Linelid Mechanism of Action

Pharmacotherapeutic group: Antibacterial agents for systemic use.
Pharmacology: Pharmacodynamics: Linezolid is a synthetic antibacterial agent, belonging to a new class of antimicrobial drugs-oxazolidinones. In vitro, it is active against aerobic gram-positive, some gram-negative bacteria and anaerobic microorganisms.
Linezolid selectively inhibits bacterial protein synthesis in bacterial cells via specific mechanism of action. Particularly, it binds to area on the bacterial ribosome (23S subunit to 50S), and prevents the formation of functional 70S initiation complex, which is a significant component of the translation process.
The following microorganisms are sensitive to Linezolid: gram-positive aerobes Enterococcus faecalis, Enterococcus faecium*, Staphylococcus aureus*, coagulase-negative staphylococci Streptococcus agalactiae*, Streptococcus pneumoniae*, Streptococcus pyogenes*, streptococci of group C, streptococci of group G; gram-positive anaerobes Clostridium perfringens, Peptostreptococcus anaerobius, Peptostreptococcus spp.
Resistant microorganisms: Haemophilus influenza, Moraxella catarrhalis, Neisseria species Enterobacteriaceae, Pseudomonas spp.
Pharmacokinetics: (S)-Linezolid is biologically active and metabolized in the body with formation of inactive derivatives. Solubility of Linezolid in water is approximately 3 mg/mL and doesn't depend on pH in the range 3-9. Maximum (C_max) and minimum (C_min) Linezolid plasma concentrations (mean value and [standard deviation]) at steady state after drug intravenous administration twice a day at the dose of 600 mg were 15.1 [2.5] mg/L and 3.68 [2.68] mg/L, respectively.
Distribution: At the average volume of distribution ate steady state accounts for 40-50 L in healthy volunteers, corresponding to total body water. Grade of binding to plasma proteins accounts for approximately 31%, and doesn't depend on drug plasma concentration.
Linezolid concentrations were found in different body fluids in limited number of volunteers within conducting the studies under course use of the drug. The ratio of Linezolid concentrations in saliva relative to plasma was 1.2:1, and for sweat relative to plasma was from 0.55:1, respectively. The ratio of concentrations in epithelial lining fluid and in lung alveolar cells to maximum plasma concentration at steady state was 4.5:1 and 0.15:1, respectively.
Pharmacokinetic data obtained in pediatric patients with ventriculoperitoneal shunts, demonstrated variability of Linezolid concentrations in cerebrospinal fluid after single and multiple drug administration; steady drug therapeutic concentration in cerebrospinal fluid has not been achieved and maintained. So, the use of Linezolid for empiric antimicrobial therapy in pediatric patients with infections of central nervous system is not recommended.
Metabolism: Linezolid is primarily metabolized by oxidation of morpholine ring that leads to formation of two inactive carboxylic acid derivatives with opened ring: aminoethoxyacetic acid metabolite (PNU-142300) and hydroxyethyl glycine metabolite (PNU-142586). Hydroxyethyl glycine metabolite (PNU-142586) is a predominant human metabolite, formed by means of non-enzymatic process. Aminoethoxyacetic acid metabolite (PNU-142300) is defined in smaller quantity. Other "small" inactive metabolites were identified as well.
Elimination: In patients with normal renal function or with insignificantly or moderately expressed renal failure. Linezolid at steady state is primarily excreted with urine in form of metabolite PNU-142586 (40%), as unchanged (30%), and in form of metabolite PNU-142300 (10%). Unchanged drug is practically not found in feces, while part of each of main metabolites, PNU-142586 and PNU-142300, is 6% and 3%, respectively. Average Linezolid half-life is 5-7 hours. Non-renal clearance accounts for approximately 65% of Linezolid total clearance. Small degree of non-linearity in clearance was observed with increase in dose of Linezolid.
It is probably due to lower renal and non-renal drug clearance at high concentrations. However, changes in clearance were small and didn't affect the half-life.
Pharmacokinetics in special populations: Patients with renal failure: after single administration at dose of 600 mg, 7-8-fold increase of systemic exposure of two main Linezolid metabolite in plasma was observed in patients with severe renal failure (creatinine clearance <30 mL/min). But exposure value for area under curve "concentration-time" (AUC) for parent compound was unchanged. Though some quantity of main Linezolid metabolites is removed from the body by hemodialysis, level of metabolites in plasma after single administration at dose of 600 mg was still high after hemodialysis as compared to patients with normal renal function or with insignificant or moderately expressed renal failure. In 24 patients with expressed renal failure, 21 from which was on regular hemodialysis, maximum plasma concentration of two main metabolites in some days of drug administration were approximately 10-fold the concentrations observed in patients with normal renal function. Maximum Linezolid plasma levels were not altered. Clinical significance of these observations was not determined, as currently only limited data are available.
Patients with liver failure: limited data show that pharmacokinetics of Linezolid and their metabolites PNU-142300 and PNU-142586 is not altered in patients with mild or moderately expressed liver failure (Child-Pugh class A or B). Linezolid pharmacokinetic attributes in patients with severe liver failure (Child-Pugh class C) were not investigated. However, as Linezolid is metabolized by means of non-enzymatic process, it's not expected that impaired liver function could significantly affect its metabolism.
Elderly: pharmacokinetics in Linezolid in persons over 65 years and older is not substantially changed.
Women: lower volume of distribution is more specific for women than for men, and mean clearance (corrected according to body weight) is decreased approximately by 20%. Plasma concentrations are higher in women that could be partially explained by difference in body weight. As half-life mean value in women and men doesn't not substantially differ, it's not expected that plasma concentration in women will be substantially differ, it's not expected that plasma concentration in women will be substantially higher than well-tolerated one, and the dose adjustment is not necessary.