We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×

Developing an isotope dilution UHPLC–MS/MS method to quantify linezolid in human plasma: application to therapeutic drug monitoring

    Yanping Guan‡

    Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, PR China

    ‡Authors contributed equally

    Search for more papers by this author

    ,
    Xiaoxia Yu‡

    Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, PR China

    ‡Authors contributed equally

    Search for more papers by this author

    ,
    Ying Wang

    Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, PR China

    ,
    Qinhai Li

    Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, PR China

    ,
    Dan Liang

    Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, PR China

    ,
    Hua Zhu

    Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, PR China

    ,
    Chuxiong Chen

    Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, PR China

    ,
    Boyu Dong

    Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, PR China

    ,
    Jiebin Ou

    Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, PR China

    ,
    Kaifeng Qiu

    Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, PR China

    &
    Junyan Wu

    *Author for correspondence: Tel.: +020 81332427;

    E-mail Address: wujunyan@mail.sysu.edu.cn

    Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, PR China

    Published Online:https://doi.org/10.4155/bio-2020-0098

    Aim: To optimize clinical efficacy and reduce the drug-exposure-related toxicity of linezolid, whose concentrations show wide inter-variabilities, a simple and reliable quantitative assay for therapeutic drug monitoring is necessary. Results: A UHPLC–MS/MS assay has been established for determination of linezolid in human plasma and fully validated according to the US FDA guidelines. After a simple, isotope-dilluted precipitation with methanol, the analytes were separated by a straightforward isocratic mode and the MS/MS was conducted under the ESI+ mode fitted with SRM. The calibration curves proved acceptable linearity in the range of 0.1–30.0 µg/ml. Conclusion: The present assay is currently used in routine clinical practice, being applied to therapeutic drug monitoring and helps to optimize individual dosing regimens and manage adverse effects in ICU patients.

