title: Global Urine Metabolomics in Patients Treated with First-Line Tuberculosis Drugs and Identification of a Novel Metabolite of Ethambutol.
abstract: Population level variation of drug metabolism phenotype (DMP) has great implications in treatment outcome, drug-related side effects, and resistance development. In this study, we used a gas chromatography-time of flight-mass spectrometry (GC-TOF-MS)-based untargeted urine metabolomics approach to understand the DMP of a tuberculosis (TB) patient cohort (n= 20) from Tripura, a state in the northeastern part of India. Urine samples collected at different postdose time points (2 h, 6 h, 12 h, 24 h, 36 h, and 48 h) from these newly diagnosed TB patients receiving first-line anti-TB drugs were analyzed, and we have successfully detected three of the four first-line drugs,viz, isoniazid (INH), ethambutol (ETB), and pyrazinamide (PZA). The majority of their known metabolites, acetyl-isoniazid (AcINH), isonicotinic acid (INA), isonicotinuric acid (INTA), 2,2'-(ethylenediimino)-dibutyric acid (EDBA), 5-hydroxypyrazinamide (5OH-PZA), pyrazinoic acid (POA), and 5-hydroxypyrazinoic acid (5OH-POA), were also detected. Analyzing the variation in abundances of drugs and their known metabolites and calculating the metabolic ratios in these samples, we offer comprehensive DMP information on this small patient cohort that represents Tripura, India. The majority (75%) of these patients are found to be slow acetylators of INH. The average metabolic ratios of POA/PZA and 5OH-POA/POA are 3.16 ± 3.03 and 6.09 ± 6.15, respectively. Employing correlation analysis of the metabolomics metadata and a manual prediction of drug catabolism, we have proposed 2-aminobutyric acid (AABA) as a novel metabolite of ETB. These observations indicate the usefulness of GC-MS-based metabolomics to characterize the DMP at a population level and also to identify novel drug metabolites.
authors.affiliation: Immunology group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India mrinaldu@gmail.com dranjan_gb@yahoo.in ranjan@icgeb.res.in.
authors.forename: Mrinal Kumar
authors.initials: MK
authors.lastname: Das
authors.affiliation: Immunology group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Arya
authors.affiliation: Department of Tuberculosis and Respiratory Disease, Agartala Government Medical College, Agartala, Tripura, India.
authors.forename: Sanjita
authors.initials: S
authors.lastname: Debnath
authors.affiliation: Department of Tuberculosis and Respiratory Disease, Agartala Government Medical College, Agartala, Tripura, India.
authors.forename: Rahul
authors.initials: R
authors.lastname: Debnath
authors.affiliation: Department of Tuberculosis and Respiratory Disease, Agartala Government Medical College, Agartala, Tripura, India.
authors.forename: Anindita
authors.initials: A
authors.lastname: Lodh
authors.affiliation: Immunology group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India School of Life Sciences, Sambalpur University, Sambalpur, Odisha, India.
authors.forename: Subasa Chandra
authors.initials: SC
authors.lastname: Bishwal
authors.affiliation: Department of Tuberculosis and Respiratory Disease, Agartala Government Medical College, Agartala, Tripura, India mrinaldu@gmail.com dranjan_gb@yahoo.in ranjan@icgeb.res.in.
authors.forename: Anjan
authors.initials: A
authors.lastname: Das
authors.affiliation: Immunology group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India mrinaldu@gmail.com dranjan_gb@yahoo.in ranjan@icgeb.res.in.
authors.forename: Ranjan Kumar
authors.initials: RK
authors.lastname: Nanda
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000613:Aminobutyrates / Q000652:urine*; D000995:Antitubercular Agents / Q000627:therapeutic use / Q000652:urine*; D001711:Biotransformation; D016022:Case-Control Studies; D002849:Chromatography, Gas; D004977:Ethambutol / Q000627:therapeutic use / Q000652:urine*; D005260:Female; D006801:Humans; D007194:India; D007538:Isoniazid / Q000627:therapeutic use / Q000652:urine; D008297:Male; D055432:Metabolomics; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000502:physiology; D011718:Pyrazinamide / Q000627:therapeutic use / Q000652:urine; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000382:microbiology / Q000652:urine*
chemical_list: D000613:Aminobutyrates; D000995:Antitubercular Agents; D011718:Pyrazinamide; C012223:alpha-aminobutyric acid; D004977:Ethambutol; D007538:Isoniazid
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