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The Application of Mass Spectrometry in Drug Metabolism and Pharmacokinetics

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Advanced Imaging and Bio Techniques for Convergence Science

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1310))

Abstract

Drug metabolism and pharmacokinetics (DMPK) are fundamental in drug discovery. New chemical entities (NCEs) are typically evaluated with various in vitro and in vivo assays, which are time-consuming and labor intensive. These experiments are essential in identifying potential new drugs. Recently, mass spectrometry (MS) has played a key role in examining the drug-like properties of NCEs. Quantitative and qualitative mass spectrometry approaches are routinely utilized to obtain high-quality data in an efficient, timely, and cost-effective manner. Especially, liquid chromatography (LC) coupled with MS technology has been refined for metabolite identification (Met ID), which is critical for lead optimization. These qualitative and quantitative MS approaches and their specific utility in DMPK characterization will be described in this chapter.

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References

  • Ackermann BL, Berna MJ, Eckstein JA, Ott LW, Chaudhary AK (2008) Current applications of liquid chromatography/mass spectrometry in pharmaceutical discovery after a decade of innovation. Annu Rev Anal Chem 1:357–396

    Article  CAS  Google Scholar 

  • Baranczewski P, StaÅ„czak A, Sundberg K, Svensson R, Wallin A, Jansson J, Garberg P, Postlind H (2006) Introduction to in vitro estimation of metabolic stability and drug interactions of new chemical entities in drug discovery and development. Pharmacol Rep 58(4):453–472

    CAS  PubMed  Google Scholar 

  • Benet LZ, Spahn-Langguth H, Iwakawa S, Volland C, Mizuma T, Mayer S, Mutschler E, Lin ET (1993) Predictability of the covalent binding of acidic drugs in man. Life Sci 53:PL141–PL146

    Article  CAS  PubMed  Google Scholar 

  • Berry LM, Zhao Z (2008) An examination of IC50 and IC50-shift experiments in assessing time-dependent inhibition of CYP3A4, CYP2D6 and CYP2C9 in human liver microsomes. Drug Metab Lett 2(1):51–59

    Article  CAS  PubMed  Google Scholar 

  • Boelsterli UA (2002) Xenobiotic acyl glucuronides and acyl CoA thioesters as protein-reactive metabolites with the potential to cause idiosyncratic drug reactions. Curr Drug Metab 3(4):439–450

    Article  CAS  PubMed  Google Scholar 

  • Boelsterli UA, Zimmerman HJ, Kretz-Rommel A (1995) Idiosyncratic liver toxicity of nonsteroidal anti-inflammatory drugs: molecular mechanisms and pathology. Crit Rev Toxicol 25(3):207–235

    Article  CAS  PubMed  Google Scholar 

  • Bolze S, Bromet N, Gay-Feutry C, Massiere F, Boulieu R, Hulot T (2002) Development of an in vitro screening model for the biosynthesis of acyl glucuronide metabolites and the assessment of their reactivity toward human serum albumin. Drug Metab Dispos 30(4):404–413

    Article  CAS  PubMed  Google Scholar 

  • Bylda C, Thiele R, Kobold U, Volmer DA (2014) Recent advances in sample preparation techniques to overcome difficulties encountered during quantitative analysis of small molecules from biofluids using LC-MS/MS. Analyst 139(10):2265–2276

    Article  CAS  PubMed  Google Scholar 

  • Byrdwell WC (2001) Atmospheric pressure chemical ionization mass spectrometry for analysis of lipids. Lipids 36(4):327–346

    Article  CAS  PubMed  Google Scholar 

  • Caldwell J (1996) The role of drug metabolism studies for efficient drug discovery and development: opportunities to enhance time- and cost-efficiency. Pharm Sci 2:117–119

    CAS  Google Scholar 

  • Chen D, Lin S, Xu W, Huang M, Chu J, Xiao F, Lin J, Peng (2015) Qualitative and quantitative analysis of the major constituents in Shexiang Tongxin dropping pill by HPLC-Q-TOF-MS/MS and UPLC-QqQ-MS/MS. Molecules 20(10):18597–18619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chu I, Nomeir AA (2006) Utility of mass spectrometry for in vitro ADME assays. Curr Drug Metab 7(5):467–477

