Mass Spectrometry for Drug Discovery and Drug Development (Korfmacher/Mass Spectrometry for Drug Discovery and Drug Development) || Index

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    Abscesses, examined by IMS, 291Absolute chemical structure, in-depth

    knowledge of, 246Absolute metabolite quantitation kit, 393Absolute quantitation, from tissue samples,

    233234Absorption assays, 98Absorption, distribution, metabolism, and

    excretion (ADME) assays. See also ADME entries; In vitro ADME entries

    frequently performed, 9798mass spectrometry for in vitro, 97113

    Absorption, distribution, metabolism, and excretion (ADME) parameters, therapeutic siRNAs and, 372

    Absorption/distribution/metabolism/excretion/toxicity (ADMET) assays, 304

    Absorption, metabolism, and excretion (AME) studies, 131

    Accelerator mass spectrometry (AMS), 2, 2728

    Acetonitrileeffect of, 69in sample extraction, 133134, 135

    Acetonitrile methanol elution, 6365Acetonitrile precipitation, 81

    Mass Spectrometry for Drug Discovery and Drug Development, First Edition. Edited by Walter A. Korfmacher. 2013 John Wiley & Sons, Inc. Published 2013 by John Wiley & Sons, Inc.

    Acid hydrolysis, MALDI-MS and, 369Acidic matrices, 368Active drug compounds, assessing

    homogeneity of, 324325Active pharmaceutical ingredients (APIs),

    249impurities in, 191

    Acylglucuronides, 56, 73, 74, 133Adduct ions, 3Adenosine triphosphate (ATP), depletion

    of, 318ADME program, for drug registration, 129.

    See also Absorption, distribution, metabolism, and excretion (ADME) entries

    ADME properties, of siRNAs, 364ADME studies, 117, 129, in animals, 132ADME support, 102Adverse drug reactions (ADRs), 339340AEE788 vascular endothelial growth factor

    receptor inhibitor, 318320Affinity selectionMS (ALIS) method, 261,

    262Agilent, 106Albumin depletion method, 178179Alkali ion exchange, with ammonium ions,


  • 428 INDEx

    Alternative fragmentation process, 28Alternative ionization methods, 28Alzheimers biomarkers, 42Ambient desorption techniques, 711Ambient ionization mass spectrometry, 7Ambient sampling/ionization techniques,

    109Ambient surface profiling, LESA for,

    221238Amine adducted ions, in PEGylated protein

    analysis, 167Ammonium hydroxide (NH4OH), 412Ammonium ions, alkali ion exchange with,

    368AMS system, components of, 28. See also

    Accelerator mass spectrometry (AMS)Amyloid peptides, HPLC-MS/MS

    quantification of, 413-Amyloid peptides, 408410Analog-to-digital converter (ADC), 344Analyte expression, 60Analyte extractionLESA in, 231232organic solvents for, 6768using LLE, 6667

    Analytesanalysis of, 34, 8annotation of, 395, 396capturing quantitative information on, 394

    chromatographically separating from phospholipids, 65

    ionization efficiency of, 225post-acquisition extraction of accurate masses of, 107

    Analyte stabilization, chemical agents in, 57

    Analytical approaches, fingerprinting techniques and, 391392

    Analytical data acquisition, in metabolomics, 390

    Analytical fingerprints, 391Analytical instrumentation, creation of, 49Analytical/wet chemistry techniques, 142Anatomy, intact protein analysis of,

    284288AnimalsADME studies in, 132metabolic profiles in, 130

    Animal studiesAUC pooling method in, 136incurred sample from, 81

    Anion exchange, 367Annotationof analytes, 395, 396in nontargeted metabolomics, 395, 396

    Antibacterial compounds, cannibalistic factors as, 291

    Antibiotic-resistant bacteria strains, 291Antibody fragmentation, 208Anticoagulants, 57Antidrug antibody purification method,

    178179Antioxidants, 133Antisense oligonucleotide therapeutic

    discovery, 372APCI HPLC-MS applications, 6. See also

    Atmospheric pressure chemical ionization (APCI); High-performance liquid chromatographymass spectrometry (HPLC-MS)

    APCI ionization mechanism, 6APCI-MS, 6. See also Mass spectrometry

    entriesAPI sources, introduction of samples into,

    108. See also Atmospheric pressure ionization (API)

    API techniques, 28AQ4N prodrug, 318Aqueous mobile phase, phase collapse and,

    7576Area under the curve (AUC), 135, 136Artificial deamidation, minimizing, 212Artificial degradation, in peptide mapping,

    211213Asn deamidation/isomerization scheme,

    205. See also Asparagine (Asn) residues

    Asparagine (Asn) residues, deamidation of, 167, 177, 204

    Aspartate (Asp)isoAsp residues from, 206isomerization of, 177

    Aspartate products, isoaspartate vs., 177Astemizole, MALDI imaging results for,

    316, 317Atmospheric pressure chemical ionization

    (APCI), 1, 56, 109, 240, 241, 245Atmospheric pressure IEM, 5. See also Ion

    evaporation model (IEM)Atmospheric pressure ionization (API), 1sources of, 39

    Atmospheric pressure ionization methods/techniques, 8, 240

  • INDEx 429

    Atmospheric pressure ion source geometries, 2

    Atmospheric pressure MALDI (API-MALDI), 13. See also Matrix-assisted laser desorption/ionization (MALDI)

    Atmospheric pressure photoionization (APPI), 1, 5, 67, 240, 241, 250

    Atmospheric pressure solid probe analysis (ASAP), 9

    AUC plasma pooling, volume calculation for, 135

    AUC pooling method, in animal studies, 136

    Automated anion-exchange purification/desalting HPLC system, 367

    Automated component detection, 121Automated compound purification systems,

    243Automated infusion, 108Automated optimization workflows, 404Automated tryptic digestion, 156Automatic analyte extraction, LESA in,

    231232Automatic gain control (AGC) procedure,

    17Automaton, 100Autoradiography, 221222. See also Whole

    body autoradiography (WBA)MALDI imaging as a complement to, 323

    Autoradiography imaging, 304, 305. See also Quantitative whole-body autoradiography entries

    Autosampling, fraction-collecting, 367368Avion TriVersa-NanoMate robotic ion

    source, 222, 223Axial ejection, radial ejection vs., 19

    Background subtraction (BgS), 48, 47, 48with noise reduction algorithm, 348350real-time dynamic, 123

    Bacteria, antibiotic-resistant strains of, 291Bacterial colonies, study of, 290291Bacterial infection, IMS applied to, 290292Best quantification strategy, 408-amyloid peptides, 408410-RAM flow scintillation analyzer (FSA),

    136, 137BgS-NoRA, 348350. See also Background

    subtraction (BgS)Bile metabolic profiling, 49Bioactivation, 352

    Bioactivation potential, of drug candidates, 340

    Bioanalysis, with full scan acquisition, 105106

    Bioanalytical (BA) applications, 240Bioanalytical mass spectrometry (MS),

    99100Bioanalytical methods, 55for target quantitation, 78

    Biochemical changes, 4142Biological drugsdefined, 149MS analysis of, 149190qualitative/quantitative analysis of, xii

    Biological fluids, tracking siRNAs in, 360Biological matrices. See also Biomatricesanalysis of siRNA from, 372376endogenous components in, 127extracting siRNAs from, 365366

    Biological properties, assessment of, 248259

    Biological sample analysis, HRMS for, 414415

    Biological samplescollection, storage, and preparation of, 5659

    drug-derived material in, 133ensuring stability of, 133pooling of, 135136

    Biologic pharmaceuticals, characteristics of, 201. See also Biologics drugs

    Biologicscharacterization of, 191chemical degradations in, 210degradation characterization in, 201211future developments in imaging, 326impurities and degradation products in small-molecule, 191220

    MALDI-MS technique and, 192Biologics drugs, U.S. market for, 201202Biomarker concentration measurements, 42Biomarker measurement assays, targeted

    metabolomic analyses vs., 393394Biomarker research, 42Biomarkers, 4142in disease assessment, 403interest in, 289

    Biomatrices, isolation of siRNAs from, 364. See also Biological matrices

    Biomedical field, AMS in, 28Biotransformation analysis, of radioactive

    samples, 136, 137

  • 430 INDEx

    Biotransformation studies, samples for, 132133

    Blood samples, 118119Boronphenylalanine (BPA)-mediated boron

    neutron capture therapy, 307Bottom-up methods, 192Brain regions, IMS in redefining, 286287Breast cancer, IMS and, 289Breast cancer tissues, imaging, 290Bromine, in trapping agents, 341n-Butyl chloride, 67, 68

    C16:0 lyso-PC, extraction of, 68Cancer biology, IMS studies of, 288290. See

    also Breast cancer entries; Oncology drugs; Tumor entries

    Cancer tissue microarrays, analyzing after in situ digestion, 293. See also Pancreatic cancer tissue microarray

    Cancilla, Mark T., ix, 357Cannibalistic factors, as antibacterial

    compounds, 291Capillary columns, monolithic, 367Capillary electrophoresis (CE), 391, 394Caprioli, Richard M., ix, 277, 327, 328CaptiveSpray ion source, 4849Carboxylic acid metabolite, 74Cassette analysis, 104Cassette incubation, 104Cassette incubation/HRAM analysis

    approach, 106. See also High-resolution accurate mass (HRAM) systems

    Cation exchange (CEx), in desalting samples, 365. See also CEx fractionation

    Cation exchange chromatography, 155Cations, effects of small, 60Centroid data, 79Centroiding methodology, 419Centroid mode, MEWS applied in, 420Cetrorelix, 410CEx fractionation, 169. See also Cation

    exchange (CEx)Chalcone synthetase gene, suppression of,

    357Charge residue, 5Charge residue model (CRM), 4, 5Charge state reduction methods, in

    PEGYLATED protein analysis, 167Charge states, CID behavior of, 369370,

    371Chelating agents, 365

    Chemical agents, in analyte stabilization, 57Chemical biomarkers, 42Chemical degradants, detection of, 210Chemical degradation, 204210Chemical derivatizationapplications of, 140141for structural elucidation, 140141

    Chemical derivatization experiments, 192Chemically modified oligonucleotidesfragmentation of, 370sequencing program for, 378

    Chemically reactive metabolites, 339Chemical modifications. See also Chemically

    modified oligonucleotidesapplied to siRNAs, 358360influence on LC-MS response, 362364

    Chemical stability, assessing, 251Chemical structure(s)in-depth knowledge of, 246growing variety of, 241

    Chemical testing, 251253Chemistry, in drug discovery process, 239Chemometrics, in metabolomics, 390Chen, Guodong, ix, 191Chick heart, visualizing molecular

    morphology of, 285286Chinese hamster ovary (CHO) cells, 207,

    208Chip-based infusion nano-ESI system, 9, 10Chip-based nESI emitter array, 222223.

