Mass Spectrometry in Drug Metabolism and Disposition: Basic Principles and Applications (Wiley Series on Pharmaceutical Science and Biotechnology: Practices, Applications and Methods)

785 Pages·2011·20.292 MB·English

by  Mike S. Lee, Mingshe Zhu

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
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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
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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
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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
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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
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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
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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
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