Serial blood and urine samples were obtained after the first- and multiple-dose administrations for up to 18 days. Non-compartmental pharmacokinetic analyses were used to describe the disposition of linezolid. Plasma linezolid concentrations and area under the concentration-time curves (AUC) increased proportionally with dose irrespective of the route of administration. Plasma linezolid concentrations remained above the MIC90 for susceptible target pathogens (4.0 mg/L) for the majority of the 12 hr dosing interval. Mean clearance, half-life and volume of distribution were similar irrespective of dose for both the oral and intravenous routes. Linezolid was well tolerated and the frequency of drug-related adverse events was similar between the linezolid and placebo groups. Oral and intravenous linezolid exhibit linear pharmacokinetics, with concentrations remaining above the target MIC90 /minimal inhibitory concentration/ for most of the dosing interval. These results support a twice-daily schedule for linezolid and demonstrate the feasibility of converting from intravenous to oral dosing without a dose adjustment. [Stalker DJ et al; J Antimicrob Chemother 51 (5): 1239-46 (2003)] PubMed Abstract
Well absorbed after oral administration; absolute bioavailability approximately 100%; food has no effect.
Linezolid is well absorbed following oral administration (absolute bioavailability approximately 100%) and is readily distributed into well-perfused tissues.
Data obtained from 318 adult patients treated under the linezolid compassionate-use protocol were used to develop a population model of the pharmacokinetics of intravenous and oral linezolid. All of the patients received 600 mg of linezolid every 12 hr, intravenously and/or orally. Blood samples (2 to 10 per patient; median, 4) were obtained and assayed for linezolid by high-performance liquid chromatography. These data and patient covariates were modeled by iterative two-stage analysis, and model discrimination was done by Akaike's information criterion. Of the patient covariates considered (age, sex, ideal body weight, baseline serum albumin, hepatic or renal dysfunction, underlying malignancy, organ transplantation, surgical status, global severity of illness, site of infection, route of administration, and location of care [intensive-care unit, general floor, or outpatient]), only normalized creatinine clearance (CL(CR)) and body weight explained significant portions of the variance and were incorporated into the pharmacokinetic model. The final model included central and peripheral compartments with parallel capacity-limited (nonrenal) and first-order (renal [CL(R)]) clearances. Volumes and clearances were normalized to the ideal body weight, and CL(R) was modeled as proportional to CL(CR). Compared to previously studied adult volunteers, intrinsic clearance was approximately 60% higher and the maximum rate of metabolism was twice as high in these debilitated patients, resulting in lower area under the time-concentration curve (AUC) values (P PubMed Abstract
There are a number of physiologic and developmental differences between children and adults that can influence the absorption, distribution, metabolism and elimination of a drug. Therefore it is important to determine the specific pharmacokinetic characteristics for individual drugs in pediatric patients so that appropriate age-specific dosage regimens can be developed and evaluated in clinical trials. The pharmacokinetics of linezolid in pediatric patients has been evaluated in 4 clinical trials, including >180 patients ranging in age from preterm newborn infants up to 18 years of age. In all of these studies, patients received a single intravenous dose of linezolid. Plasma linezolid concentrations have been determined by validated high performance liquid chromatography (adult studies) or liquid chromatography/mass spectrometry/mass spectrometry (pediatric studies) methods. The pharmacokinetics of linezolid, especially elimination clearance, is age-dependent. Children younger than 12 years of age have a smaller area under the drug concentration-time curve, a faster clearance and a shorter elimination half-life than adults. Although clearance rates in newborn infants are similar to those in adults, clearance increases rapidly during the first week of life, becoming 2- to 3-fold higher than in adults by the seventh day of life. The clearance of linezolid decreases gradually among young children, becoming similar to adult values by adolescence. The pharmacokinetics of linezolid in children age 12 years and older is not significantly different from that of adults. Because of the higher clearance and lower area under the drug concentration-time curve, a shorter dosing interval for linezolid is required for children younger than 12 years of age to produce adequate drug exposure against target Gram-positive pathogens. [Jungbluth GL et al; Pediatr Infect Dis J 22 (9 Suppl): S153-7 (2003)] PubMed Abstract
Twelve patients undergoing total hip replacement were given 600 mg of linezolid as a 20 min iv infusion along with conventional prophylaxis of 1 g of cefamandole immediately before surgery. Routine total hip arthroplasty was carried out, and at timed intervals during surgery samples of bone, fat, muscle and blood were collected for assay by high-performance liquid chromatography analysis. Samples of the hematoma fluid that formed around the operation site and further blood samples for assay were also collected at timed intervals following the operation. The penetration of linezolid into bone was rapid, with mean concentrations of 9.1 mg/L (95% CI 7.7-10.6 mg/L) achieved at 10 min after the infusion, decreasing to 6.3 mg/L (95% CI 3.9-8.6 mg/L) at 30 min. Correction for the simultaneous blood concentrations gave mean values for bone penetration of 51% at 10 min, 60% at 20 min and 47% at 30 min. Although the penetration of linezolid into fat was also rapid, mean concentrations and degree of penetration were c. 60% of those in bone; at 10 min they were 4.5 mg/L (95% CI 3.0-6.1 mg/L; penetration 27%); at 20 min they were 5.2 mg/L (95% CI 4.0-6.4 mg/L; penetration 37%); and at 30 min, 4.1 mg/L (95% CI 3.3-4.8 mg/L; penetration 31%). For muscle the corresponding values were 10.4 mg/L (95% CI 8.1-12.7 mg/L; penetration 58%) at 10 min, 13.4 mg/L (95% CI 10.2-16.5 mg/L; penetration 94%) at 20 min and 12.0 mg/L (95% CI 9.2-14.8 mg/L; penetration 93%) at 30 min. Mean concentrations of linezolid in the hematoma fluid drained from around the operation site were 8.2 mg/L at 6-8 hr and 5.6 mg/L at 10-12 h after the infusion, and 7.0 mg/L at 2-4 h following a second 600 mg infusion given 12 hr post-operatively. [Lovering AM et al; J Antimicrob Chemother 50 (1): 73-7 (2002)] PubMed Abstract
