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Review Article

Applications of mass spectrometry in drug metabolism: 50 years of progress

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Pages 71-87 | Received 11 Sep 2014, Accepted 17 Dec 2014, Published online: 02 Feb 2015

References

  • Anari MR, Sanchez RI, Bakhtiar R, et al. (2004). Integration of knowledge-based metabolic predictions with liquid chromatography data-dependent tandem mass spectrometry for drug metabolism studies: Application to studies on the biotransformation of indinavir. Anal Chem 76:823–832
  • Aubry AF, Christopher LJ, Wang J, et al. (2014). Reflecting on a decade of metabolite screening and monitoring. Bioanalysis 6:651–664
  • Baillie TA. (2009). Approaches to the assessment of stable and chemically reactive drug metabolites in early clinical trials. Chem Res Toxicol 22:263–266
  • Baillie TA, Davis MR. (1993). Mass spectrometry in the analysis of glutathione conjugates. Biol Mass Spectrom 22:319–325
  • Baillie TA, Pearson PG, Rashed MS, Howald WN. (1989). The use of mass spectrometry in the study of chemically-reactive drug metabolites. Application of MS/MS and LC/MS to the analysis of glutathione- and related S-linked conjugates of N-methylformamide. J Pharm Biomed Anal 7:1351–1360
  • Bakhoum SF, Agnes GR. (2005). Study of chemistry in droplets with net charge before and after Coulomb explosion: Ion-induced nucleation in solution and implications for ion production in an electrospray. Anal Chem 77:3189–3197
  • Ballard KD, Raftery MJ, Jaeschke H, Gaskell SJ. (1991). Multiple scan modes in the hybrid tandem mass spectrometric screening and characterization of the glutathione conjugate of 2-furamide. J Am Soc Mass Spectrom 2:55–68
  • Barbara JE, Castro-Perez JM. (2011). High-resolution chromatography/time-of-flight MSE with in silico data mining is an information-rich approach to reactive metabolite screening. Rapid Commun Mass Spectrom 25:3029–3040
  • Barber M, Bordoli RS, Sedgewick RD, Tyler AN. (1981). Fast atom bombardment of solids (F.A.B.): A new ion source for mass spectrometry. J Chem Soc Chem Commun 7:325–327
  • Bateman KP, Castro-Perez J, Wrona M, et al. (2007). MSE with mass defect filtering for in vitro and in vivo metabolite identification. Rapid Commun Mass Spectrom 21:1485–1496
  • Beckey HD. (1969). Field desorption mass spectrometry: A technique for the study of thermally unstable substances of low volatility. Int J Mass Spectrom Ion Phys 2:500–503
  • Bieri RH, Greaves J. (1987). Characterization of benzo(a)pyrene metabolites by high performance liquid chromatography-mass spectrometry with a direct liquid introduction interface and using negative chemical ionization. Biomed Environ Mass Spectrom 14:555–561
  • Brown SY, Garland WA, Fukuda EK. (1990). Isolation and characterization of an unusual glucuronide conjugate of rimantadine. Drug Metab Dispos 18:546–547
  • Caldwell GW, Yan Z, Tang W, et al. (2009). ADME optimization and toxicity assessment in early- and late-phase drug discovery. Curr Top Med Chem 9:965–980
  • Caprioli RM. (1990). Bombardment mass spectrometry. Anal Chem 62:477A–485A
  • Caprioli RM, Lin SN. (1990). On-line analysis of penicillin blood levels in the live rat by combined microdialysis/fast-atom bombardment mass spectrometry. Proc Natl Acad Sci USA 87:240–243
  • Castro-Perez J, Plumb R, Granger JH, et al. (2005). Increasing throughput and information content for in vitro drug metabolism experiments using ultra-performance liquid chromatography coupled to a quadrupole time-of-flight mass spectrometer. Rapid Commun Mass Spectrom 19:843–848
  • Castro-Perez JM. (2007). Current and future trends in the application of HPLC-MS to metabolite-identification studies. Drug Discov Today 12:249–256
  • Chen C, Gonzalez FJ, Idle JR. (2007). LC-MS-based metabolomics in drug metabolism. Drug Metab Rev 39:581–597
