Mass Spectrometry in Drug Metabolism and Disposition: Basic Principles and Applications (Wiley Series on Pharmaceutical Science and Biotechnology: Practices, Applications and Methods) PDF
Preview Mass Spectrometry in Drug Metabolism and Disposition: Basic Principles and Applications (Wiley Series on Pharmaceutical Science and Biotechnology: Practices, Applications and Methods)
MASS SPECTROMETRY IN DRUG METABOLISM AND DISPOSITION ffirs 1March2011;11:28:26 WILEY SERIES ON PHARMACEUTICAL SCIENCE AND BIOTECHNOLOGY: PRACTICES, APPLICATIONS AND METHODS SeriesEditor: Mike S. Lee Milestone Development Services MikeS.Lee(cid:1)IntegratedStrategiesforDrugDiscoveryUsingMassSpectrometry BirendraPramanik,MikeS.Lee,andGuodongChen(cid:1)CharacterizationofImpurities andDegradantsUsingMassSpectrometry MikeS.LeeandMingsheZhu(cid:1)MassSpectrometryinDrugMetabolismandDisposition: BasicPrinciplesandApplications ffirs 1March2011;11:28:26 MASS SPECTROMETRY IN DRUG METABOLISM AND DISPOSITION Basic Principles and Applications Edited by Mike S. Lee Milestone Development Services Mingshe Zhu Bristol-Myers Squibb ffirs 1March2011;11:28:26 Copyrightr2011byJohnWiley&Sons,Inc.Allrightsreserved. PublishedbyJohnWiley&Sons,Inc.,Hoboken,NewJersey PublishedsimultaneouslyinCanada Nopartofthispublicationmaybereproduced,storedinaretrievalsystem,ortransmittedinany formorbyanymeans,electronic,mechanical,photocopying,recording,scanning,orotherwise, exceptaspermittedunderSection107or108ofthe1976UnitedStatesCopyrightAct,without eitherthepriorwrittenpermissionofthePublisher,orauthorizationthroughpaymentofthe appropriateper-copyfeetotheCopyrightClearanceCenter,Inc.,222RosewoodDrive,Danvers, MA01923,(978)750-8400,fax(978)750-4470,oronthewebatwww.copyright.com.Requeststo thePublisherforpermissionshouldbeaddressedtothePermissionsDepartment,JohnWiley& Sons,Inc.,111RiverStreet,Hoboken,NJ07030,(201)748-6011,fax(201)748-6008,oronlineat http://www.wiley.com/go/permission. 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Wileyalsopublishesitsbooksinavarietyofelectronicformats.Somecontentthatappearsinprint maynotbeavailableinelectronicformats.FormoreinformationaboutWileyproducts,visitour websiteatwww.wiley.com. LibraryofCongressCataloging-in-PublicationData: Massspectrometryindrugmetabolismanddisposition:basicprinciplesandapplications/editedby MikeS.Lee,MingsheZhu. p.;cm. Includesbibliographicalreferencesandindex. ISBN978-0-470-40196-5(cloth) 1.Drugs—Metabolism—Analysis. 2.Metabolites—Spectra. 3.Massspectrometry. 4.Massspectrometry. I.Lee,MikeS.,1960- II.Zhu,Mingshe. [DNLM:1.PharmaceuticalPreparations—metabolism. 2.Biopharmaceutics—methods. 3.DrugDesign. 4.MassSpectrometry—methods. 5.Pharmacokinetics.QV38] RM301.55.M3672011 615u.7—dc22 2010028341 PrintedinSingapore 10 9 8 7 6 5 4 3 2 1 ffirs 1March2011;11:28:26 CONTENTS FOREWORD ix TomBaillie PREFACE xi MikeLeeandMingsheZhu CONTRIBUTORS xv PART I BASIC CONCEPTS OF DRUG METABOLISM AND DISPOSITION 1 1 Progression of Drug Metabolism 3 RonaldE.White 2 Common Biotransformation Reactions 13 BoWenandSidneyD.Nelson 3 Metabolic Activation of Organic Functional Groups Utilized in Medicinal Chemistry 43 AmitS.Kalgutkar 4 Drug-Metabolizing Enzymes, Transporters, and Drug–Drug Interactions 83 StevenW.LouieandMagangShou 5 Experimental Models of Drug Metabolism and Disposition 151 GangLuo,ChuangLu,XinxinDing,andDongluZhang 6 Principles of Pharmacokinetics: Predicting Human Pharmacokinetics in Drug Discovery 197 TakehitoYamamoto,AkihiroHisaka,andHiroshiSuzuki 7 Drug Metabolism Research as Integral Part of Drug Discovery and Development Processes 229 W.GriffithHumphreys v TOC 1March2011;11:35:40 vi CONTENTS PART II MASS SPECTROMETRY IN DRUG METABOLISM: PRINCIPLES AND COMMON PRACTICE 255 8 Theory and Instrumentation of Mass Spectrometry 257 Ge´rardHopfgartner 9 Common Liquid Chromatography–Mass Spectrometry (LC–MS) Methodology for Metabolite Identification 291 LinXu,LewisJ.Klunk,andChandraPrakash 10 Mass Spectral Interpretation 321 Li-KangZhangandBirendraN.Pramanik 11 Techniques to Facilitate the Performance of Mass Spectrometry: Sample