    See also Nanoelectrospray (nESI) entries; nESI chip

    Chowdhury, Swapan K., ix, 339Chromatographic elution behavior, of

    phospholipids, 6265Chromatographic retention time, 60Chromatographic separation, 55, 73, 372,

    396397direct MS analysis without, 108109between drugs and metabolites, 7071, 72

    Chromatographic surface, 13Chromatographyenhancing, 7477mass spectrometry metabolomics and, 396397

    reversed-phase, 6265Chromatography-interfaced techniques,

    392CID behavior, of charge states, 369370,

    371. See also Collision-induced dissociation (CID)

    CID experiments, 26

  • INDEx 431

    CID fragmentation, 207CID MALDI TOF/TOF, 23. See also

    Matrix-assisted laser desorption/ionization (MALDI); Tandem TOF combinations (TOF/TOF); Time-of-flight (TOF) entries

    CID MS/MS, 24. See also Tandem mass spectrometry (MS/MS)

    Circulating human metabolites, characterization of, 132, 136

    Clot formation, minimization of, 57Clozapinedistribution of, 323, 324, 325in zebrafish, 324, 325

    Clozapine measurement, 309, 310Cluster-assisted desorption, 9Cluster ion sources, 307Coefficients of variation (CVs), 410Collision cells, 15, 16, 22, 23, 24Orbitrap, 26

    Collision energy (CE), 16, 404predicting, 407

    Collision gases, 17, 18, 27Collision-induced dissociation (CID), 1516,

    1920, 38. See also CID entries; MS2 trap CID

    GSH and, 340, 342, 343of phospholipids, 6162of siRNA duplexes, 364

    Collision-induced fragmentation (CID), 176, 177

    in determining PEGylation site, 166Colon cancer biomarkers, 43Column/mobile phase combinations, testing,

    83Column mobile phase screening, 7475Columns, monolithic, 59Column selection, 75Column stationary phase screening, 7475Column washing, via increasing organic

    component, 65Commercial libraries, 395, 396Comparability studies, 150Compensation voltage (CV), 80Complex mixtures, analytical techniques

    for, 192Compound-specific analysis, 99Compound-specific in vitro ADME

    experiments, 100. See also Absorption, distribution, metabolism, and excretion (ADME) entries; In vitro ADME entries

    Concentrationtime plasma profiles, 131, 132

    Consortium projects, human metabolome, 395

    Constant neutral loss scan (CNLS), 341, 342

    Continuous beams, 22Controlled gas-phase synthesis, 248Control sample background subtraction

    routines, 46Conventional imaging technologies,

    304305Co-solvent method, 250COSY spectrum, 264Covalent binding, 258259adverse drug reactions and, 339340

    Cross-ring cleavage, 159160Cryo-sectioning, 313314Crystallin proteins, 287288CTC autosampler valve configurations, 100,

    101C-terminal lysine variation, 208C-trap, 26, 345Cuyckens, Filip, ix, 405Cyanide, 258259Cyanide-trapped reactive iminium ions,

    350Cyclotron frequency (f), 25Cyclotronic motion, 2425CYP phenotyping, 130. See also

    Cytochrome P450 (CYP) entriesCys disulfide bonds, 207Cysteine (Cys), 208Cysteine connectivitiesanalysis of, 164characterization of, 160MS for determining, 161

    Cysteine residues, degradants/impurities related to, 207

    Cytochrome P450 (CYP) enzyme activities, 99

    Cytochrome P450 (CYP) isoforms, identifying, 130

    Data acquisition/analysis, 315Data analysis, 376378Data analysis/interpretation, in

    metabolomics, 390Data independent MS/MS strategy, 156Data interpretation software, 107Data interrogation routines, automating,


  • 432 INDEx

    Data mining, post-run, 123Data mining toolsfor metabolite detection/identification, 256258

    for reactive metabolite screening, 345351

    use of, 256258Data processing, in metabolomics, 390Data processing software tools, 121DBS-LESA-MS approach, 232. See also

    Dried blood spots (DBS) cards; LESA entries; Liquid extraction surface analysis (LESA); Mass spectrometry entries

    DC voltages, 15. See also RF/DC potentialsDead time, minimizing, 103Dealkylation tool, 256Deamidated peptides, detection of,

    204206Deamidationof asparagine residues, 167, 177, 204minimizing, 212of therapeutic proteins, 168170

    Deconvoluted ESI mass spectra, 374Deconvoluted ESI-TOF mass spectra, 152,

    154. See also Time-of-flight (TOF) entries

    Deconvoluted mass spectra, 209Deconvolution software, 406, 419Decoy oligodeoxynucleotides, 326, 327Defensins, 289Deglycosylated heavy chain (HC) mAb

    fragments, intact mass analysis of, 154. See also mAb entries; Monoclonal antibodies (mAbs)

    Degradant molecular weights, 198199Degradants, cysteine-related, 207Degradant structures, 198, 200Degradation, in peptide mapping, 211213Degradation pathways, 198, 199201Degradation productscharacterization of, xii, 191in small-molecule pharmaceuticals/biologics, 191220

    Dempster, J. J., 1De novo sequencing, 369Derivatization, 326327Derivatization techniques, 140141for distinguishing oxidation and glucuronidation sites, 141

    Desalting, 365Desaturation, 124

    DESI imaging, 309311. See also Desorption electrospray ionization (DESI)

    MALDI imaging vs., 311DESI technology, in many research areas,

    308309Desorption electrospray ionization (DESI),

    7, 8, 109, 306, 307311, 329, 391. See also Electrospray ionization (ESI)

    application to tissue distribution studies, 309

    direct tissue analysis by, 309in drug imaging studies, 309image resolution of, 311ionization efficiency of, 311

    Desorption/ionization on porous silicon (DIOS), 1112

    Deuterium exchange information, 171Development, intact protein analysis of,

    284288Diclofenac glucuronide detection, 229, 230Differential ion mobility (DMS), 27Differential mass spectrometry (DMS), 42Digested peptides, 292294Dillen, Lieve, ix, 403Dilute-and-shoot technique, 58Diluted solutions, electrospray analysis of,

    45Dimethyl sulfoxide (DMSO), in sample

    extraction, 134, 135Direct analysis in real time (DART), 7, 89,

    109LESA vs., 229231

    Direct ESI technologies, 260. See also Electrospray ionization (ESI)

    Direct injection/infusion (DI), 396Direct MS analysis, without

    chromatographic separation, 108109. See also Mass spectrometry entries

    Direct online solid phase extraction (SPE), 103104

    Direct tissue analysis, 314Discovery metabolite identification, 116DiscoveryQuant Optimize software,

    100102Discriminant analysis. See Principal

    component analysis (PCA) followed by discriminant analysis (DA) (PCA-DA)

    Diseaseprotein aggregation and, 210RNAi and, 357

    Disease assessment, peptide biomarkers in, 403

  • INDEx 433

    Disulfide bondsformation of, 160mapping of, 207

    Disulfide-containing peptides, identification of, 160

    Disulfide-linked hinge dipeptide, mass spectra of, 163

    Disulfide-linked peptide ions, 207Disulfide-linked structures, 161Disulfide mapping, 160164Disulfides, of IgG2, 161162Dithiothreitol (DTT), 211212Dopant radical cations, 7Dose administration, in in vivo AME study,

    131Dosed samples, 119Dried blood spots (DBS) cards, 231232Droplet pick-up mechanism, 8Drug analysis, matrices for, 314Drug candidate metabolites, rapid

    characterization of, 46Drug candidatesbioactivation potential of, 340concentrations of, 42incubation of, 130optimal pharmaceutical formulation of, 249

    safety of, 116therapeutic protein, 179

    Drug compoundsfirst-pass metabolism of, 321, 322metabolic stability of, 253

    Drug concentration(s), 56understanding, 60

    Drug-derived material(s)in biological samples, 133maximum recovery of, 134profiling of, 137, 138

    Drug detection, from tissue surfaces, 312Drug development. See also Drug

    discovery/developmentdiscovery stage of, 244mass spectrometers in, 135metabolite identification in, 115147therapeutic mAbs in, 177

    Drug development programs, immunological assays and, 403404

    Drug development studies, 117Drug discovery, xi, 191, 244. See also Drug

    metabolism discovery assaysADME assays in, 97mass spectrometers in, 135

    metabolomics in, 388390MSI technologies for, 305312pace of, 258

    Drug discovery/developmentLESA applications in, 224229QWBA and, 221222role of drug distribution studies in, 304

    Drug discovery process(es), 239aspects of, 248249improving, 240

    Drug distributionLESA and whole-body, 225227whole-body images of, 309311

    Drug distribution studies, role in drug discovery/development, 304

    Drugdrug interaction (DDI) assays, 98Drugdrug interactions (DDIs), 130reducing, 39

    Drug extraction, LLE for, 6669Drug imaging, sample preparation for,

    313315Drug measurement, accuracy and recision

    of, 80Drug metabolism, 27qualitative/quantitative workflows in, 3841

    Drug metabolism and pharmacokinetic (DMPK) processes, 239

    Drug metabolism discovery assays, 40Drug metabolism studies, 14mass spectrometric approaches/instruments in, 126

    techniques in, 1Drug metabolite identification, using mass

    defect filters, 4548Drug/metabolite imaging applications,

    imaging mass spectrometry for, 315326

    Drug metabolitesdetection/identification of, 120121extraction of, 348349

    Drug physicochemical/biological properties, assessment of, 248259

    Drug potency, 40Drug product degradation profiles, 191Drug products/substances, purity of, 243Drug purity, 243upgrading, 245