  • Chen C, Krausz KW, Idle JR, Gonzalez FJ. (2008). Identification of novel toxicity-associated metabolites by metabolomics and mass isotopomer analysis of acetaminophen metabolism in wild-type and Cyp2e1-null mice. J Biol Chem 283:4543–4559
  • Chen WG, Zhang C, Avery MJ, Fouda HG. (2001). Reactive metabolite screen for reducing candidate attrition in drug discovery. Adv Exp Med Biol 500:521–524
  • Chindarkar NS, Wakefield MR, Stone JA, Fitzgerald RL. (2014). Liquid chromatography high-resolution TOF analysis: Investigation of MSE for broad-spectrum drug screening. Clin Chem 60:1115–1125
  • Clarke NJ, Rindgen D, Korfmacher WA, Cox KA. (2001). Systematic LC/MS metabolite identification in drug discovery. Anal Chem 73:430A–439A
  • Cuyckens F, Hurkmans R, Castro-Perez JM, et al. (2009). Extracting metabolite ions out of a matrix background by combined mass defect, neutral loss and isotope filtration. Rapid Commun Mass Spectrom 23:327–332
  • De Brabander HF, De Wasch K, Impens S, et al. (2001). Gas chromatography–mass spectrometry for residue analysis: Some basic concepts. Chromatogr Sci Ser 86:441–454
  • De Souza DP. (2013). Detection of polar metabolites through the use of gas chromatography-mass spectrometry. Methods Mol Biol 1055:29–37
  • Dempster AJ. (1918). A new method of positive ray analysis. Phys Rev 11:316–325
  • Dickinson DA, Forman HJ. (2002). Cellular glutathione and thiols metabolism. Biochem Pharmacol 64:1019–1026
  • Dieckhaus CM, Fernández-Metzler CL, King R, et al. (2005). Negative ion tandem mass spectrometry for the detection of glutathione conjugates. Chem Res Toxicol 18:630–638
  • Du F, Ruan Q, Zhu M, Xing J. (2013). Detection and characterization of ticlopidine conjugates in rat bile using high-resolution mass spectrometry: Applications of various data acquisition and processing tools. J Mass Spectrom 48:413–422
  • Fang ZZ, Gonzalez FJ. (2014). LC-MS-based metabolomics: An update. Arch Toxicol 88:1491–1502
  • Fernández-Metzler CL, Owens KG, Baillie TA, King RC. (1999). Rapid liquid chromatography with tandem mass spectrometry-based screening procedures for studies on the biotransformation of drug candidates. Drug Metab Dispos 27:32–40
  • Garland WA, Trager WF, Nelson SD. (1974). Direct (non-chromatographic) quantification of drugs and their metabolites from human plasma utilizing chemical ionization mass spectrometry and stable isotope labeling: Quinidine and lidocaine. Biomed Mass Spectrom 1:124–129
  • Grabenauer M, Krol WL, Wiley JL, Thomas BF. (2012). Analysis of synthetic cannabinoids using high-resolution mass spectrometry and mass defect filtering: Implications for nontargeted screening of designer drugs. Anal Chem 84:5574–5581
  • Haroldsen PE, Reilly MH, Hughes H, et al. (1988). Characterization of glutathione conjugates by fast atom bombardment/tandem mass spectrometry. Biomed Environ Mass Spectrom 15:615–621
  • Henion J, Skrabalak D, Dewey E, Maylin G. (1983). Micro LC/MS in drug analysis and metabolism studies. Drug Metab Rev 14:961–1003
  • Hop CECA, Prakash C. (2005). Metabolite identification by LC–MS: Applications in drug discovery and development. In: Chowdhury SK, ed. Identification and quantification of drugs, metabolites and metabolizing enzymes by LC–MS. New York: Elsevier, 123–158
  • Hopfgartner G, Husser C, Zell M. (2003). Rapid screening and characterization of drug metabolites using a new quadrupole-linear ion trap mass spectrometer. J Mass Spectrom 38:138–150
  • Hopfgartner G, Tonoli D, Varesio E. (2012). High-resolution mass spectrometry for integrated qualitative and quantitative analysis of pharmaceuticals in biological matrices. Anal Bioanal Chem 402:2587–2596
  • Hopfgartner G, Varesio E, Tschäppät V, et al. (2004). Triple quadrupole linear ion trap mass spectrometer for the analysis of small molecules and macromolecules. J Mass Spectrom 39:845–855