Preparation, Liquid Chromatography, and Non-Mass-Spectrometric Detection 353 MarkHayward,MariaD.Bacolod,QingPingHan,ManuelCajina, andZackZou PART III APPLICATIONS OF NEW LC(cid:1)MS TECHNIQUES IN DRUG METABOLISM AND DISPOSITION 383 12 Quantitative In Vitro ADME Assays Using LC–MS as a Part of Early Drug Metabolism Screening 385 WalterKorfmacher 13 High-Resolution Mass Spectrometry and Drug Metabolite Identification 407 RussellJ.Mortishire-Smith,HaiyingZhang,andKevinP.Bateman 14 Distribution Studies of Drugs and Metabolites in Tissue by Mass Spectrometric Imaging 449 RichardF.Reich,DanielP.Magparangalan,TimothyJ.Garrett, andRichardA.Yost 15 Use of Triple Quadrupole–Linear Ion Trap Mass Spectrometry as a Single LC–MS Platform in Drug Metabolism and Pharmacokinetics Studies 483 WenyingJian,MingYao,BoWen,ElliottB.Jones,andMingsheZhu 16 Quantitative Drug Metabolism with Accelerator Mass Spectrometry 525 JohnS.Vogel,PeterLohstroh,BradKeck,andStephenR.Dueker 17 Standard-Free Estimation of Metabolite Levels Using Nanospray Mass Spectrometry: Current Statutes and Future Directions 567 Jing-TaoWu TOC 1March2011;11:35:40 CONTENTS vii 18 Profiling and Characterization of Herbal Medicine and Its Metabolites Using LC–MS 579 ZeperAbliz,RuipingZhang,PingGeng,DongmeiDai, JiumingHe,andJianLiu 19 Liquid Chromatography Mass Spectrometry Bioanalysis of Protein Therapeutics and Biomarkers in Biological Matrices 613 FuminLiandQinC.Ji 20 Mass Spectrometry in the Analysis of DNA, Protein, Peptide, and Lipid Biomarkers of Oxidative Stress 645 StacyL.GelhausandIanA.Blair 21 LC–MS in Endogenous Metabolite Profiling and Small-Molecule Biomarker Discovery 685 MichaelD.Reily,PetiaShipkova,andSerhiyHnatyshyn Appendix 723 Index 727 TOC 1March2011;11:35:40 FOREWORD Studies in the areas of drug metabolism and pharmacokinetics have assumed progressivelygreaterimportance inpharmaceuticalresearchoverthepasttwo decades, reflecting an increased awareness of the critical impact on successful drugdevelopmentoftheabsorption,metabolism,distribution,elimination,and toxicity(ADMET)propertiesofcandidatetherapeuticagents.Indeed,therole ofdrugmetabolismstudiesinthepharmaceuticalindustry,formerlylimitedto later phases of the development process, now spans the continuum from early discovery efforts through lead optimization, preclinical development, clinical trials, and postmarketing surveillance. Information on the identities and exposurelevelsofdrugmetabolites,firstinanimalsandsubsequentlyinhuman subjects, represents an essential component of preclinical and clinical safety assessment programs and, in those cases where circulating metabolites are pharmacologically active, provides the basis for assessing their pharmacoki- netic/pharmacodynamic (PK/PD) relationshipsand contribution totheeffects oftheparentdrug.Chemicallyreactivedrugmetabolites,whichcanbedetected andcharacterizedthroughspecializedinvitro“trapping”techniques,generally are viewed as risk factors in drug development in light of their association with several forms of drug-induced toxicities, and early information on their identities is key to the design of optimized new chemical entities that lack this potential liability. Thedetection,structuralcharacterization,andquantitativeanalysisofdrug metabolites in complex biological matrices often is a challenging endeavor, given thelow levels that derive fromhighlypotentparentcompoundsthat are administeredatdosesofafewmilligramsperdayorless.Asaresult,stringent demands are placed on the analytical methodology employed for drug metabolism studies conducted either in vitro or in vivo, in terms of sensitivity and specificity of detection, and of wide dynamic range. In this regard, mass spectrometry, which always has been an important technique in drug metabo- lismstudies,rapidlybecamethedominanttechnologyinthefieldfollowingthe introduction, in the early 1990s, of the first commercial LC(cid:1)MS/MS systems. Over the past decade, remarkable technical advances have been made in ion sourcedesignandionizationmethods,rapidscanningandhighlysensitivemass analyzers, efficient methods for