    Drug quantitation, 28, 74interference with, 6970

    Drug retention, MALDI imaging and, 323

  • 434 INDEx

    Drugs. See also Pharmaceutical entries; Therapeutic entries

    bringing to market, 37chromatographic separation of, 8182generated from metabolites, 82imaging in whole-body sections, 321322

    imaging mass spectrometry for, 303337instability of, 56, 133ionization efficiencies of, 127PEGylated, 164poor penetration of, 291qualitative analysis of, 414quantitative performance measures for, 40

    radiolabeled, 116sample denaturing for dissociating, 178

    Drug safety, 191Drugs/metabolitesapplication of MS to tissue distributions of, 329

    extraction of, 224225Drug SRM channel, 82. See also Selected

    reaction monitoring (SRM) entriesDrug stability, evaluating, 133Drug targets, 259characterization of, 259

    Du, Yi, ix, 149Dual-column system, 59Dual ion sources, 250Dual spray source, 22Dummy transitions, 410Duplex intensities, measured by

    MALDI-MS, 368Duplex siRNA, 361362. See also Small

    interfering RNAs (siRNAs)collision-induced dissociation of, 364, 369370

    Duplex siRNA metabolites, characterizing, 373375

    Duty cycles, 420421enhanced, 421

    Dwell times, 17, 410, 411Dynamic protein affinity selection mass

    spectrometry, 261

    ECD experiments, 206. See also Electron capture dissociation (ECD)

    EC oxidation, 5Eicosanoid metabolites, 393Eikel, Daniel, ix, 221Electrochemical (EC) oxidation reaction, 5

    Electron capture dissociation (ECD), 48, 176177, 180, 206

    Electron capture ionization, 6Electron ionization dissociation (EID), 206Electron transfer dissociation (ETD), 48,

    176177, 180, 206. See also ETD fragmentation

    on an ion trap, 177Electron volts (eVs), 16Electrophile-associated idiosyncratic drug

    reactions, 46Electrophiles, 340reacting GSH with, 340343

    Electrospray (ESI) selected reaction monitoring (SRM), 6162

    Electrospray analysis, 4of diluted solutions, 45

    Electrospray-assisted laser desorption/ionization (ELDI), 10

    Electrospray HPLC-MS, MALDI-MS vs., 1213. See also High-performance liquid chromatographymass spectrometry (HPLC-MS)

    Electrospray ionization (ESI), 1, 25, 240, 245. See also Desorption electrospray ionization (DESI); ESI entries

    introduction of, 277MALDI vs., 13matrix effects in, 5960in positive and negative ion modes, 406407

    siRNA chemistries and, 361Electrospray ionization (ESI)-quadrupole

    (Q) mass spectrometry (MS), 151Electrospray process, 3Electrospraysflow rates for, 4pneumatically assisted, 2

    Electrospray spectrum, for Enfuvirtide, 406Electrostatically trapped ions, 38Electrostatic mirror, 21Elemental compositions, 246Elementsmasses of, 347quantitation of, 1314

    ELISA hybridization technique, 367. See also Enzyme-linked immunosorbent assay (ELISA)

    ELISA methods, 177Elution, isocratic, 65Elution behavior, of phospholipids, 6265Emary, William Bart, ix, 37

  • INDEx 435

    Embryo implantation, protein changes during, 284285

    Endogenous biomarker measurement assays, targeted metabolomic analyses vs., 393394

    Endogenous components, 133effects of, 60

    Endogenous peptides, intact, 294296Endonuclease degradation, 374375Enfuvirtide, 406, 412413, 415416, 417Enhanced duty cycle, 421Enhanced product ion (EPI) scans, 20Enzymatic digestion, 169, 412Enzyme-linked immunosorbent assay

    (ELISA), 42, 43. See also ELISA entries

    siRNAs and, 360Epidermal growth factor receptor (EGFR),

    318Epimerization, 57, 73ESCi sources, 245ESI analysis, siRNAs and, 362. See also

    Electrospray ionization (ESI) entriesESI efficiencyeffect on mobile phase, 75siRNA hydrophobicity and, 364

    ESI-ion trap, 151ESI-ISF-CID method, in determining

    PEGylation site, 166167. See also Collision-induced dissociation (CID); In-source fragmentation (ISF)

    ESI mass spectra, deconvoluted, 374ESI-MS, 210, 211. See also Mass

    spectrometry entriesin PEGylated protein analysis, 167

    ESI-MS isotopic distribution, 169ESI-Orbitrap mass spectrometry (MS),

    151ESI-QTOF-MS, 151. See also Fast scanning

    Q-TOF MS/MS systems; Q-TOF MS; Quadrupole time-of-flight (Q-TOF); Time-of-flight (TOF) entries

    ESI response derivatization, 407ESI-TOF, 179. See also Time-of-flight (TOF)

    entriescoupling with HPLC separation, 151RP-HPLC combined with, 153

    ESI-TOF mass spectra, 168ESI-TOF MS, 151, 152Ester groups, metabolites containing, 74ETD fragmentation, 207. See also Electron

    transfer dissociation (ETD)

    Ethyl acetate, 67, 68E to Z isomerization, 73Exonuclease degradation, 374375Experiments, resolving power of, 396Extracted ion chromatograms (EICs), 40,

    45, 79, 107, 122, 405obtained with MEWs, 418

    Extracted ion chromatogram (EIC) search, 160

    Extraction columns, 58, 59Extraction methodologies, 134Extraction of dissolved ions under

    atmospheric pressure (EDIAP), 2Extraction solvent, optimizing, 224Ex vivo imaging technologies, 304

    Fab region, 208. See also Fragment-antibody binding (Fab) mAb fragments

    FAIMS devices, 80, 174. See also Field asymmetric waveform ion mobility entries

    False positives, eliminating, 346Fast-atom bombardment (FAB), 11Fast-atom bombardment (FAB)-MS, 164Fast flow injection analysis (FIA), 241. See

    also Flow injection analysis (FIA)Fast-flow online extraction technique, 58Fast Fourier transform (FT), 345Fast scanning Q-TOF MS/MS systems, 253.

    See also Q-TOF MS; Time-of-flight (TOF) entries

    Fast-scanning triple quadrupole instruments, 410

    FDA MIST guidance, 116. See also Food and Drug Administration (FDA)

    Fenn, John, 2Fexofenadine, 225227, 321322FIA-based method development

    approaches, 100Fibrinogen clots, 57FIEHNLIB library, 395Field asymmetric waveform ion mobility

    (FAIMS), 27. See also FAIMS devices; High-field asymmetric waveform ion mobility spectrometry (FAIMS); Ion mobility spectrometry (IMS)

    Field asymmetric waveform ion mobility mass spectrometry (FAIMS), 404

    Fingerprinting profiling, 390, 391392Fingerprinting techniques, analytical

    approaches and, 391392

  • 436 INDEx

    First-in-human (FIH) studies, 81, 116, 120use of samples from, 117119

    First-pass metabolism, of drug compounds, 321, 322

    Fixatives, alternative, 280Fixed mode, 16Fixed tissue samples, 279280Flanagan, W. Michael, ix, 357Flight time, of ions, 343Flow injection analysis (FIA), 100, 102, 396.

    See also Fast flow injection analysis (FIA)

    Flow-injection RP-HPLC-MS technique, 170. See also Reversed-phase entries

    Flow scintillation analyzer (FSA), 136, 137Fluorescence enhancement/detection, 262,

    263, 264Fluticasone MS/MS fragmentation, 226. See

    also Tandem mass spectrometry (MS/MS)

    Fluticasone study, 225Food and Drug Administration (FDA), on

    PEGylated drugs, 164Food and Drug Administration (FDA)

    guidance, 116Forced degradation studies, 252Formalin-fixed paraffin embedded (FFPE)

    samples, 293294, 296Formalin-fixed tissue, 280Formic acid, analyte response and, 75Fourier transform (FT), 345Fourier transformion cyclotron resonance

    (FT-ICR), 2425, 115, 344345. See also FT-ICR entries

    Fourier transformion cyclotron resonance (FTICR)-MS, 19. See also Mass spectrometry entries

    Fourier transformion cyclotron resonance (FT-ICR)-MS mass spectrometers, 245, 295

    Fourier transform mass spectrometry (FT-MS), 2427. See also Mass spectrometry entries

    ion detection and, 25Fraction-collecting autosampling, 367368Fragment-antibody binding (Fab) mAb

    fragments, 152, 153. See also Fab regionFragmentationof chemically modified oligonucleotides, 370

    ion trap mass spectrometry and, 414of peptides, 406407

    Fragmentation pathways, 193194, 247mapping, 248

    Fragmentation patterns, 196Fragmentation process, alternative, 28Fragmentation spectra, 175Fragment-crystallizable (Fc) mAb

    fragments, 152, 153. See also Monoclonal antibodies (mAbs)

    Fragmented ions, intact protein ions and, 175

    Fragmented peptides, 156Fragmented protein ions, 156Fragment identification, 208Fragment ions, 193, 194, 206of GSH conjugates, 340, 342mass data on, 199

    Free radicals, 340Free thiol content, reducing, 207Free thiolsinvestigating, 179mass spectrometric analysis of, 161

    Frequency-sweep signal, 344345Fresh frozen tissue samples, 279Frontal affinity chromatography, 261FT-ICR instruments, ECD and, 176177FT-ICR mass analyzer, 344FT-Orbitrap, 115Full issue image analysis, 278Full scan acquisition, bioanalysis with,

    105106Full scan HRAM-based bioanalysis,

    advantages of, 106. See also High-resolution accurate mass (HRAM) systems

    Full scan HRMS, 415. See also High-resolution mass spectrometry (HRMS)

    Full scan MS analysis, 120. See also Mass spectrometry

    Full scan MS data, 43Full scan MS/MS experiments, 223Full scan tandem mass spectrometry, with

    triple quadrupole instruments, 22Full width at half maximum (FWHM),

    3839, 79, 416Full width at half maximum units, 15

    Gas chromatography (GC), 397Gas chromatographymass spectrometry

    (GC-MS), 391, 392, 394Gas phase chemistry, 28Gas-phase ionization process, 6, 7Gas phase ions, 5

  • INDEx 437

    Gas-phase synthesis, controlled, 248Gene expression, post-transcriptional

    control of, 357Generic data acquisition modes, 108Genomics, 388Global precursor scan, 28GLP preclinical multi-day toxicity testing,