  • Jian W, Yao M, Wen B, Zhu M. (2011). Use of triple quadrupole–linear ion trap mass spectrometry as a single LC–MS platform in drug metabolism and pharmacokinetics studies. In: Lee M, Zhu, M, eds. Mass spectrometry in drug metabolism and disposition: Basic principles and applications. London (UK): John Wiley & Sons Ltd., 483–524 (Chapter 15)
  • Jian W, Yao M, Zhang D, Zhu M. (2009). Rapid detection and characterization of in vitro and urinary N-acetyl-l-cysteine conjugates using quadrupole-linear ion trap mass spectrometry and polarity switching. Chem Res Toxicol 22:1246–1255
  • Johnson CH, Patterson AD, Idle JR, Gonzalez FJ. (2012). Xenobiotic metabolomics: Major impact on the metabolome. Annu Rev Pharmacol Toxicol 52:37–56
  • King R, Fernandez-Metzler C. (2006). The use of Qtrap technology in drug metabolism. Curr Drug Metab 7:541–545
  • Kola I, Landis J. (2004). Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 3:711–715
  • Kwok DW, Pillai G, Vaughan R, et al. (1990). Preparative high-performance liquid chromatography and preparative thin-layer chromatography isolation of tocainide carbamoyl-O-beta-d-glucuronide: Structural characterization by gas chromatography-mass spectrometry and fast atom bombardment-mass spectrometry. J Pharm Sci 79:857–861
  • Laine R. (2008). Metabolic stability: Main enzymes involved and best tools to assess it. Curr Drug Metab 9:921–927
  • Lee MS, Kerns EH. (1999). LC/MS applications in drug development. Mass Spectrom Rev 18:187–279
  • Liang Y, Wang G, Xie L, Sheng L. (2011a). Recent development in liquid chromatography/mass spectrometry and emerging technologies for metabolite identification. Curr Drug Metab 12:329–344
  • Liang Y, Xiao W, Dai C, et al. (2011b). Structural identification of the metabolites for strictosamide in rats bile by an ion trap-TOF mass spectrometer and mass defect filter technique. J Chromatogr B Analyt Technol Biomed Life Sci 879:1819–1822
  • Liu T, Du F, Zhu F, Xing J. (2011). Metabolite identification of artemether by data-dependent accurate mass spectrometric analysis using an LTQ-Orbitrap hybrid mass spectrometer in combination with the online hydrogen/deuterium exchange technique. Rapid Commun Mass Spectrom 25:3303–3313
  • Luijten W, Damien G, Marchand B, Capart J. (1988). Analysis of almitrine and its metabolites in plasma using on-line fast atom bombardment liquid chromatography/mass spectrometry. Biomed Environ Mass Spectrom 16:93–97
  • Ma L, Wen B, Ruan Q, Zhu M. (2008a). Rapid screening of glutathione-trapped reactive metabolites by linear ion trap mass spectrometry with isotope pattern-dependent scanning and postacquisition data mining. Chem Res Toxicol 21:1477–1483
  • Ma S, Chowdhury SK. (2012). Application of LC-high-resolution MS with ‘intelligent’ data mining tools for screening reactive drug metabolites. Bioanalysis 4:501–510
  • Ma S, Chowdhury SK. (2013). Data acquisition and data mining techniques for metabolite identification using LC coupled to high-resolution MS. Bioanalysis 5:1285–1297
  • Ma S, Chowdhury SK, Alton KB. (2006). Application of mass spectrometry for metabolite identification. Curr Drug Metab 7:503–523
  • Ma S, Li Z, Lee KJ, Chowdhury SK. (2010). Determination of exposure multiples of human metabolites for MIST assessment in preclinical safety species without using reference standards or radiolabeled compounds. Chem Res Toxicol 23:1871–1873
  • Ma S, Zhu M. (2009). Recent advances in applications of liquid chromatography-tandem mass spectrometry to the analysis of reactive drug metabolites. Chem Biol Interact 179:25–37
  • Ma X, Chen C, Krausz KW, et al. (2008b). A metabolomic perspective of melatonin metabolism in the mouse. Endocrinology 149:1869–1879