    Article  CAS  PubMed  Google Scholar 

  • Clarke NJ, Rindge D, Korfmacher WA, Cox KA (2001) Systematic LC/MS metabolite identification in drug discovery. Anal Chem 73(15):430A–439A

    Article  CAS  PubMed  Google Scholar 

  • Coles B (1984-1985) Effects of modifying structure on electrophilic reactions with biological nucleophiles. Drug Metab Rev 15(7):1307-1334

    Google Scholar 

  • Ding A, Zia-Amirhosseini P, McDonagh AF, Burlingame AL, Benet LZ (1995) Reactivity of tolmetin glucuronide with human serum albumin. Identification of binding sites and mechanisms of reaction by tandem mass spectrometry. Drug Metab Dispos 23(3):369–376

    CAS  PubMed  Google Scholar 

  • Fenn JB, Mann M, Meng CK, Wong SF, Whitehouse CM (1989) Electrospray ionization for mass spectrometry of large biomolecules. Science 246(4926):64–71

    Article  CAS  PubMed  Google Scholar 

  • Food and Drug Administration (2008) Guidance for industry: safety testing of drug metabolites Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079266.pdf. Last accessed 13th January 2015

  • Gao H, Deng S, Obach RS (2010) A simple liquid chromatography-tandem mass spectrometry method to determine relative plasma exposures of drug metabolites across species for metabolite safety assessments. Drug Metab Dispos 38(12):2147–2156

    Article  CAS  PubMed  Google Scholar 

  • Guo T, Chan M, Soldin SJ (2004) Steroid profiles using liquid chromatography-tandem mass spectrometry with atmospheric pressure photoionization source. Arch Pathol Lab Med 128:469–475

    Article  PubMed  Google Scholar 

  • Hakala KS, Kostiainen R, Ketola RA (2006) Feasibility of different mass spectrometric techniques and programs for automated metabolite profiling of tramadol in human urine. Rapid Commun Mass Spectrom 20(14):2081–2890

    Article  CAS  PubMed  Google Scholar 

  • Ho CS, Lam CWK, Chan MHM, Cheung RCK, Law LK, Lit LCW, Ng KF, Suen MWM, Tai HL (2003) Electrospray ionisation mass spectrometry: principles and clinical applications. Clin Biochem Rev 24(1):3–12

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hoke SH, Morand KL, Greis KD, Baker TR, Harbol KL, Dobson RLM (2001) Transformations in pharmaceutical research and development, driven by innovations in multidimensional mass spectrometry-based technologies. Int J Mass Spectrom 212(1–3):135–196

    Article  CAS  Google Scholar 

  • Holcapek M, Kolárová L, Nobilis M (2008) High-performance liquid chromatography-tandem mass spectrometry in the identification and determination of phase I and phase II drug metabolites. Anal Bioanal Chem 391(1):59–78

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hopfgartner G, Varesio E, Tschäppät V, Grivet C, Bourgogne E, Leuthold LA (2004) Triple quadrupole linear ion trap mass spectrometer for the analysis of small molecules and macromolecules. J Mass Spectrom 39(8):845–855

    Article  CAS  PubMed  Google Scholar 

  • Hsieh Y (2008) HPLC-MS/MS in drug metabolism and pharmacokinetics screening. Expert Opin Drug Metab Toxicol 4(1):93–101

    Article  CAS  PubMed  Google Scholar 

  • Hsieh Y, Korfmacher W (2006) Increasing speed and throughput when using HPLC-MS/MS systems for drug metabolism and pharmacokinetic screening. Curr Drug Metab 7(5):479–489

    Article  CAS  PubMed  Google Scholar 

  • Huang J, Bathena SP, Alnouti Y (2010) Metabolite profiling of praziquantel and its analogs during the analysis of in vitro metabolic stability using information-dependent acquisition on a hybrid triple quadrupole linear ion trap mass spectrometer. Drug Metab Pharmacokinet 25(5):487–499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • ICH Harmonised Tripartite Guideline (2009) Guidance on nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals M3 (R2). Available at: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplinary/M3_R2/Step4/M3_R2_Guideline.pdf. Last Accessed 13 January 2015