    42GLP-toxicology studies, 120Glucocorticoid receptor (GR) agonistsliquid extraction surface analysis and, 225

    skin penetration for, 316317Glucuronidation sites, derivatization

    techniques for distinguishing, 141Glutamate (Glu), isoGlu residues from, 206Glutamine (Gln) residues, 204Glutathione (GSH), 258259reacting with electrophiles, 340343for trapping/quantitation of reactive metabolites, 351

    Glutathione (GSH) conjugates, 123. See also GSH entries

    Glutathione (GSH) drug conjugates, 4648Glycan composition, correlation to

    attachment site, 160Glycansbiosynthesis of, 158mass spectrometric fragmentation of, 159160

    released from glycoproteins/glycopeptides, 158

    Glycerophospholipids, 60, 61classes of, 61

    Glycoforms, quantitation of, 158159Glycopeptides, analysis of, 158Glycoproteins, analysis of, 158Glycosidic cleavage, 159160Glycosylation, 179of immunoglobulin G, 172

    Glycosylation analysis, 158160Gradient effect, removing, 127Gradient methods, 250GSH adducts, 347, 349, 350. See also

    Glutathione (GSH) entriesdetecting, 350MS/MS survey scan for, 343

    GSH conjugate detection, 340343GSH conjugates, 346347classes of, 343fragment ions of, 340, 342screening, 341, 346347

    GSH-metabolite detection, 229GSH-related species, detecting, 258Guanidine hydrochloride (GdnHCl),


    Hard electrophiles, 340Hard ionization techniques, 306Hard nucleophiles, 340Hardware ruggedness, 3940HC subunits, analyzing, 153. See also

    Heavy chain (HC) mAb fragmentsH/D HPLC-MS exchange experiments,

    195196. See also High-performance liquid chromatographymass spectrometry (HPLC-MS); Hydrogen deuterium (H/D) exchange (HDx)

    HDx data analysis, automating, 173. See also Hydrogen deuterium (H/D) exchange (HDx)

    HDx MS. See also Hydrogen deuterium (H/D) exchange MS

    applications of, 171173challenges related to, 173development of, 173

    HDx MS experiments, basic principles of, 171

    HDx studies, ion mobility MS and, 173Heart, visualizing molecular morphology

    of chick, 285286Heat-stabilized tissue, 279, 280Heavy chain (HC) mAb fragments, 152,

    153, 154, 155Helium, as collision gas, 17, 18Hematoxylin and eosin (H&E) sections,

    291292Henion, Jack D., ix, 221Hepatocyte incubations, 130Hepatocytes, covalent binding in, 340Hepatotoxicity, 339Heterogeneous charge-transfer mechanism,

    8Hexane, 67HFIP (1,1,1,3,3,3-hexafluoro-2-propanol),

    366367HFIP/TEA ion-pairing system, 366367High-aqueous reversed-phase

    chromatography, phase collapse and, 7576

    High-energy CID, 24. See also Collision-induced dissociation (CID)

    High energy collision (HCD) cell, 26

  • 438 INDEx

    High-field asymmetric waveform ion mobility spectrometry (FAIMS), 80. See also Field asymmetric waveform ion mobility entries; Ion mobility spectrometry (IMS)

    High mass ions, 21High MW therapies, 4344. See also

    Molecular weights (MWs)High organic mobile phase, 77High-performance liquid chromatography

    (HPLC), 102103. See also HPLC entries

    chromatographic separations and, 396397

    hyphenation of, 262High-performance liquid chromatography

    high-resolution mass spectrometry (HPLC-HRMS), xi, 44

    High-performance liquid chromatographymass spectrometry (HPLC-MS), 1, 2, 7, 115, 120, 150, 249, 404. See also APCI HPLC-MS applications; HPLC-MS entries

    applications of, 3941coupled with in-line radioactive detector, 136

    with high-resolution mass spectrometers, 105108

    in impurity/degradation product analysis, 213

    in PEGylated protein analysis, 167sensitivity and specificity of, 251

    High-performance liquid chromatographytandem mass spectrometry (HPLC-MS/MS), xi, 55, 77, 109110, 150, 404. See also HPLC-MS/MS entries

    in determining PEGylation site, 166importance of, 240in impurity/degradation product analysis, 213

    peptide mapping using, 211with triple quadrupole mass spectrometers, 100105

    High-performance liquid chromatography (HPLC) with high-resolution accurate mass spectrometry (HPLC-HRAMS), 7879. See also HPLC-HRAMS entries

    ability to detect ions, 78for drug quantitation, 79HPLC-SRM vs., 7879platforms for, 78

    High resolution (HR), product ion selection at, 420

    High-resolution accurate mass spectrometers, 7778

    High-resolution accurate mass spectrometry (HRAMS), 56, 7779

    High-resolution accurate mass (HRAM) systems, for metabolomics, 397. See also LC-HRAM

    High-resolution instruments, improvements in, 405

    High-resolution mass spectrometry (HRMS), xi, 40, 41, 43, 106, 343345, 405. See also HRMS entries

    for biological sample analysis, 414415for biomarker discovery and compound assessment, 42

    future trends in, 28implementation of, 40for new drug discovery applications, 3754

    for peptide quantification, 414420for regulated analysis, 41role in quantitative bioanalysis, 421technological advancements in, 37

    High-resolution mass spectrometers (HRMSs), 49, 115

    future trends in, 142for metabolite detection, 121123for structural elucidation, 123124use of, 121124

    High-resolution MS experiments, 192. See also Mass spectrometry

    High-resolution MS hardware, 106High spatial/mass resolution system, 43High-throughput assay methods, rapid

    implementation of, 249High-throughput indirect mass

    spectrometric screening assays, 261High-throughput screening (HTS)

    libraries, 239. See also HTS compound libraries

    HILIC column technologies, 241. See also Hydrophilic interaction liquid chromatography (HILIC)

    Hillenkampf, F., 11HIV-fusion inhibitor, 412HMDB library, 395Homogeneous/heterogeneous reaction

    environments, coupling of MS to, 261Honing, Maarten, ix, 239Hopfgartner, Grard, ix, 1

  • INDEx 439

    HPLC-atmospheric pressure chemical ionization (APCI)-MS, 140

    HPLC-electrospray ionization (ESI)-MS, 127

    HPLC ESI-MS, 366. See also Electrospray ionization (ESI); High-performance liquid chromatographymass spectrometry (HPLC-MS)

    HPLC-ESI-MS/MS, 140. See also High-performance liquid chromatographytandem mass spectrometry (HPLC-MS/MS)

    HPLC-HRAMS bioanalytical methods, mass resolving power for, 7879. See also High-performance liquid chromatography (HPLC) with high-resolution accurate mass spectrometry (HPLC-HRAMS)

    HPLC-HRAMS parameters, evaluation of, 79

    HPLC-MS analysis, 128. See also High-performance liquid chromatographymass spectrometry (HPLC-MS)

    HPLC-MS assays, 44HPLC-MSE, 156. See also MSE entriesHPLC-MS injections, 120HPLC-MS methods, performance of, 59HPLC-MS/MS-based assay methods, 251.

    See also High-performance liquid chromatographytandem mass spectrometry (HPLC-MS/MS)

    improved sensitivity of, 249HPLC-MS/MS bioanalysis, 5556, 75lysophospholipids in, 6869quantitative, 85

    HPLC-MS/MS bioanalytical methods, development of, 82

    HPLC-MS/MS method development, 100HPLC/MS/MS peptide mapping analysis,

    204206HPLC-MS/MS quantification, of amyloid

    peptides, 413HPLC-MS/radiometry, sample analysis

    using, 136139HPLC-MS response, 127HPLC-MS techniquesadvances in, 142in structural elucidation, 140

    HPLC-NSI-MS, 127HPLC separation, coupling ESI-TOF with,

    151HPLC separation methods, 116

    HPLC-SRM bioanalytical methods, 77. See also Selected reaction monitoring (SRM) entries

    HPLC-HRAMS vs., 7879HPLC systems, to remove gradient effect,

    127HPLC-UVbased purity assays, 252. See

    also Ultraviolet (UV) entriesHPLC-UV-MS, 245HPLC-UV quantitative analysis, 251HRAM mass spectrometers, for

    metabolomics, 397HRAMS resolving power, 7879. See also

    High-resolution accurate mass spectrometry (HRAMS)

    HR-HPLC/MS/MS experiments, 196, 213. See also High-performance liquid chromatographytandem mass spectrometry (HPLC-MS/MS); High resolution entries

    HR-LC/MS/MS experiments, 196. See also Liquid chromatographytandem mass spectrometry (LC-MS/MS)

    HRMS instruments, 121, 420, 421. See also High-resolution mass spectrometry (HRMS)

    for quantitative bioanalysis, 414HRMS research, future trends in, 4849HRMS spectral data, transformation of raw,

    419420HRMS SRM strategy, 420. See also Selected

    reaction monitoring (SRM) entriesHRMS systems, 3839HRMS technologies, 345346, 405advances in, 343, 351

    HSH trapped adducts, rapid detection of, 349

    HSQC NMR spectrum, 264. See also Nuclear magnetic resonance (NMR)

    HTS compound libraries, 251252. See also High-throughput screening (HTS) libraries

    Human ADME studies, 132. See also Absorption, distribution, metabolism, and excretion (ADME) entries

    Human cancer tissue, investigations of, 288

    Human circulating metabolites, 128profile of, 118

    Human metabolism data, 117118Human metabolite testing, qualifications

    regarding, 116

  • 440 INDEx

    Human metabolome consortium projects, 395

    Human Metabolome Project, 395Human Plasma Metabolome (HuPMet),

    395Human plasma phospholipids, techniques

    for monitoring, 63Hybrid FT-ICR instruments, 345. See also

    Fourier transformion cyclotron resonance (FT-ICR)

    Hybrid ion activation techniques, 370Hybrid mass spectrometers, 19, 22, 27, 120Hydrazine-based derivatives, 327Hydrochlorothiazide, 232Hydrodynamic instability, 45Hydrogen deuterium (H/D) exchange