  • Mahajan MK, Evans CA. (2008). Dual negative precursor ion scan approach for rapid detection of glutathione conjugates using liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom 22:1032–1040
  • Mauriala T, Chauret N, Oballa R, et al. (2005). A strategy for identification of drug metabolites from dried blood spots using triple-quadrupole/linear ion trap hybrid mass spectrometry. Rapid Commun Mass Spectrom 19:1984–1992
  • Meyer GM, Maurer HH. (2013). Qualitative metabolism assessment and toxicological detection of xylazine, a veterinary tranquilizer and drug of abuse, in rat and human urine using GC-MS, LC-MSn, and LC-HR-MSn. Anal Bioanal Chem 405:9779–9789
  • Mondello L, Tranchida PQ, Dugo P, Dugo G. (2008). Comprehensive two-dimensional gas chromatography–mass spectrometry: A review. Mass Spectrom Rev 27:101–124
  • Mortishire-Smith RJ, Castro-Perez JM, Yu K, et al. (2009). Generic dealkylation: A tool for increasing the hit-rate of metabolite rationalization, and automatic customization of mass defect filters. Rapid Commun Mass Spectrom 23:939–948
  • Mortishire-Smith RJ, O’Connor D, Castro-Perez JM, Kirby J. (2005). Accelerated throughput metabolic route screening in early drug discovery using high-resolution liquid chromatography/quadrupole time-of-flight mass spectrometry and automated data analysis. Rapid Commun Mass Spectrom 19:2659–2670
  • Munson MSB, Field FH. (1966). Chemical ionization mass spectrometry I. General introduction. J Am Chem Soc 88:2621–2630
  • Nassar AE, Adams PE. (2003). Metabolite characterization in drug discovery utilizing robotic liquid-handling, quadrupole time-of-flight mass spectrometry and in-silico prediction. Curr Drug Metab 4:259–271
  • Nedderman AN, Dear GJ, North S, et al. (2011). From definition to implementation: A cross-industry perspective of past, current and future MIST strategies. Xenobiotica 41:605–622
  • Nelson SD, Mitchell JR, Pohl LR. (1977). The use of chemical ionization mass spectrometry and stable isotope labeling in the analysis of reactive intermediates in drug metabolism. In: Frigerio A, Ghisalberti EL, eds. Mass spectrometry in drug metabolism, Plenum Press, New York. 237–276
  • Nelson SD, Trager WF. (2003). The use of deuterium isotope effects to probe the active site properties, mechanism of cytochrome P450-catalyzed reactions, and mechanisms of metabolically dependent toxicity. Drug Metab Dispos 31:1481–1498
  • Nelson SD, Vaishnav Y, Kambara H, Baillie TA. (1981). Comparative electron impact, chemical ionization and field desorption mass spectra of some thioether metabolites of acetaminophen. Biomed Mass Spectrom 8:244–251
  • Nocerini MR, Yost GS, Carlson JR, et al. (1985). Structure of the glutathione adduct of activated 3-methylindole indicates that an imine methide is the electrophilic intermediate. Drug Metab Dispos 13:690–694
  • Omichinski JG, Soderlund EJ, Dybing E, et al. (1988). Detection and mechanism of formation of the potent direct-acting mutagen 2-bromoacrolein from 1,2-dibromo-3-chloropropane. Toxicol Appl Pharmacol 92:286–294
  • Parker CE, de Wit JS, Smith RW, et al. (1988). Analysis of glutathione conjugates and related compounds by thermospray mass spectrometry. Biomed Environ Mass Spectrom 15:623–633
  • Parkinson A. (2001). Biotransformation of xenobiotics. In: Klaassen CD, ed. Casarett and Doul’s toxicology: The basic science of poisons. New York: McGraw-Hill, 133–224
  • Patterson AD, Gonzalez FJ, Idle JR. (2010). Xenobiotic metabolism: A view through the metabolometer. Chem Res Toxicol 23:851–860
  • Pearson PG, Howald WN, Nelson SD. (1990). Screening strategy for the detection of derivatized glutathione conjugates by tandem mass spectrometry. Anal Chem 62:1827–1836
  • Peterman SM, Duczak N Jr, Kalgutkar AS, et al. (2006). Application of a linear ion trap/orbitrap mass spectrometer in metabolite characterization studies: Examination of the human liver microsomal metabolism of the non-tricyclic anti-depressant nefazodone using data-dependent accurate mass measurements. J Am Soc Mass Spectrom 17:363–375