  • Ikonomou MG, Blades AT, Kebarle P (1991) Electrospray-ion spray: a comparison of mechanisms and performance. Anal Chem 63(18):1989–1998

    Article  CAS  Google Scholar 

  • Kebarle P (2000) A brief overview of the present status of the mechanisms involved in electrospray mass spectrometry. J Mass Spectrom 35(7):804–817

    Article  CAS  PubMed  Google Scholar 

  • Kebarle P, Tang L (1993) From ions in solution to ions in the gas phase-the mechanism of electrospray mass spectrometry. Anal Chem 65(22):972A–986A

    CAS  Google Scholar 

  • King R, Fernandez-Metzler C (2006) The use of Qtrap technology in drug metabolism. Curr Drug Metab 7(5):541–545

    Article  CAS  PubMed  Google Scholar 

  • Kola I, Landis J (2004) Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 3:711–715

    Article  CAS  PubMed  Google Scholar 

  • Korfmacher WA (2005) Using mass spectrometry for drug metabolism studies. CRC Press, Boca Raton, FL, pp 83–93

    Google Scholar 

  • Korfmacher WA (2009) Advances in the integration of drug metabolism into the lead optimization paradigm. Mini-Rev Med Chem 9(6):703–716

    Article  CAS  PubMed  Google Scholar 

  • Kostiainen R, Kotiaho T, Kuuranne T, Auriola S (2003) Liquid chromatography/atmospheric pressure ionization-mass spectrometry in drug metabolism studies. J Mass Spectrom 38(4):357–372

    Article  CAS  PubMed  Google Scholar 

  • Laine R (2008) Metabolic stability: main enzymes involved and best tools to assess it. Curr Drug Metab 9(9):921–927

    Article  CAS  PubMed  Google Scholar 

  • Lee KS, Oh SJ, Kim HM, Lee KH, Kim SK (2011) Assessment of reactive metabolites in drug–induced liver injury. Arch Pharm Res 34(11):1879–1886

    Article  CAS  PubMed  Google Scholar 

  • Lee JY, Lee SY, Oh SJ, Lee KH, Jung YS, Kim SK (2012) Assessment of drug-drug interactions caused by metabolism-dependent cytochrome P450 inhibition. Chem Biol Interact 198(1-3):49–56

    Article  CAS  PubMed  Google Scholar 

  • Lee JY, Lee SY, Lee K, Oh SJ, Kim SK (2015) Determination of species-difference in microsomal metabolism of amitriptyline using a predictive MRM-IDA-EPI method. Chem Biol Interact 5(229):109–118

    Article  CAS  Google Scholar 

  • Leinonen A, Kuuranne T, Kostiainen R (2002) Liquid chromatography/mass spectrometry in anabolic steroid analysis--optimization and comparison of three ionization techniques: electrospray ionization, atmospheric pressure chemical ionization and atmospheric pressure photoionization. J Mass Spectrom 37(7):693–698

    Article  CAS  PubMed  Google Scholar 

  • Lipinski CA (2000) Drug-like properties and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods 44(1):235–249

    Article  CAS  PubMed  Google Scholar 

  • Liu DQ, Hop CE (2005) Strategies for characterization of drug metabolites using liquid chromatography-tandem mass spectrometry in conjunction with chemical derivatization and on-line H/D exchange approaches. J Pharm Biomed Anal 37(1):1–18

    Article  PubMed  CAS  Google Scholar 

  • Onakpoya IJ, Heneghan CJ, Aronson JK (2016) Post-marketing withdrawal of 462 medicinal products because of adverse drug reactions: a systematic review of the world literature. BMC Med 14:10

    Article  PubMed  PubMed Central  Google Scholar 

  • Peterman SM, Duczak N Jr, Kalgutkar AS, Lame ME, Soglia JR (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 7(3):363–375