    Papers of special note have been highlighted as: • of interest

    Reference

    • 1. Hashemian SM, Farhadi T, Ganjparvar M. Linezolid: a review of its properties, function, and use in critical care. Drug Des. Devel. Ther. 12, 1759–1767 (2018).
    • 2. Durand GA, Raoult D, Dubourg G. Antibiotic discovery: history, methods and perspectives. Int. J. Antimicrob. Agents 53(4), 371–382 (2019).
    • 3. Sazdanovic P, Jankovic SM, Kostic M, Dimitrijevic A, Stefanovic S. Pharmacokinetics of linezolid in critically ill patients. Expert Opin. Drug Metab. Toxicol. 12(6), 595–600 (2016).
    • 4. Trotman RL, Williamson JC, Shoemaker DM, Salzer WL. Antibiotic dosing in critically ill adult patients receiving continuous renal replacement therapy. Clin. Infect. Dis. 41(8), 1159–1166 (2005).
    • 5. Stalker DJ, Jungbluth GL. Clinical pharmacokinetics of linezolid, a novel oxazolidinone antibacterial. Clin. Pharmacokinet. 42(13), 1129–1140 (2003).
    • 6. Pea F, Furlanut M, Cojutti P et al. Therapeutic drug monitoring of linezolid: a retrospective monocentric analysis. Antimicrob. Agents Chemother. 54(11), 4605–4610 (2010).
    • 7. Pea F, Viale P, Cojutti P, Del Pin B, Zamparini E, Furlanut M. Therapeutic drug monitoring may improve safety outcomes of long-term treatment with linezolid in adult patients. J. Antimicrob. Chemother. 67(8), 2034–2042 (2012). • Gives an introduction of necessity of therapeutic drug monitoring for linezolid.
    • 8. Cepeda JA, Whitehouse T, Cooper B et al. Linezolid versus teicoplanin in the treatment of Gram-positive infections in the critically ill: a randomized, double-blind, multicentre study. J. Antimicrob. Chemother. 53(2), 345–355 (2004).
    • 9. Rayner CR, Forrest A, Meagher AK, Birmingham MC, Schentag JJ. Clinical pharmacodynamics of linezolid in seriously ill patients treated in a compassionate use programme. Clin. Pharmacokinet. 42(15), 1411–1423 (2003).
    • 10. Smith PF, Birmingham MC, Noskin GA et al. Safety, efficacy and pharmacokinetics of linezolid for treatment of resistant Gram-positive infections in cancer patients with neutropenia. Ann. Oncol. 14(5), 795–801 (2003).
    • 11. Kishor K, Dhasmana N, Kamble SS, Sahu RK. Linezolid induced adverse drug reactions – an update. Curr. Drug Metab. 16(7), 553–559 (2015).
    • 12. Cattaneo D, Orlando G, Cozzi V et al. Linezolid plasma concentrations and occurrence of drug-related haematological toxicity in patients with Gram-positive infections. Int. J. Antimicrob. Agents 41(6), 586–589 (2013).
    • 13. Cattaneo D, Gervasoni C, Cozzi V, Castoldi S, Baldelli S, Clementi E. Therapeutic drug management of linezolid: a missed opportunity for clinicians? Int. J. Antimicrob. Agents 48(6), 728–731 (2016).
    • 14. Zoller M, Maier B, Hornuss C et al. Variability of linezolid concentrations after standard dosing in critically ill patients: a prospective observational study. Crit. Care 18(4), 374–385 (2014).
    • 15. Zander J, Maier B, Zoller M, Teupser D, Vogeser M. Quantification of linezolid in serum by LC–MS/MS using semi-automated sample preparation and isotope dilution internal standardization. Clin. Chem. Lab. Med. 52(3), 381–389 (2014). • The current assay was improved based on this published method.
    • 16. La Marca G, Villanelli F, Malvagia S et al. Rapid and sensitive LC–MS/MS method for the analysis of antibiotic linezolid on dried blood spot. J. Pharm. Biomed. Anal. 67–68, 86–91 (2012).
    • 17. Phillips OA, Abdel-Hamid ME, Al-Hassawi NA. Determination of linezolid in human plasma by LC–MS-MS. Analyst 126(5), 609–614 (2001).
    • 18. Satyanarayana Raju T, Vishweshwari Kutty O, Ganesh V, Yadagiri Swamy P. A validated stability-indicating LC method for the separation of enantiomer and potential impurities of Linezolid using polar organic mode. J. Pharm. Anal. 2(4), 272–278 (2012).
    • 19. Souza E, Felton J, Crass RL, Hanaya K, Pai MP. Development of a sensitive LC–MS/MS method for quantification of linezolid and its primary metabolites in human serum. J. Pharm. Biomed. Anal. 178, 112968 (2020).
    • 20. Yin L, Feng Y, Tong J et al. Ultrahigh-throughput absolute quantitative analysis of linezolid in human plasma by direct analysis in real time mass spectrometry without chromatographic separation and its application to a pharmacokinetic study. Anal. Bioanal. Chem. 411(20), 5139–5148 (2019).
    • 21. Castoldi S, Cozzi V, Baldelli S, Fucile S, Clementi E, Cattaneo D. Comparison of the ARK immunoassay with high-performance liquid chromatography with ultraviolet detection for therapeutic drug monitoring of linezolid. Ther. Drug Monit. 40(1), 140–143 (2018).
    • 22. Hara S, Uchiyama M, Yoshinari M et al. A simple high-performance liquid chromatography for the determination of linezolid in human plasma and saliva. Biomed. Chromatogr. 29(9), 1428–1431 (2015).
    • 23. Hopfgartner G, Bourgogne E. Quantitative high-throughput analysis of drugs in biological matrices by mass spectrometry. Mass Spectrom. Rev. 22(3), 195–214 (2003).
    • 24. Van Dongen WD, Niessen WMA. LC-MS systems for quantitative bioanalysis. Bioanalysis 4(19), 2391–2399 (2012).
    • 25. US FDA. Bioanalytical Method Validation Guidance for Industry (2018). http://www.fda.gov/downloads/drugs/guidances/ucm070107.pdf
    • 26. Nukui Y, Hatakeyama S, Okamoto K et al. High plasma linezolid concentration and impaired renal function affect development of linezolid-induced thrombocytopenia. J. Antimicrob. Chemother. 68(9), 2128–2133 (2013).