  • Plumb R, Castro-Perez J, Granger J, et al. (2004). Ultra-performance liquid chromatography coupled to quadrupole-orthogonal time-of-flight mass spectrometry. Rapid Commun Mass Spectrom 18:2331–2337
  • Pohl LR, Nelson SD, Garland WA, Trager WF. (1975). The rapid identification of a new metabolite of warfarin via a chemical ionization mass spectrometry ion doublet technique. Biomed Mass Spectrom 2:23–30
  • Porubek DJ, Nelson SD. (1988). A gas chromatographic/mass spectrometric assay for catechol estrogens in microsomal incubations: Comparison with a radiometric assay. Biomed Environ Mass Spectrom 15:157–161
  • Prakash C, Shaffer CL, Nedderman A. (2007). Analytical strategies for identifying drug metabolites. Mass Spectrom Rev 26:340–369
  • Prakash C, Soliman V. (1997). Metabolism and excretion of a novel antianxiety drug candidate, CP-93,393, in Long Evans rats. Differentiation of regioisomeric glucuronides by LC/MS/MS. Drug Metab Dispos 25:1288–1297
  • Rodrigues AD. (2008). Drug–drug interactions, In: Rodrigues AD, ed. Drugs and the pharmaceutical sciences. 2nd ed. New York: Informa Healthcare, USA Inc, 1–719
  • Ruan Q, Peterman S, Szewc MA, et al. (2008). An integrated method for metabolite detection and identification using a linear ion trap/Orbitrap mass spectrometer and multiple data processing techniques: Application to indinavir metabolite detection. J Mass Spectrom 43:251–261
  • Ruan Q, Zhu M. (2010). Investigation of bioactivation of ticlopidine using linear ion trap/orbitrap mass spectrometry and an improved mass defect filtering technique. Chem Res Toxicol 23:909–917
  • Sasame HA, Liberato DJ, Gillette JR. (1987). The formation of glutathione conjugate derived from propranolol. Drug Metab Dispos 15:349–355
  • Scott RPW, Scott CG, Munroe M, Hess J. (1974). Interface for on-line liquid chromatography–mass spectroscopy analysis. J Chromatogr 99:395–405
  • Shen BQ, Xu K, Liu L, et al. (2012). Conjugation site modulates the in vivo stability and therapeutic activity of antibody–drug conjugates. Nat Biotechnol 30:184–189
  • Shimizu A, Chiba M. (2013). Ion mobility spectrometry–mass spectrometry analysis for the site of aromatic hydroxylation. Drug Metab Dispos 41:1295–1299
  • Shimizu Y. (1984). Adduct ion formation in isobutane chemical ionization of aliphatic olefins. Mass Spectroscopy, 32:357–364
  • Siegel D, Meinema AC, Permentier H, et al. (2014). Integrated quantification and identification of aldehydes and ketones in biological samples. Anal Chem 86:5089–5100
  • Singh J, Petter RC, Baillie TA, Whitty A. (2011). The resurgence of covalent drugs. Nat Rev Drug Discov 10:307–317
  • Streeter AJ, Bjorge SM, Axworthy DB, et al. (1984). The microsomal metabolism and site of covalent binding to protein of 3′-hydroxyacetanilide, a nonhepatotoxic positional isomer of acetaminophen. Drug Metab Dispos 12:565–576
  • Taylor EW, Jia W, Bush M, Dollinger GD. (2002). Accelerating the drug optimization process: Identification, structure elucidation, and quantification of in vivo metabolites using stable isotopes with LC/MSn and the chemiluminescent nitrogen detector. Anal Chem 74:3232–3238
  • Tiller PR, Yu S, Bateman KP, et al. (2008a). Fractional mass filtering as a means to assess circulating metabolites in early human clinical studies. Rapid Commun Mass Spectrom 22:3510–3516
  • Tiller PR, Yu S, Castro-Perez J, et al. (2008b). High-throughput, accurate mass liquid chromatography/tandem mass spectrometry on a quadrupole time-of-flight system as a ‘first-line’ approach for metabolite identification studies. Rapid Commun Mass Spectrom 22:1053–1061