    (HDx), 140, 171173, 180, 213combined with MALDI-MS, 211, 260261

    Hydrogen/deuterium exchange experiments, 48

    Hydrogen deuterium (H/D) exchange MS, 252. See also HDx MS entries

    Hydrophilic interaction liquid chromatography (HILIC), 77, 241, 397

    Hydrophobicity, ion-pairing reagents with increasing, 366367. See also siRNA hydrophobicity

    Hydroxy acid drugs, 7071, 72lactone metabolites of, 73

    ICH: M3(R2) guidance, 116ICR cell, 345. See also Fourier transform

    ion cyclotron resonance (FT-ICR)Idiosyncratic drug reactions, electrophile-

    associated, 46IgG1 antibody, 208. See also

    Immunoglobulin entriesIgG2 disulfides, 161162IgG2 isoform composition, 162IgG2 mAb, modified form of, 154155. See

    also Monoclonal antibodies (mAbs)Imaging, unconventional applications for,

    323326. See also Autoradiography imaging; DESI imaging; Drug/metabolite imaging application; Drug imaging; Magnetic resonance imaging (MRI); MALDI imaging entries; Mass spectrometry imaging entries; Semi-quantitative imaging technology; SIMS imaging; Tissue images

    Imaging analysis, matrix applications for, 281

    Imaging-capable MS platforms, 304Imaging data, quantification of, 328329Imaging mass spectrometry (IMS). See also

    IMS entries; Ion mobility mass spectrometry (IMMS, IMS); Ion mobility spectrometry (IMS); Mass spectrometry imaging (MSI)

    abscesses examined by, 291applications to bacterial imaging, 290292applications to cancer research, 288290applications to histology, 284288in classifying HER2 status, 289for drugs and metabolites, 303337fundamentals of, 312315future developments in, 326329imaging via, 277lens protein distribution and, 287288methodology of, 278284molecular morphology visualization using, 285286

    peptide analysis via, 294296of proteins/peptides, 277302in redefining brain regions, 286287sample preparation for, 278280

    Imaging technologiesconventional, 304305optimizing and advancing, 277

    Imatinib, distribution/quantitation of, 328Iminium ions, cyanide-trapped reactive, 350Immunoglobulin G (IgG), glycosylation of,

    172. See also IgG entriesImmunoglobulin (Ig) molecules, 152Immunological assays, drug development

    programs and, 403404Impuritiescharacterization of, xii, 191cysteine-related, 207profiling and identification of, 251in small-molecule pharmaceuticals/biologics, 191220

    Impurity ions, characterization of, 194197Impurity profiling, 243245of large biomolecules, 419

    Impurity structures, 197IMS instrumentation, 281283. See also

    Imaging mass spectrometry (IMS); Ion mobility mass spectrometry (IMMS, IMS); Ion mobility spectrometry (IMS)

    IMS technology, as a tool for in situ molecular assays, 296

    IMS-TOF device, 48, 50. See also Time-of-flight (TOF) entries

  • INDEx 441

    Incubation/analysis, 107Incubations, microsomal and hepatocyte,

    130Incurred sample applications, in method

    development, 8082Incurred sample extract, analysis of, 84Incurred sample reanalysis (ISR), 56. See

    also ISR conceptIncurred samples, 56for method testing, 8384pooled, 81

    Induced degradation, 212Inductively coupled plasma (ICP), 1314Inductively coupled plasmaatomic

    emission spectroscopy (ICP-AES), 325326

    Inductively coupled plasma mass spectrometry (ICP-MS), 1, 1314

    Industrial validation, 262Information assembly, 82Information-dependent analysis (IDA),

    108Information-dependent analysis (IDA) MS

    experiments, 223224Infrared (IR) lasers, 10Infrared (IR) multiphoton dissociation

    (IRMPD), 176, 370Ingelse, Benno, ix, 239Inhaled tiotropium (ITP), spatial

    distribution of, 316Initial metabolism assessment, strategy for,

    130Injection solvents, 85In-line radioactive detector, HPLC-MS

    coupled with, 136Inorganic ions, analysis of, 3In situ digestion, 292In-source decay (ISD), 284in determining PEGylation site, 166

    In-source fragmentation (ISF), 124in determining PEGylation site, 166

    In-source fragmentation spectra, 175Instrumentation, 3839, 115. See also

    Analytical instrumentation; FT-ICR instruments; High-resolution instruments; HRMS instruments; Hybrid FT-ICR instruments; Ion cyclotron resonance instrument; Ion mobility instruments; Ion trap instruments; LIT-FT-ICR instruments; MALDI-TOF instruments; Mass spectrometric approaches/instruments;

    MS instrumentation; NanoMate instruments; Orbital trapping instruments; Q-trap instrument; Quadrupole instruments; Quadrupole-time-of-flight (QqTOF) instruments; TOF instruments; TOF trapping instruments; Triple quadrupole (QqQ, QQQ) instruments

    Instrumentation duty cycles, impact of, 420421

    Intact duplex detection, disadvantages of, 375

    Intact endogenous peptides, 294296Intact glycoproteins, analysis of, 158Intact lysozyme, bioanalysis of, 418419Intact mAb molecules, HPLC-MS analysis

    of, 153154Intact mass analysis, 151155, 179Intact protein analysis, applications of,

    284292Intact protein ions, fragmented ions and,

    175Intelligent data-dependent acquisition

    processes, 142Intelligent data mining tools, in screening

    reactive metabolites, 339355Interference, 6974Intermediate formation, 258Internal standards (IS, ISTD), 410radiolabeled peptides as, 178

    In vitro ADME assay automation, 109. See also Absorption, distribution, metabolism, and excretion (ADME) entries

    In vitro ADME assays, mass spectrometry for, 97113

    In vitro ADME assay samples, analyses of, 99

    In vitro ADME bioanalysis, 99100, 102In vitro ADME profiling, 110In vitro ADME sample reduction, through

    cassette incubation/analysis, 104In vitro ADME samples, analyses of, 103In vitro ADME support, 100, 102103, 106,

    109In vitro experiments, 97In vitro incubations, 258In vitroin vivo correlations (IVIVCs), 97In vitro metabolic stability assays, 107In vitro metabolism profiles, comparing,

    375376In vitro screening assays, 249

  • 442 INDEx

    In vitro studies, with radiolabeled test article, 130

    In vivo AME studies, dose administration and sample collection in, 131

    In vivo cassette dosing, 40In vivo DDI potentials, 99In vivo fixed tissue, 279In vivo imaging technologies, 304In vivo MRI, 326. See also Magnetic

    resonance imaging (MRI)In vivo studies, with radiolabeled test

    article, 130136Ion accumulation, 18Ion chromatograms, 348Ion cyclotron frequency (f), 344345Ion cyclotron resonance instrument, 25Ion cyclotron resonance mass systems, 2Ion detection, 1415, 25Ion/electron molecule reactions, 9Ion evaporation, 5Ion evaporation model (IEM), 4, 5Ion exchange (IEx) chromatography, 162,

    171Ion filtering devices, 48Ion-flight-time equation, 343Ionic compounds, 11Ion/ion reactions, 370Ionization, of peptides, 406407Ionization efficiency, 241of analytes, 225of DESI, 311enhancement of, 407reduction in, 362

    Ionization methods, alternative, 28Ionization process, 7Ionization suppression, 108109Ionization techniques, 1, 214, 21improvements in, 245variety in, 252

    Ionization technologies, future trends in, 142

    Ion mobility, 28differences in, 80

    Ion mobility instruments, 174, 282Ion mobility mass spectrometry (IMMS,

    IMS), 27, 173174, 180, 404. See also IMS entries; Ion mobility spectrometry (IMS)

    advantages of, 174HDx studies and, 173

    Ion mobility separation (IMS), 48, 50. See also IMS entries

    Ion mobility separation, 173174, 283Ion mobility spectrometry (IMS), 173174,

    180. See also IMS entriescoupled with MS instruments, 173174

    Ion motion, 14in quadrupoles, 14

    Ion-pairing (IP) reagents, 362with increasing hydrophobicity, 366367

    Ion-pair reversed-phase HPLC (IP-RP-HPLC), 366

    Ions, electrostatically trapped, 38Ion separation, 27Ion signal intensity, 170Ionspray, 2. See also Electrospray entriesIon suppression, 60Ion trap instruments, 413414. See also

    Orbitrap entries; Q-trap instrumentIon trap mass spectrometers, 255. See also

    IT mass spectrometersIon trap mass spectrometry, 413414Ion traps (ITs), 1720, 115. See also Linear

    ion traps (LITs); Quadrupole ion trap entries; Two-dimensional (2D) ion traps (LTQs)

    linear quadrupole, 38mass ranges of, 18

    Ion trap technology, published reports on, 414

    IS addition, 69Isoaspartate (isoAsp, iso-Asp)amount in proteins, 167168Asp products vs., 177

    Isoaspartate (isoAsp) residues, 206Isobaric metabolitesidentification of, 123124interference from, 7173

    Isobaric phase 2 metabolites, 124, 125Isobaric phosphate prodrugs, 73Isobaric structures, differentiating between,

    159Isocratic elution, 65Isoelectric focusing (IEF), 204Isoglutamate (isoGlu) residues, 206Isomeric metabolites, 82interference from, 71, 72

    Isopropyl alcohol elution, 6365Isotope envelopes, 375Isotope pattern filter (IPF), 350351Isotopic metabolites, interference from,

    7071, 72, 73Isotopic peaks, 416Isotopic ratios, 2728

  • INDEx 443

    ISR concept, 81. See also Incurred sample reanalysis (ISR)

    ISTD peptides/proteins, 179IT mass spectrometers, 120121. See also

    Ion trap entriesIT-TOF hybrid mass spectrometer, 344. See

    also Time-of-flight (TOF) entries

    Jemal, Mohammed, ix, 55Jetstream spray device, 41

    Karas, M., 11Ketone metabolites, 73Kidney abscesses, examined by IMS, 291Kinetic assays, 250251Kinetic energy, in TOF analysis, 2021Kinetic method, 248Kits, absolute metabolite quantitation,

    393Korfmacher, Walter A., ix, xiiKretschmer algorithm, 378

    Label/tracer requirements, 305Lactone group, 5657Lactone metabolites, of hydroxy acid drugs,

    73Lactones, chromatographic separation

    interference due to, 7071, 72Ladder sequence ions, 407Large biomolecules, impurity profiling of,