    Article  CAS  Google Scholar 

  • Plumb R, Castro-Perez J, Granger J, Beattie I, Joncour K, Wright A (2004) Ultra-performance liquid chromatography coupled to quadrupole-orthogonal time-of-flight mass spectrometry. Rapid Commun Mass Spectrom 18(19):2331–2337

    Article  CAS  PubMed  Google Scholar 

  • Polasek TM, Miners JO (2007) In vitro approaches to investigate, mechanism-based inactivation of CYP enzymes. Expert Opin Drug Metab Toxicol 3(3):321–329

    Article  CAS  PubMed  Google Scholar 

  • Prakash C, Shaffer CL, Nedderman A (2007) Analytical strategies for identifying drug metabolites. Mass Spectrom Rev 26(3):340–369

    Article  CAS  PubMed  Google Scholar 

  • Raffaelli A, Saba A (2003) Atmospheric pressure photoionization mass spectrometry. Mass Spectrom Rev 22:318–331

    Article  CAS  PubMed  Google Scholar 

  • Riley RJ, Martin IJ, Cooper AE (2002) The influence of DMPK as an integrated partner in modern drug discovery. Curr Drug Metab 3(5):527–550

    Article  CAS  PubMed  Google Scholar 

  • Rodrigues AD (2008) Drug–drug interactions. In: Rodrigues AD (ed) Drugs and the pharmaceutical sciences, 2nd edn. Informa Healthcare, New York, pp 1–719

    Google Scholar 

  • Rosenberg E (2003) The potential of organic (electrospray- and atmospheric pressure chemical ionisation) mass spectrometric techniques coupled to liquid-phase separation for speciation analysis. J Chromatogr A 1000(1–2):841–889

    Article  CAS  PubMed  Google Scholar 

  • Rousu T, Herttuainen J, Tolonen A (2010) Comparison of triple quadrupole, hybrid linear ion trap triple quadrupole, time-of-flight and LTQ-Orbitrap mass spectrometers in drug discovery phase metabolite screening and identification in vitro-amityptiline and verapamil as model compounds. Rapid Commun Mass Spectrom 24(7):939–957

    Article  CAS  PubMed  Google Scholar 

  • Sallustio BC, Fairchild BA, Pannall PR (1997) Interaction of human serum albumin with the electrophilic metabolite 1-O-gemfibrozil-β-D-glucuronide. Drug Metab Dispos 25(1):55–60

    CAS  PubMed  Google Scholar 

  • Sawamura R, Okudaira N, Watanabe K, Murai T, Kobayashi Y, Tachibana M, Ohnuki T, Masuda K, Honma H, Kurihara A, Okazaki O (2010) Predictability of idiosyncratic drug toxicity risk for carboxylic acid-containing drugs based on the chemical stability of acyl glucuronide. Drug Metab Dispos 38(10):1857–1864

    Article  CAS  PubMed  Google Scholar 

  • Shou WZ, Magis L, Li AC, Naidong W, Bryant MS (2005) A novel approach to perform metabolite screening during the quantitative LC-MS/MS analyses of in vitro metabolic stability samples using a hybrid triple-quadrupole linear ion trap mass spectrometer. J Mass Spectrom 40(10):1347–1356

    Article  CAS  PubMed  Google Scholar 

  • Spahn-Langguth H, Benet LZ (1992) Acyl glucuronides revisited: is the glucuronidation process a toxification as well as a detoxification mechanism? Drug Metab Rev 24(1):5–47

    Article  CAS  PubMed  Google Scholar 

  • Spahn-Langguth H, Dahms M, Hermening A (1996) Acylglucuronides: covalent binding and its potential relevance. Adv Exp Med Biol 387:313–328

    Article  CAS  PubMed  Google Scholar 

  • Stachulski AV, Harding JR, Lindon JC, Maggs JL, Park BK, Wilson ID (2006) Acyl glucuronides: biological activity, chemical reactivity, and chemical synthesis. J Med Chem 49(24):6931–6945