  • Tolonen A, Turpeinen M, Pelkonen O. (2009). Liquid chromatography–mass spectrometry in in vitro drug metabolite screening. Drug Discov Today 14:120–133
  • Tremaine LM, Stroh JG, Roofed RA. (1989). Characterization of a carbamic acid ester glucuronide of the secondary amine sertraline. Drug Metab Dispos 17:58–63
  • Wen B. (2012). Metabonomics in understanding drug metabolism and toxicity. In: Larry W, Peter K, eds. Part VII: Role of metabolism in toxicology and pharmacology of “Encyclopedia of Drug Metabolism and Interactions” vol. 4. London (UK): John Wiley & Sons Ltd, 1–29 (Chapter 9)
  • Wen B, Chen Y, Fitch WL. (2009). Metabolic activation of nevirapine in human liver microsomes: Dehydrogenation and inactivation of cytochrome P450 3A4. Drug Metab Dispos 37:1557–1562
  • Wen B, Coe KJ, Rademacher P, et al. (2008a). Comparison of in vitro bioactivation of flutamide and its cyano analogue: Evidence for reductive activation by human NADPH:cytochrome P450 reductase. Chem Res Toxicol 21:2393–2406
  • Wen B, Fitch WL. (2009a). Screening and characterization of reactive metabolites using glutathione ethyl ester in combination with Q-trap mass spectrometry. J Mass Spectrom 44:90–100
  • Wen B, Fitch WL. (2009b). Analytical strategies for the screening and evaluation of chemically reactive drug metabolites. Expert Opin Drug Metab Toxicol 5:39–55
  • Wen B, Ma L, Nelson SD, Zhu M. (2008b). High-throughput screening and characterization of reactive metabolites using polarity switching of hybrid triple quadrupole linear ion trap mass spectrometry. Anal Chem 80:1788–1799
  • Wen B, Ma L, Rodrigues AD, Zhu M. (2008c). Detection of novel reactive metabolites of trazodone: Evidence for CYP2D6-mediated bioactivation of m-chlorophenylpiperazine. Drug Metab Dispos 36:841–850
  • Wen B, Ma L, Zhu M. (2008d). Bioactivation of the tricyclic antidepressant amitriptyline and its metabolite nortriptyline to arene oxide intermediates in human liver microsomes and recombinant P450s. Chem Biol Interact 173:59–67
  • Wen B, Nelson SD. (2011). Common biotransformation reactions. In: Lee M, Zhu M, eds. Mass spectrometry in drug metabolism and disposition: Basic principles and applications. London (UK): John Wiley & Sons Ltd., 13–41 (Chapter 2)
  • Wrona M, Mauriala T, Bateman KP, et al. (2005). ‘All-in-one’ analysis for metabolite identification using liquid chromatography/hybrid quadrupole time-of-flight mass spectrometry with collision energy switching. Rapid Commun Mass Spectrom 19:2597–2602
  • Xia YQ, Miller JD, Bakhtiar R, et al. (2003). Use of a quadrupole linear ion trap mass spectrometer in metabolite identification and bioanalysis. Rapid Commun Mass Spectrom 17:1137–1145
  • Xie C, Zhong D, Yu K, Chen X. (2012). Recent advances in metabolite identification and quantitative bioanalysis by LC-Q-TOF MS. Bioanalysis 4:937–959
  • Xiong A, Yang F, Fang L, et al. (2014). Metabolomic and genomic evidence for compromised bile acid homeostasis by senecionine, a hepatotoxic pyrrolizidine alkaloid. Chem Res Toxicol 27:775–786
  • Yan Z, Caldwell GW, Maher N. (2008). Unbiased high-throughput screening of reactive metabolites on the linear ion trap mass spectrometer using polarity switch and mass tag triggered data-dependent acquisition. Anal Chem 80:6410–6422
  • Yao M, Ma L, Duchoslav E, Zhu M. (2009). Rapid screening and characterization of drug metabolites using multiple ion monitoring dependent product ion scan and postacquisition data mining on a hybrid triple quadrupole-linear ion trap mass spectrometer. Rapid Commun Mass Spectrom 23:1683–1693
  • Yao M, Ma L, Humphreys WG, Zhu M. (2008). Rapid screening and characterization of drug metabolites using a multiple ion monitoring-dependent MS/MS acquisition method on a hybrid triple quadrupole-linear ion trap mass spectrometer. J Mass Spectrom 43:1364–1375