inducing fragmentation of parent ions, rapid- responsedetectorswithwidedynamicrange,andpowerfuldataacquisitionand processing systems with sophisticated software packages and expert systems designed specifically for investigations in drug metabolism. The evolution of ix fbetw 1March2011;11:27:46 x FOREWORD hybridmassanalyzersforMS/MSstudies,andancillarytechniquessuchasion mobility spectrometry, have added new dimensions to the mass spectrometry experiment,whiletheadventofhighmassresolutioncapabilitiesonanLCtime scale(evenwith“fast”chromatography)ishavingatrulyrevolutionaryimpact on the utility of LC(cid:1)MS/MS in this field. MassSpectrometryinDrugMetabolismandDisposition:BasicPrinciplesand Applicationsaddresseseachoftheseareasthroughaseriesofchaptersauthored by eminent scientists well versed in the application of contemporary mass spectrometry techniques to problems in drug metabolism and pharmacoki- netics, with an emphasis on issues in drug discovery and development. The reader cannot help but be impressed by the capabilities of the current generation of LC(cid:1)MS/MS instruments, which provide a combination of sensitivity, specificity, versatility, and speed of analysis that was difficult to envisage only a few years ago, and which have transformed the way drug metabolismstudiesareconducted.Onecanonlywonder whatliesintheyears ahead! Thomas A. Baillie Seattle, WA August, 2010 fbetw 1March2011;11:27:46 PREFACE Two decades ago, drug metabolism research in the pharmaceutical industry was limited to radiolabeled in vivo drug disposition studies conducted in late stages of development. Drug metabolite identification was accomplished via a longandtediousprocess:metaboliteseparationandisolationfollowedbymass spectrometricandnuclearmagneticresonanceanalysis.Now,drugmetabolism plays a critical role in the drug discovery and development process from lead optimization to clinical drug–drug interaction studies. Commercialized liquid chromatography/mass spectrometry (LC/MS) platforms have become the dominant analytical instrument employed in drug metabolism and pharmaco- kinetics (DMPK) studies and revolutionized the productivity of drug metabo- lismresearch.Certainly,theneedforfast,sensitiveandaccuratemeasurements of drugs and metabolites in complex biological matrices has driven the con- tinueddevelopmentofnovelLC/MStechnology.Drugmetabolismscienceand mass spectrometry technology have been integrated into an inseparable arena in drug discovery and development as well in related academic research activities. This book provides a unique thesis on mass spectrometry in drug metabolism with specific emphasis on both principles and applications in drug design and development. We believe that this integration will provide a unique contribution to the field that details both drug metabolism and analytical perspectives. Therefore, this book can be used as a teaching and/or referencetooltodelineateandunderstandthe“why”and“how”withregardto the many creative uses of mass spectrometry in drug metabolism and disposi- tion studies. This work, authored by internationally renowned researchers, represents a combination of complementary backgrounds to bring technical andculturalawarenesstothisveryimportantendeavorwhileservingtoaddress needs within academia and industry. The book is organized into three parts. Part I provides the reader with the basic concepts of drug metabolism and disposition. These concepts are intended to build a unique foundation of knowledge for drug metabolism and the subsequent studies performed during drug discovery and drug devel- opment endeavors. The book begins with an elegant perspective on drug metabolism. This review or perhaps “state of the union” provides unique insightintowhereweare,howwegotthere,andwhereweappeartobeheaded. Next we delve into the details of drug metabolism with a chapter on common biotransformation reactions. Further detail is provided in Chapter 3 from a medicinal chemistry perspective as the metabolic activation of organic xi fpref 1March2011;11:35:10
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