    419Large peptides, direct analysis of, 158Larger molecule therapies, analysis of, 326Larger proteins, quantitative workflows for,

    404Laser ablation electrospray ionization

    (LAESI), 1011, 109Laser beams, to probe tissue, 43Laser desorption, 10Laser diode array thermal desorption

    (LDTD), 109Laser-induced dissociation (LID) MS/MS,

    24Laser ionization, 11Lasers, 282283LC-ARC system, 139. See also Liquid

    chromatography entriesLC column effect, 66LC-ESI-MS, 279. See also Electrospray

    ionization (ESI); Mass spectrometry entries

    LC-fluorescence, 263

    LC-HRAM, 106. See also High-resolution accurate mass (HRAM) systems

    LC mobile/stationary phases, screening of, 83

    LC-MS chromatograms, 263. See also Liquid chromatographymass spectrometry (LC-MS)

    LC-MS data, 118fingerprinting analysis of, 391, 392

    LC-MS/MS bioanalysis, avoiding pitfalls in, 5680. See also Liquid chromatographytandem mass spectrometry (LC-MS/MS)

    LC-MS/MS ion chromatogram, 346LC-MS/MS methods, in analyses of small

    molecules from biological matrices, 372

    LC-MS/MS platforms, 303LC-MS/MS quantitation data, discrepancies

    in, 329LC-MS/MS screening, development of, 248LC-MS peptide maps, mirror plots of, 157LC-MS platforms, 243LC-MS response, influence of

    oligonucleotide sequence/chemical modifications on, 362364

    LC-MS spectra, 124LC-MS (FT) spectra, 125. See also Fourier

    transform mass spectrometry (FT-MS)LC-MS techniques, siRNA-related, 366368LC-MS total ion chromatogram, 193LC platforms, 243LC-Q-TOF MS/MS, 242. See also Fast

    scanning Q-TOF MS/MS systems; Time-of-flight (TOF) entries

    LC-SRM, 106. See also Selected reaction monitoring (SRM) entries

    LC-SRM technique, 77LC subunits, analyzing, 153LC/UV chromatograms, 199. See also

    Ultraviolet (UV) entriesLead compound, discovery of, 239240Lead optimization (LO) compounds, 243Lean thinking initiative, 240Lens protein distribution, 287288LESA applications. See also Liquid

    extraction surface analysis (LESA)additional, 229233in drug discovery/development, 224229future for, 232

    LESA-LC approach, 233. See also Liquid chromatography entries

  • 444 INDEx

    LESA-LC-MS approach, 233. See also Liquid chromatographymass spectrometry (LC-MS)

    LESA-MS profiling, 225. See also Mass spectrometry entries

    LESA-MS-SRM, 227, 228. See also Selected reaction monitoring (SRM) entries

    LESA sampling process, 227229LESA schematic, 223LESA spatial resolution, 233LESA system operation, 233Libraries, web-based, 395, 396Light chain (LC) mAb fragments, 152, 153,

    155. See also Monoclonal antibodies (mAbs)

    Limited throughput issue, solutions to, 245Limit of quantification (LOQ), 178. See also

    Lower limit of quantitation (LLOQ)of siRNAs, 362

    Linear ion traps (LITs), 12, 1819, 120, 344, 405. See also LIT entries

    quadrupole ion traps vs., 17Linear quadrupole ion trap, 38, 120Lipid analysis, 229Lipid nanoparticles (LNPs), 4445Lipinski rule of five, 246Lipophilicity, assessment of, 249250Liquid chromatography (LC), coupled with

    triple quadrupole mass spectrometer, 100. See also LC entries

    Liquid chromatographyhigh-resolution mass spectrometry (LC-HRMS), in screening reactive metabolites, 339355

    Liquid chromatographymass spectrometry (LC-MS), 242, 305, 391, 392, 394. See also LC-MS entries

    quadrupoles used for, 15of siRNAs, 362

    Liquid chromatography (LC) separation, 170

    Liquid chromatographytandem mass spectrometry (LC-MS/MS). See also LC-MS/MS entries

    approaches for reactive metabolite screening, 340343

    for quantification of therapeutic mAbs, 178

    Liquid extraction probe, 9Liquid extraction surface analysis (LESA),

    xii, 221238. See also LESA entriesin automatic analyte extraction, 231232DART vs., 229231glucocorticoid receptor agonists and, 225

    for identifying pesticides, 229interest in, 234outlook and future development of, 233234

    shotgun lipidomic approaches and, 229spatial resolution of, 224whole-body drug distribution and, 225227

    Liquid extraction surface analysis mass spectrometry (LESA-MS), 222. See also LESA-MS entries

    advantages and limitations of, 234235applications of, 234applied to toxicological samples, 231extraction efficiency of, 227229

    Liquid extraction surface analysis (LESA) process, 222224

    Liquid junction, 224Liquidliquid extraction (LLE), 57, 58, 84,

    134, 366. See also LLE entriesfor drug and metabolite extraction, 6669

    Liquid microjunction surface sampling probe (LMJ-SSP), 910, 222

    Liquid scintillation counting (LSC), 28LIT/FT-CR combination, 25. See also

    Fourier transform mass spectrometry (FT-MS); Linear ion traps (LITs)

    LIT-FT-ICR instruments, 345. See also Fourier transformion cyclotron resonance (FT-ICR) entries

    LIT MALDI, 13. See also Linear ion traps (LITs); Matrix-assisted laser desorption/ionization (MALDI)

    LIT-TOFMS, 19. See also Mass spectrometry entries; Time-of-flight (TOF) entries

    LLE extract, 65. See also Liquidliquid extraction (LLE)

    LLE-SPE combination extraction method, 365366. See also Solid phase extraction (SPE)

    LLOQ chromatograms, for Enfuvirtide, 417. See also Lower limit of quantitation (LLOQ)

    LLOQ peak areas, 410, 411Locked nucleic acids (LNAs), 361Lock masses, 22LockSpray, 22Loss of adduct, 159160Lower limit of quantitation (LLOQ), 38, 40,

    41, 66, 78, 82, 99, 408412. See also LLOQ chromatograms

    Low mass ions, 21

  • INDEx 445

    Low molecular weight compounds (LMWCs), 1, 12. See also Molecular weights (MWs)

    analysis of, 13LTQ-FT, 44. See also Fourier transform

    mass spectrometry (FT-MS); Two-dimensional (2D) ion traps (LTQs)

    LTQ-Orbitrap, 2627LTQ-Orbitrap mass spectrometers, 121, 347advantages of, 193

    Lung tumor tissue, protein profiles from, 288

    Lx-0722, 122Lyso-PC, in LLE plasma extracts, 6768Lyso-PC phospholipid class, 61, 62. See also

    Phosphatidylcholine (PC) phospholipid class

    in HPLC-MS/MS bioanalysis, 6869Lyso-PC species, 68Lysophospholipids, 61, 62, 65Lysozyme, bioanalysis of, 418419

    M + 1/M + 2 isotopic contributions, 73M10 metabolite, 124Ma, Shuguang, x, 339mAb fragments, 151152. See also

    Monoclonal antibodies (mAbs)mAb ISTD, 178mAb quantification methods, improvements

    in, 178mAb therapeutic proteins, structure of, 153Macromolecule exclusion, 59Magnetic resonance imaging (MRI),

    304305. See also In vivo MRI; MRI contrast agent

    Magnetron motion, 25MALDI analyses, 281, 282283. See also

    Matrix-assisted laser desorption/ionization (MALDI)

    MALDI images, 319, 320as complementing autoradiography, 323in whole-body sections, 321322

    MALDI imaging, 233, 310, 329derivatization for, 327DESI imaging vs., 311development of, 326future developments in, 326329unconventional applications for, 323326

    MALDI imaging analysis, 323MALDI imaging experiment, 227, 229MALDI ion production process, 23MALDI lasers, 312MALDI mass spectrometric imaging, 306

    MALDI mass spectrometry, H/D exchange and, 260261. See also MALDI MS entries; MALDI-TOF MS; Matrix-assisted laser desorption/ionizationmass spectrometry (MALDI-MS)

    MALDI matrices, 11, 12, 280MALDI-MS/MS imaging, of astemizole,

    316, 317. See also MALDI mass spectrometry; Matrix-assisted laser desorption/ionizationmass spectrometry (MALDI-MS); Tandem mass spectrometry (MS/MS)

    MALDI MS platform, 304MALDI spectra, 159MALDI/SRM, 109. See also Selected

    reaction monitoring (SRM) entriesMALDI-TOF instruments, 21, 283, 312313.

    See also Time-of-flight (TOF) entriesMALDI-TOF MSin characterizing PEGylated proteins, 165in detecting siRNA duplexes, 362

    MALDI-TOF reISD MS, 166. See also Reflectron entries

    Mammalian gene expression, altering, 357Mammalian systems, investigating for

    neuropeptide distribution, 295Mass accuracy data, 196197Mass analyzers, 1428, 115, 240. See also

    FT-ICR mass analyzerchoosing, 253coupled to MALDI sources, 281for MS analysis, 26quadrupole, 14, 15, 1617, 407408TOF, 11, 13, 22, 23, 344variety in, 252

    Mass-based data mining tools, for reactive metabolite screening, 345351

    Mass-based pattern isotope filter, 351Mass chromatograms, 105Mass data, on fragment ions, 199Mass defect, 347Mass defect filtering (MDF), 46, 121. See

    also MDF entriesMass defect filters (MDFs), 256, 347348drug metabolite identification using, 4548

    Mass determination, effects on, 22Mass extraction window (MEW), 416419centroid mode and, 420effect of, 79

    Mass ladders, 368369Mass measurements, metabolite

    differentiation and, 375, 376

  • 446 INDEx

    Mass-MetaSite, 108Mass reflectron, 21Mass resolution, 25, 46Mass resolving powerfor HPLC-HRAMS bioanalytical methods, 7879

    influence on quantification, 416419Mass-selective axial instability mode,

    1718Mass-selective ejection, 17Mass spectral interference, 56Mass spectrometers (MSs), 241in drug discovery/development, 135for metabolite profiling studies, 121for metabolomics experiments, 397miniaturization of, 28