  • Yu X, Cui D, Davis MR. (1999). Identification of in vitro metabolites of Indinavir by “intelligent automated LC-MS/MS” (INTAMS) utilizing triple quadrupole tandem mass spectrometry. J Am Soc Mass Spectrom 10:175–183
  • Zhang D, Cheng PT, Zhang H. (2007). Mass defect filtering on high resolution LC/MS data as a methodology for detecting metabolites with unpredictable structures: Identification of oxazole-ring opened metabolites of muraglitazar. Drug Metab Lett 1:287–292
  • Zhang H, Ma L, He K, Zhu M. (2008a). An algorithm for thorough background subtraction from high-resolution LC/MS data: Application to the detection of troglitazone metabolites in rat plasma, bile, and urine. J Mass Spectrom 43:1191–1200
  • Zhang H, Patrone L, Kozlosky J, et al. (2010). Pooled sample strategy in conjunction with high-resolution liquid chromatography–mass spectrometry-based background subtraction to identify toxicological markers in dogs treated with ibipinabant. Anal Chem 82:3834–3839
  • Zhang H, Yang Y. (2008). An algorithm for thorough background subtraction from high-resolution LC/MS data: Application for detection of glutathione-trapped reactive metabolites. J Mass Spectrom 43:1181–1190
  • Zhang H, Zhang D, Ray K. (2003). A software filter to remove interference ions from drug metabolites in accurate mass liquid chromatography/mass spectrometric analyses. J Mass Spectrom 38:1110–1112
  • Zhang H, Zhang D, Ray K, Zhu M. (2009a). Mass defect filter technique and its applications to drug metabolite identification by high-resolution mass spectrometry. J Mass Spectrom 44:999–1016
  • Zhang H, Zhu M, Ray KL, et al. (2008b). Mass defect profiles of biological matrices and the general applicability of mass defect filtering for metabolite detection. Rapid Commun Mass Spectrom 22:2082–2088
  • Zhang JY, Wang F, Zhang H, et al. (2014). Rapid identification of polymethoxylated flavonoids in traditional chinese medicines with a practical strategy of stepwise mass defect filtering coupled to diagnostic product ions analysis based on a hybrid LTQ-Orbitrap mass spectrometer. Phytochem Anal 25:405–414
  • Zhang Z, Zhu M, Tang W. (2009b). Metabolite identification and profiling in drug design: Current practice and future directions. Curr Pharm Des 15:2220–2235
  • Zheng J, Ma L, Xin B, et al. (2007). Screening and identification of GSH-trapped reactive metabolites using hybrid triple quadrupole linear ion trap mass spectrometry. Chem Res Toxicol 20:757–766
  • Zhu M, Ma L, Zhang D, et al. (2006). Detection and characterization of metabolites in biological matrices using mass defect filtering of liquid chromatography/high resolution mass spectrometry data. Drug Metab Dispos 34:1722–1733
  • Zhu M, Ma L, Zhang H, Humphreys WG. (2007). Detection and structural characterization of glutathione-trapped reactive metabolites using liquid chromatography-high-resolution mass spectrometry and mass defect filtering. Anal Chem 79:8333–8341
  • Zhu M, Zhang D, Zhang H, Shyu WC. (2009a). Integrated strategies for assessment of metabolite exposure in humans during drug development: Analytical challenges and clinical development considerations. Biopharm Drug Dispos 30:163–184
  • Zhu M, Zhang H, Humphreys WG. (2011). Drug metabolite profiling and identification by high-resolution mass spectrometry. J Biol Chem 2286:25419–25425
  • Zhu P, Ding W, Tong W, et al. (2009b). A retention-time-shift-tolerant background subtraction and noise reduction algorithm (BgS-NoRA) for extraction of drug metabolites in liquid chromatography/mass spectrometry data from biological matrices. Rapid Commun Mass Spectrom 23:1563–1572
  • Zhu P, Tong W, Alton K, Chowdhury S. (2009c). An accurate-mass-based spectral-averaging isotope-pattern-filtering algorithm for extraction of drug metabolites possessing a distinct isotope pattern from LC-MS data. Anal Chem 81:5910–5917

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