Abstract
A study was undertaken to determine the neuroprotective potential of Linezolid (LIN) in an animal model. Female Sprague–Dawley rats were either given a single (100 mg/kg) dose or treated daily for 4 weeks. A validated LC–MS/MS method was used to measure LIN levels in plasma and brain, this was paired with mass spectrometry imaging to determine the tissue spatial distribution of the drug. The results showed that after a single dose there was poor penetration of the drug into the brain. With multiple doses there were high tissue levels, with the drug reaching steady state in subsequent weeks. LIN displayed a promising distribution pattern with localisation in the brainstem. Systemic circulation is fed into the brain by the carotid and vertebral arteries which enter through the brain stem, therefore high drug concentrations is this area may protect against infectious agents entering via this route.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ager S, Gould K (2012) Clinical update on linezolid in the treatment of Gram-positive bacterial infections. Infect Drug Resist 5:87–102
Baijnath S, Naiker S, Shobo A, Moodley C, Adamson J, Ngcobo B, Bester LA, Singh S, Kruger HG, Naicker T (2015) Evidence for the presence of clofazimine and its distribution in the healthy mouse brain. J Mol Histol 46:439–442
Beer R, Engelhardt KW, Pfausler B, Broessner G, Helbok R, Lackner P, Brenneis C, Kaehler ST, Georgopoulos A, Schmutzhard E (2007) Pharmacokinetics of intravenous linezolid in cerebrospinal fluid and plasma in neurointensive care patients with staphylococcal ventriculitis associated with external ventricular drains. Antimicrob Agents Chemother 51:379–382
Chandrasekhar S, Babu G, Mohapatra DK (2011) Practical Syntheses of (2S)-R207910 and (2R)-R207910. Eur J Org Chem 2011:2057–2061
Coleman MT, Chen RY, Lee M, Lin PL, Dodd LE, Maiello P, Via LE, Kim Y, Marriner G, Dartois V (2014) PET/CT imaging reveals a therapeutic response to oxazolidinones in macaques and humans with tuberculosis. Sci Transl Med 6:265ra167
Dryden MS (2011) Linezolid pharmacokinetics and pharmacodynamics in clinical treatment. J Antimicrob Chemother 66:iv7–iv15
Gee T, Ellis R, Marshall G, Andrews J, Ashby J, Wise R (2001) Pharmacokinetics and tissue penetration of linezolid following multiple oral doses. Antimicrob Agents Chemother 45:1843–1846
Krzysztofiak A, Bozzola E, Lancella L, Quondamcarlo A, Gesualdo F, Ugazio AG (2010) Linezolid therapy of brain abscess. Pediatr Infect Dis J 29:1063–1064
MacGowan AP (2003) Pharmacokinetic and pharmacodynamic profile of linezolid in healthy volunteers and patients with Gram-positive infections. J Antimicrob Chemother 51:ii17–ii25
Magee DJ (2014) Orthopedic physical assessment. Elsevier Health Sci 3:148–152
Marra A, Lamb L, Medina I, George D, Gibson G, Hardink J, Rugg J, Van Deusen J, O’Donnell JP (2012) Effect of linezolid on the 50 % lethal dose and 50 % protective dose in treatment of infections by Gram-negative pathogens in naive and immunosuppressed mice and on the efficacy of ciprofloxacin in an acute murine model of septicemia. Antimicrob Agents Chemother 56:4671–4675
Moellering RC (2003) Linezolid: the first oxazolidinone antimicrobial. Ann Intern Med 138:135–142
Munyeza CF, Shobo A, Baijnath S, Bratkowska D, Naiker S, Bester LA, Singh SD, Maguire GE, Kruger HG, Naicker T (2015) Rapid and widespread distribution of doxycycline in rat brain: a mass spectrometric imaging study. Xenobiotica 46:385–392