    Article  CAS  PubMed  Google Scholar 

  • Tucker GT, Houston JB, Huang SM (2001) Optimizing drug development: strategies to assess drug metabolism/transporter interaction potential–toward a consensus. Br J Clin Pharmacol 52(1):107–117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang M, Dickinson RG (1998) Disposition and covalent binding of diflunisal and diflunisal acyl glucuronide in the isolated perfused rat liver. Drug Metab Dispos 26(2):98–104

    CAS  PubMed  Google Scholar 

  • Wienkers LC, Heath TG (2005) Predicting in vivo drug interactions form in vitro drug discovery data. Nat Rev Drug Discov 4(10):825–833

    Article  CAS  PubMed  Google Scholar 

  • Williams AM, Dickinson RG (1994) Studies on the reactivity of acyl glucuronides-VI. Modulation of reversible and covalent interaction of diflunisal acyl glucuronide and its isomers with human plasma protein in vitro. Biochem Pharmacol 47(3):457–467

    Article  CAS  PubMed  Google Scholar 

  • Williams AM, Worrall S, De Jersey J, Dickinson RG (1995) Studies on the reactivity of acyl glucuronides-VIII. Generation of an antiserum for the detection of diflunisal-modified proteins in diflunisal-dosed rats. Biochem Pharmacol 49(2):209–217

    Article  CAS  PubMed  Google Scholar 

  • Yan Z, Caldwell GW (2004) Stable-isotope trapping and high-throughput screenings of reactive metabolites using the isotope MS signature. Anal Chem 76(23):6835–6847

    Article  CAS  PubMed  Google Scholar 

  • 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 Spectorm 23(11):1683–1693

    Article  CAS  Google Scholar 

  • 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(10):1110–1112

    Article  CAS  PubMed  Google Scholar 

  • Zhang MY, Pace N, Kerns EH, Kleintop T, Kagan N, Sakuma T (2005) Hybrid triple quadrupole linear ion trap mass spectrometry in fragmentation mechanism studies: application to structure elucidation of buspirone and one of its metabolites. J Mass Spectrom 40(8):1017–1029

    Article  CAS  PubMed  Google Scholar 

  • Zhang H, Zhu M, Ray KL, Ma L, Zhang D (2008) Mass defect profiles of biological matrices and the general applicability of mass defect filtering for metabolite detection. Rapid Commun Mass Spectrom 22(13):2082–2088

    Article  CAS  PubMed  Google Scholar 

  • Zhang H, Zhang D, Ray K, Zhu M (2009) Mass defect filter technique and its applications to drug metabolite identification by high-resolution mass spectrometry. J Mass Spectrom 44(7):999–1016

    Article  CAS  PubMed  Google Scholar 

  • 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(21):8333–8341

    Article  CAS  PubMed  Google Scholar 

  • Zhu M, Zhang H, Humphreys WG (2011) Drug metabolite profiling and identification by high resolution mass spectrometry. J Biol Chem 286(29):25419–25425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Convergence Medicine Research Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul, South Korea

    Ji-Yoon Lee & Soo Jin Oh

  2. College of Pharmacy, Chungnam National University, Daejeon, South Korea

    Sang Kyum Kim

  3. College of Pharmacy, Korea University, Sejong, South Korea

    Kiho Lee

  4. College of Medicine, University of Ulsan, Seoul, South Korea

    Soo Jin Oh

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  1. Ji-Yoon Lee
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Correspondence to Soo Jin Oh .

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Editors and Affiliations

  1. Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea (Republic of)

    Jun Ki Kim

  2. Department of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea (Republic of)

    Jeong Kon Kim

  3. Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea (Republic of)

    Chan-Gi Pack

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Lee, JY., Kim, S.K., Lee, K., Oh, S.J. (2021). The Application of Mass Spectrometry in Drug Metabolism and Pharmacokinetics. In: Kim, J.K., Kim, J.K., Pack, CG. (eds) Advanced Imaging and Bio Techniques for Convergence Science. Advances in Experimental Medicine and Biology, vol 1310. Springer, Singapore. https://doi.org/10.1007/978-981-33-6064-8_20

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