    Mass spectrometric approaches, to molecular structure elucidation, 246247

    Mass spectrometric approaches/instruments, in drug metabolism studies, 126

    Mass spectrometric detection, enhancing, 7780

    Mass spectrometric imaging (MSI) applications, 13

    Mass spectrometric interference, 6973, 81Mass spectrometric monitoring, of

    phospholipids, 6162Mass spectrometric (MS) techniquesfor biologics applications, 213future development of, 170179success of, 124

    Mass spectrometry (MS), 43. See also APCI-MS

    ADME assays and, 99100advantages of, 303analyzing siRNAs by, 364application to drugs/metabolite distribution in tissues, 329

    of biological drugs, proteins, and peptides, 149190

    broad application of, 142capabilities of, 221222in characterizing PEGylated therapeutic proteins, 164165

    coupled to (semi)-preparative LC/SFC, 242243

    coupling of homogeneous/heterogeneous reaction environments to, 261

    for cysteine connectivity determination, 161

    future trends in, 28

    as the generic platform for model compounds, 262

    metabolite identification using, 115147for protein quantification, 177in PTM characterization, 167quantitative analysis of peptides using, 403425

    for quantitative in vitro ADME assays, 97113

    role in chemical structure elucidation, 245248

    role in pharmaceutical R&D, 303role in protein structure investigation, 179

    role of, 240of siRNAs, 357385siRNA sequencing by, 368372in therapeutic protein discovery/development, 149150

    utility of, xixiiMass spectrometry (MS) applicationsin biological drug discovery/development, 150

    supporting medicinal chemistry sciences, 239275

    Mass spectrometrybased techniques, for ambient surface profiling, 221238

    Mass spectrometry imaging (MSI), xii, 1. See also Imaging mass spectrometry (IMS)

    sample preparation for, 313315use of, 303304

    Mass spectrometry imaging (MSI) techniques, 221222

    Mass spectrometry imaging (MSI) technologies, for drug discovery, 305312

    Mass spectrometry metabolomics, 387401

    chromatographic/nonchromatographic solutions for, 396397

    Mass spectrometry sensitivity, lack of, 362Mass spectrum (spectra), 15. See also

    MALDI spectradeconvoluted, 209generating, 18, 21

    Matrix (matrices). See also Biological matrices; Biomatrices; MALDI matrices

    applying to tissue surfaces, 314315deposited on tissues, 281for drug analysis, 314

  • INDEx 447

    used for matrix-assisted laser desorption/ionization, 12

    used in MALDI-MS analysis, 368Matrix applications, 280281Matrix-assisted laser desorption/ionization

    (MALDI), 1, 1113, 391, 394. See also MALDI entries

    development of, 109, 312ESI vs., 13introduction of, 277protein identification and, 22sample preparation for, 365366SIMS vs., 312siRNA chemistries and, 361

    Matrix-assisted laser desorption/ionization ESI (MALDIESI), 10. See also Electrospray ionization (ESI)

    Matrix-assisted laser desorption/ionizationmass spectrometry (MALDI-MS), 1213, 192. See also MALDI mass spectrometry; MALDI-MS entries

    acid hydrolysis and, 369H/D exchange combined with, 211of siRNA, 368

    Matrix-assisted laser desorption/ionizationtime of flight (MALDI-TOF), 13, 151, 179. See also MALDI-TOF entries

    in optimizing PEGylation reaction, 165166

    Matrix effects, 5969assessment of, 60plasma phospholipid association with, 6065

    Matrix-free laser desorption/ionization, 11Matrix interference peaks, 417Matrix parameters, 280281Matrix/solvent system, analyte-appropriate,

    314Matthieu equations, 14, 17MDF-based acquisition, 123. See also Mass

    defect filtering (MDF)MDF templates, 347Medicinal chemistryin drug discovery process, 239new methodologies in, 241

    Medicinal chemistry support, 239Medicinal chemistry sciences, MS

    applications supporting, 239275Mehl, John, x, 149Metabolic activity samples, quantitation of,

    106Metabolic clearance, rapid, 258

    Metabolic hotspot screening, 253258Metabolic pathways, 253Metabolic profile data, 49Metabolic profiles, in animals, 130Metabolic stability assays, 97, 106, 253254,

    255Metabolismrole in drug safety profile, 116systematic evaluation of, 55

    Metabolism assays, 98. See also Metabolic stability assays

    Metabolite characterization, 115Metabolite conversion, 74Metabolite coverage, understanding, 129Metabolite detection, 132, 139140HRMS for, 121123

    Metabolite detection approaches, 120121Metabolite detection/identification, data

    mining tools for, 256258Metabolite differentiation, mass

    measurements and, 375, 376Metabolite exposure level, 45Metabolite exposures, estimating, 119Metabolite extraction, LLE for, 6669Metabolite formation, 124Metabolite identification, xixii, 48, 106. See

    also Drug metabolite identification; Metabolite profiling/identification

    future trends in, 141142siRNA chemistries and, 361using mass spectrometry, 115147

    Metabolite imaging applications, imaging mass spectrometry for, 315326

    Metabolite interference, 73, 8081due to conversion to parent drug, 7374

    Metabolite mass spectrometric interference, 6973

    MetabolitePilot, 108Metabolite/prodrug interference, 72Metabolite profiles, 139Metabolite profiling, 121categories of, 116117outline of studies conducted during drug development, 117

    radiolabeled test articles for, 139in studies without radiolabeled test article, 117129

    in studies with radiolabeled test article, 130141

    Metabolite profiling/identification, 115116Metabolite quantitation, 73from nonradiolabeled studies, 124129

  • 448 INDEx

    Metabolite quantitation kit, 393Metabolitescharacterization of, 46chemically reactive, 339containing ester groups, 74drug generation from, 70, 80, 82imaging in whole-body sections, 321322imaging mass spectrometry for, 303337in silico prediction of, 256instability of, 56, 133ionization efficiencies of, 127MS in-source conversion of, 80qualitative analysis of, 414unstable, 133

    Metabolite screeningusing scanning MS, 255256using targeted MS, 254255

    Metabolite screening studies, design of, 254Metabolite sequences, identified, 377Metabolites in safety testing (MIST), 116Metabolite SRM table, 84. See also Selected

    reaction monitoring (SRM) entriesMetabolite steady state, 119Metabolome, defined, 387388Metabolome measurement, 388analytical approaches for, 390395, 396main approaches to, 390MS techniques for, 390391

    Metabolome studies, procedure for, 389Metabolomic biomarkers, 42Metabolomic experiments, steps in, 389390Metabolomic libraries, 395, 396Metabolomic profiling, 388Metabolomics, xii, 388defined, 387in drug discovery, 388390future trends in, 397398mass spectrometry for, 387401MS instrumentation for, 397

    Metabolomic studies, success of, 390MetaboLynx xS with MassFragment, 108Metabonomics, 387Metaiodobenzylguanidine (MIBG),

    intratumor biodistribution of, 307Metal-enhanced SIMS (MetA-SIMS), 307.

    See also Secondary ion mass spectrometry (SIMS)

    Methanol, 74in sample extraction, 134, 135

    Methionine (Met) oxidation, 206207, 212Methionine (Met) residues, oxidation of,


    Method design, 74Method developmentincurred sample applications in, 8082steps in, 8385

    Method validation, 84852-Methyl-1-butanol, 67Methyl ester group, 74Methyl ether group, 73Methyl-tert-butyl ether (MTBE), 67, 68, 69METLIN library, 395Met sulfoxide, 207. See also Methionine

    (Met) entriesMicrochannel plate (MCP) electron

    multipliers, 2122Microplate scintillation counter, 137, 138Microplate scintillation counting (MSC),

    136Microsomal incubations, 130Microsomal metabolites, profiling of,

    121123Microspotted arrays, for imaging, 281Middle-down experiments, 176Mid-infrared (mid-IR) lasers, 10Minimally fixed tissue samples, 279Minimal resolving power, 419Mirror plots, 157MIST-related risks, 116MMCD library, 395Mobile phase screening, 7475Modified chromatographic conditions,

    8182Modified siRNAs, quantification of, 373.

    See also Small interfering RNAs (siRNAs)

    Modulated RF voltage, 22. See also Radio frequency (RF)

    Molecular constitution, 252253Molecular weights (MWs), 192. See also

    High MW therapies; MW informationmedicines with high, 43of peptide degradants, 205

    Mometasone furoate, 193194, 197Monoclonal antibodies (mAbs), 151. See

    also mAb entriesintact mass analysis of, 151152quantitative analysis of, 177179therapeutic, 149top-down MS for, 176trisulfide modifications in, 208truncation sites in, 208210

    Monolithic capillary columns, 367Monolithic columns, 59

  • INDEx 449

    MRI contrast agent, distribution of, 325326. See also Magnetic resonance imaging (MRI)

    MS2 trap CID, 18, 1920. See also Collision-induced dissociation (CID); Mass spectrometry entries

    MS acquisition schemes, 28MS analysisof free thiols, 161of IgG2 disulfides, 161162of peptides, 406

    MS-based quantification, of peptides, 404MS-based quantitation, 109110MS-based strategies, 192MS-based technologies, potential of, 259MS data, evaluating, 252MS-directed purification, 242MSE experiments, 348MSE methodology, 371372MSE mode, 108, 255256MS hardware, high-resolution, 106MS (HRAM), bioanalysis using, 106. See

    also High-resolution accurate mass (HRAM) systems

    MSI absolute quantitative data, 233234. See also Mass spectrometry imaging (MSI) entries

    MSI methods, advantages of, 234MS instrumentation, 312313advancement in, 180IMS coupled with, 173174for metabolomics, 397

    MS methodologies, potential of, 248MS-MS (IT) spectra, 125. See also Tandem

    mass spectrometry (MS/MS)MS/MS acquisition schemes, 28MS/MS analysis, advantages of, 313MS/MS data, 121123MS/MS fragmentation, 253siRNAs and, 364

    MS/MS fragmentation pattern, 315MS/MS imaging, of astemizole, 316, 317MS/MS in space, 16MS/MS spectrum (spectra), 20, 123, 124, 247MS/MS survey scans, for GSH adducts, 343MSn data, 121MSn experiments, 120MS response, 127MS techniquesfor metabolome measurement, 391recent developments in, 255

    MS technology, xii

    MTBE LLE extracts, 68. See also Liquidliquid extraction (LLE); Methyl-tert-butyl ether (MTBE)

    Multichannel electrospray inlets, 245Multichannel plate detector (MCP), 21Multiple chromatographic systems,

    nontarget metabolomic approaches utilizing, 394

    Multiple MDF templates, 347Multiplexed HPLC-MS/MS system, 103. See

    also High-performance liquid chromatographytandem mass spectrometry (HPLC-MS/MS)

    Multiplexed LC, 102. See also Liquid chromatography entries

    MultiQuant software, 107Multistage MS systems, 246. See also Mass

    spectrometry entriesMW information, for degradants, 198199.