Myrianthefs P, Markantonis SL, Vlachos K, Anagnostaki M, Boutzouka E, Panidis D, Baltopoulos G (2006) Serum and cerebrospinal fluid concentrations of linezolid in neurosurgical patients. Antimicrob Agents Chemother 50:3971–3976
Schecter G, Scott C, True L, Raftery A, Flood J, Mase S (2010) Linezolid in the treatment of multidrug-resistant tuberculosis. Clin Infect Dis 50:49–55
Seetharamsingh B, Ramesh R, Dange SS, Khairnar PV, Singhal S, Upadhyay D, Veeraraghavan S, Viswanadha S, Vakkalanka S, Reddy DS (2015) Design, synthesis, and identification of silicon incorporated oxazolidinone antibiotics with improved brain exposure. ACS Med Chem Lett 6:1105–1110
Shaikh Z, Peloquin CA, Ericsson CD (2000) Successful treatment of vancomycin-resistant Enterococcus faecium meningitis with linezolid: case report and literature review. Scand J Infect Dis 33:375–379
Shobo A, Baijnath S, Bratkowska D, Naiker S, Somboro AM, Bester LA, Singh SD, Naicker T, Kruger HG, Govender T (2015a) MALDI MSI and LC-MS/MS: Towards preclinical determination of the neurotoxic potential of fluoroquinolones. Drug Test Anal. doi:10.1002/dta.1862
Shobo A, Bratkowska D, Baijnath S, Naiker S, Bester LA, Singh SD, Maguire GEM, Kruger HG, Govender T (2015b) Visualization of time-dependent distribution of rifampicin in rat brain using MALDI MSI and quantitative LCMS/MS. Assay Drug Dev Technol 13:277–284
Shobo A, Bratkowska D, Baijnath S, Naiker S, Somboro AM, Bester LA, Singh SD, Naicker T, Kruger HG, Govender T (2015c) Tissue distribution of pretomanid in rat brain via mass spectrometry imaging. Xenobiotica 46:247–252
Slatter J, Adams L, Bush E, Chiba K, Daley-Yates P, Feenstra K, Koike S, Ozawa N, Peng G, Sams J (2002) Pharmacokinetics, toxicokinetics, distribution, metabolism and excretion of linezolid in mouse, rat and dog. Xenobiotica 32:907–924
Tsona A, Metallidis S, Foroglou N, Selviaridis P, Chrysanthidis T, Lazaraki G, Papaioannou M, Nikolaidis J, Nikolaidis P (2010) Linezolid penetration into cerebrospinal fluid and brain tissue. J Chemother 22:17–19
Tukaram SA, Smith AA, Muthu AK, Chugh Y, Manavalan R (2007) Systemic safety evaluation of central nervous system function in the rat by oral administration of linezolid. Pharmacol 2: 90–102
Villani P, Regazzi M, Marubbi F, Viale P, Pagani L, Cristini F, Cadeo B, Carosi G, Bergomi R (2002) Cerebrospinal fluid linezolid concentrations in postneurosurgical central nervous system infections. Antimicrob Agents Chemother 46:936–937
Youssef S, Hachem R, Chemaly R, Adachi J, Ying J, Rolston K, Raad I (2008) The role of vitamin B6 in the prevention of haematological toxic effects of linezolid in patients with cancer. J Antimicrob Chemother 61:421–424
Zhang X, Falagas ME, Vardakas KZ, Wang R, Qin R, Wang J, Liu Y (2015) Systematic review and meta-analysis of the efficacy and safety of therapy with linezolid containing regimens in the treatment of multidrug-resistant and extensively drug-resistant tuberculosis. J Thorac Dis 7:603–615
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Baijnath, S., Shobo, A., Bester, L.A. et al. Neuroprotective potential of Linezolid: a quantitative and distribution study via mass spectrometry. J Mol Hist 47, 429–435 (2016). https://doi.org/10.1007/s10735-016-9685-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10735-016-9685-0