Linezolid pharmacokinetics /was characterized/ after a single, 10.0-mg/kg intravenous dose in 42 infants stratified as follows: group 1 (n = 9), gestational age or=34 weeks and postnatal age or=34 weeks and postnatal age 8 days to 12 weeks. Linezolid was quantitated by a validated HPLC-triple-quadrupole mass spectrometer method from repeated blood samples (n = 7, 0.3 mL each) obtained over a 12-hour period. Pharmacokinetic parameters were determined by standard model-dependent techniques. The values (mean + or - SD) for total body clearance (CL) (0.25 + or - 0.12 L x h(-1) x kg(-1)), apparent volume of distribution (VD(ss)) (0.75 + or -- 0.19 L/kg), and elimination half-life (t(1/2)) (2.8 + or - 2.1 hours) from the entire study cohort were similar to values reported previously for children and adolescents. Examination of the linezolid pharmacokinetics as a function of age revealed that CL increased rapidly during the first week of life and as a function of postnatal age. Age stratification revealed lower values for CL in those infants aged less than 8 days (group 1, 0.12 + or - 0.06 L x h(-1) x kg(-1); group 3, 0.23 + or - 0.12 L x h(-1) x kg(-1)) as compared with those aged 8 days to 12 weeks (group 2, 0.31 + or - 0.07 L x h(-1) x kg(-1); group 4, 0.31 + or - 0.10 L x h(-1) x kg(-1)). In contrast to the results for CL, gestational age served to be the most useful predictor of VD(ss). Evaluation of the pharmacokinetic data would appear to support the use of linezolid dosing regimens currently approved for infants and young children in neonates with postnatal age greater than 7 days. [Kearns GL et al; Clin Pharmacol Ther 74 (5): 413-22 (2003)] PubMed Abstract
Twenty-four subjects with renal function that ranged from normal to severe chronic impairment were enrolled, including patients with end-stage renal disease who were maintained on hemodialysis. Hemodialysis subjects were studied while they were both on and off dialysis. Linezolid was administered as a single oral 600-mg dose, and plasma and urine samples were assayed for linezolid and metabolites for 48 hr for all subjects and for up to 96 hr for those subjects with impaired renal function not on dialysis. The total apparent oral clearance of linezolid did not change with renal function and ranged from 92.5 to 109.6 ml/min for subjects not requiring dialysis. For subjects on dialysis, the total apparent oral clearance increased from 76.6 ml/min on their off-dialysis day to 130.0 ml/min on their on-dialysis day. Approximately one-third of the dose was removed by dialysis. However, those subjects with severe renal insufficiency (creatinine clearance, PubMed Abstract
This study was designed to measure the concentrations of linezolid in bronchial mucosa, pulmonary macrophages and epithelial lining fluid and to compare them with simultaneous blood levels. Ten adult patients undergoing bronchoscopy for diagnostic purposes were given oral linezolid at a dosage of 600 mg twice a day for a total of six doses. Patients with active lung infection were excluded from the study. Flexible bronchoscopy was carried out between 2 and 8 h after the last dose of linezolid. Bronchial biopsies and bronchoalveolar lavage were carried out and a simultaneous blood sample obtained. Linezolid levels were measured using high-performance liquid chromatography (HPLC). Mean concentrations of linezolid were 13.4 mg/L in serum, 10.7 mg/kg in mucosa, 8.1 mg/L in alveolar macrophages and 25.1 mg/L in epithelial lining fluid. The mean site/serum concentration ratios were 0.79 for bronchial mucosa, 0.71 for macrophages and 8.35 for epithelial lining fluid. The MIC90 /minimum inhibitory concentration/ (PubMed Abstract
In the present pilot study the effect of food ingestion on target site pharmacokinetics of linezolid /were investigated/. For this purpose ... free concentrations of linezolid at steady state /were determined/ in the interstitial space fluid of skeletal muscle and subcutaneous adipose tissue under fasting and non-fasting conditions in healthy volunteers (n = 9) by means of in vivo microdialysis. Ingestion of food led to a marked delay in the time to reach the peak concentration (T(max)), whereas the area under the concentration-time curve from 0 to 24 hr (AUC(0-24 hr)) remained unchanged. These data suggest that the rate of linezolid absorption is decreased by food intake. However, the overall extent of linezolid absorption and the distribution of linezolid were not affected. Tissue levels of linezolid appeared sufficiently high to eradicate pathogens with a minimum inhibitory concentration of PubMed Abstract
Animal and human pharmacokinetic studies have demonstrated that linezolid readily distributes to well-perfused tissues. The plasma protein binding of linezolid is approximately 31% and is concentration-independent. The volume of distribution of linezolid at steady-state averaged 40 to 50 liters in healthy adult volunteers.
Linezolid and its metabolites are excreted in the milk of lactating rats. Concentrations in milk were similar to those in maternal plasma. It is not known whether linezolid is excreted in human milk.
Approximately 65% of a dose eliminated via nonrenal clearance; renal clearance is low, suggesting net tubular reabsorption. Almost no linezolid is found in feces as unchanged drug. Linezolid and its metabolites removed by hemodialysis.