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Simultaneous determination of first-line anti-tuberculosis drugs and their major metabolic ratios by liquid chromatography/tandem mass spectrometry

Cited 61 time in Web of Science Cited 68 time in Scopus
Authors
Song, Sang Hoon; Jun, Sun Hee; Park, Kyoung Un; Yoon, Yeomin; Lee, Jae Ho; Kim, Jin Q; Song, Junghan
Issue Date
2007-03-07
Publisher
John Wiley & Sons
Citation
Rapid Commun Mass Spectrom. 2007;21(7):1331-8.
Keywords
Antitubercular Agents/*blood/*pharmacokineticsBlood Chemical Analysis/*methodsChromatography, High Pressure Liquid/*methodsComplex Mixtures/bloodHumansIsoniazid/*analogs & derivatives/bloodRifampin/*analogs & derivatives/bloodSpectrometry, Mass, Electrospray Ionization/*methods
Abstract
Monitoring of anti-tuberculosis drug concentrations and dose adjustment can be helpful in cases that show poor response to treatment. Here, we describe a method that can rapidly and simultaneously measure the blood concentrations of four anti-tuberculosis drugs (isoniazid, rifampicin, pyrazinamide, and ethambutol) and two major metabolic ratios (acetylisoniazid/isoniazid and 25-desacetylrifampicin/rifampicin) using high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS). A C18 reversed-phase column and gradients of methanol in 0.3% formic acid and water were used for HPLC separation. The drug concentrations were determined by multiple reaction monitoring in positive ion mode and the assay performance was evaluated. We determined peak concentration ranges for each drug and acetylisoniazid/isoniazid and 25-desacetylrifampicin/rifampicin ratios by analyzing 2-h post-dose samples in patients treated with standard dosing as a first-line treatment. The preparation of 20 samples including two steps of deproteinization with 50% and 100% methanol was performed within 20 min and chromatographic separation was achieved within 4 min/sample. Interassay calibration variability data obtained over concentrations of 0-8 microg/mL for isoniazid and ethambutol and 0-80 microg/mL for rifampicin and pyrazinamide showed a linear and reproducible curve. Within-run and between-run imprecision (CVs) were 1.9-5.5% and 3.5-10.5% and the lower limits of detection and quantification were 0.01-0.5 microg/mL and 0.05-1.0 microg/mL, respectively. The isoniazid concentration was found to be inversely correlated to the acetylisoniazid/isoniazid ratio (R=-0.739, P<0.001). The devised method allows for the simple, rapid, sensitive and reproducible quantification of isoniazid, rifampicin, pyrazinamide, ethambutol and their two metabolic ratios and should be helpful for therapeutic drug monitoring in tuberculosis patients.
ISSN
0951-4198 (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17340570

http://hdl.handle.net/10371/11889
DOI
https://doi.org/10.1002/rcm.2961
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College of Medicine/School of Medicine (의과대학/대학원)Laboratory Medicine (검사의학전공)Journal Papers (저널논문_검사의학전공)
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