    See also Molecular weights (MWs)Mycobacterium tuberculosis study, 291292

    Nanoelectrospray (nESI), 4. See also Nano-ESI entries; Nanospray ionization (NSI) technique; nESI chip

    Nanoelectrospray (nESI) emitters, 222223Nanoelectrospray LC-MS, 367. See also

    Liquid chromatographymass spectrometry (LC-MS)

    Nanoelectrospray normalization techniques, 124127

    Nano-ESI interfaces, 245. See also Nanoelectrospray (nESI) entries

    Nano-ESI-QqTOF, 369. See also Time-of-flight (TOF) entries

    NanoMate instruments, 108, 118, 137NanoMate system, 9, 10Nanospray ionization (NSI) technique, 127.

    See also Nanoelectrospray entriesNd:YAG laser, 11Nd:YVO4 laser, 282283Nebulizer probe, 6Negative ESI, 83. See also Electrospray

    ionization (ESI)Negative ESI response, 75Negative ion mode, 410, 412413Negative precursor ion scan technique, 62nESI chip, 234. See also Nanoelectrospray

    (nESI) entriesNeuropeptides, analysis of, 295Neutral loss (NL) scanning, 16, 17, 120,


  • 450 INDEx

    Neutral matrices, 368New biological entities (NBEs), 239synthesis and identification of, 240248

    New chemical entities (NCEs), 239synthesis and identification of, 240248

    New drug discovery applications, high-resolution mass spectrometry for, 3754

    New molecular entities (NMEs), 97, 99New synthesis approaches, implementation

    of, 241NIST (National Institute of Standards and

    Technology) library, 395Nitrogen lasers, 11, 282N-linked glycans, 158, 160NMR technologies, 259260. See also

    Nuclear magnetic resonance (NMR)Noise reduction algorithm (NoRA),

    background subtraction with, 348350Nonchromatographic approaches, to mass

    spectrometry metabolomics, 396397Nonradiolabeled studies, metabolite

    quantitation from, 124129Nonsteroid glucocorticoid receptor (GR)

    agonists, skin penetration for, 316317

    Nontargeted metabolomic analytical techniques, 394395, 396

    Nontargeted metabolomic approaches, utilizing multiple chromatographic systems, 394

    Nontargeted metabolomics, 390, 394395, 396

    annotation in, 395, 396Normalization techniques, 124127No sample wasted approach, 136137N-terminal acetylation, 412Nuclear magnetic resonance (NMR),

    241242, 391, 392, 394. See also NMR technologies

    Nuclease cleavage, 375Nuclease protection, 374Nucleobase modifications, incorporating

    into siRNAs, 360Nucleophiles, 340

    Offline plasma extraction, 5758Olanzapine, 321Oligonucleotide desalting technique, 365Oligonucleotide extraction, 373Oligonucleotide sequences, influence on

    LC-MS response, 362364

    Oligonucleotide sequencing, 368, 370by MS/MS, 369, 378rapid, 378

    Oligonucleotide sequencing software, 376O-linked glycans, 158, 160-omics cascade, 387, 388Oncology drugs, tumor penetration by,

    318319One-column system, 59Online extraction column, 58Online extraction HPLC-MS systems, 59.

    See also High-performance liquid chromatographymass spectrometry (HPLC-MS)

    Online plasma extraction, 5859Open-access analysis, 240242Oppenheimer, Stacey R., x, 303Optimal cutting temperature (OCT),

    313314Optimized RP-HPLC, combined with

    ESI-TOF, 153. See also Reversed-phase (RP) entries; RP-HPLC-MS

    Optimize software, 100102Orbital trapping instruments. See also Ion

    trap entriesfor quantitative bioanalysis, 414TOF trapping instruments vs., 418

    Orbitrap, 48Orbitrap instruments, 421Orbitrap mass spectrometers, 38, 255,

    345Orbitrap mass systems, 2, 19, 2627Orbitrap resolution, 26Orbitrap technology, 78, 106Organic solventseffect of, 69in sample extraction, 133134used in LLE, 67

    Organisms, biochemical state of, 387Organs/tissues, imaging drugs and

    metabolites in, 315320Orthogonal acceleration TOF (oaTOF),

    421. See also Time-of-flight (TOF) entries

    Orthogonal chromatography, 81Orthogonal gas phase separation, 48Orthogonal MALDI (o-MALDI) TOF, 23.

    See also MALDI entries; Matrix-assisted laser desorption/ionization (MALDI); Time-of-flight (TOF) entries

    Orthogonal techniques, 403, 404

  • INDEx 451

    Oxidationfrom analysis of mAb molecules, 153154

    of methionine residues, 170as a modification in proteins, 206207in therapeutic proteins, 170

    Oxidation sites, derivatization techniques for distinguishing, 141

    Oxidative deamination, 73Oxidative defluorination, 124Oxidative degradation pathway, 199201

    Pancreatic cancer tissue microarray, 293IMS analysis of, 294

    Parallel artificial membrane permeability assay (PAMPA), 106, 107, 250

    Parent drugs, metabolite interference due to, 7374

    Parent/fragment information, 46Parent/metabolite quantitation, 108Parkinson brain biomarkers, 294Pauls trap, 26PC species, 68. See also Phosphatidylcholine

    (PC) phospholipid classPeak areas, 410, 411Peak picking algorithm, 351PEG-SOD, 165. See also Poly(ethylene

    glycol) (PEG)PEGylated protein therapeutics, 179PEGylated therapeutic proteins, 164PEGylation analysis, 164167PEGylation site, determining, 166Penner, Natalia, x, 115Pennings trap, 26Peptide analysis, 13, 292294, 294296mass-spectrometric, 149190quantitative, xii, 403quantitative mass-spectrometric, 403425

    using full scan HRMS, 415Peptide biomarkers, in disease assessment,

    403Peptide degradants, molecular weights of,

    205Peptide drug candidates, quantitative

    methods for, 412Peptide fragmentation, 412Peptide fragments, 295296Peptide mapping, 155158, 174artificial degradation in, 211213drawbacks of, 155156improving, 156

    steps in, 155therapeutic protein characterization and, 155

    using HPLC-MS/MS, 211Peptide mapping approach, 210Peptide mapping HPLC-MS/MS analysis,

    207, 211. See also High-performance liquid chromatographytandem mass spectrometry (HPLC-MS/MS)

    Peptide mass mapping, 179Peptide quantificationhigh-resolution mass spectrometry for, 414420

    selected reaction monitoring for, 407414

    Peptide quantification approaches, 405Peptidesas degradation products, 212disulfide-containing, 160in drug development programs, 403404fragmented, 156imaging mass spectrometry of, 277302ionization and fragmentation of, 406407

    lower ion intensities of, 408MS-based quantification of, 404

    Peptide separation, 406Peptide SRM methods, 404. See also

    Selected reaction monitoring (SRM) entries

    Peptidic HIV-fusion inhibitor, 412Permeability assays, 9799pH, of plasma samples, 57Pharmaceutical compounds, analysis of,

    7475Pharmaceutical mapping, in tissues, 312Pharmaceutical products, small molecule

    impurities in, 193Pharmaceutical relevant molecules,

    fragmentation behavior of, 247Pharmaceuticals. See also Drug entries;

    Therapeutic entriesdegradation profiling of, 198derivatizing, 326327impurities and degradation products in small-molecule, 191220

    MS role in R&D of, 303Pharmacokinetic (PK) parameters,

    therapeutic siRNAs and, 372Pharmacokinetic (PK) predictions, 39Pharmacokinetic (PK) profiles/profiling, 40,

    132, 136

  • 452 INDEx

    Pharmacokinetics (PK), 97imaging data quantification for, 328329improving, 164systematic evaluation of, 55

    Pharmacokinetic (PK) studies, 44Phase 2 metabolites, 48Phase collapse, aqueous mobile phase and,

    7576Phosphate prodrugs, 7173Phosphatidic acid (PA) phospholipid class,

    61, 62Phosphatidylcholine (PC) phospholipid

    class, 61, 62Phosphatidylethanolamine (PE)

    phospholipid class, 61, 62Phosphatidylglycerol (PG) phospholipid

    class, 61, 62Phosphatidylinositol (PI) phospholipid

    class, 61, 62Phosphatidylserine (PS) phospholipid class,

    61, 62Phospholipid avoidance strategies, 6569Phospholipid chromatographic elution

    profiles, 64Phospholipid detection, all-inclusive

    technique in, 62Phospholipid extraction, 68Phospholipid removal, during sample

    extraction, 6669Phospholipidschromatographically separating analytes from, 65

    chromatographic elution behavior of, 6265

    chromatographic fate of, 6768collision-induced dissociation of, 6162mass spectrometric monitoring of, 6162rapid elution of, 65

    Phospholipid structures, 61Phosphorothionate-modified siRNAs, 360.

    See also Small interfering RNAs (siRNAs)

    Photoionization probe, 7Photostability testing, 251253Physical degradation, 210211Physicochemical properties, assessment of,

    99, 248259PK/metabolite characterization, 48. See also

    Pharmacokinetic (PK) entriesPK/pharmacodynamic (PD) correlations,

    42Placebo samples, 119

    Plasma. See also Serum entriescollection and storage of, 5657pooling approaches for, 135136

    Plasma concentrationtime profiles, 131, 132

    Plasma extractionoffline, 5758online, 5859

    Plasma phospholipidsassociation with matrix effects, 6065bioanalytical risks posed by, 67

    Plasma pooling, volume calculation for, 135Plasma sample collection, 132Plasma sample extraction procedures,

    evaluating, 84Plasma samples, 118pH of, 57profiling, 129

    Plug and play formats, 407Pneumatically assisted electrosprays, 2Pneumatic nebulization, 5Polar analytesretention and separation of, 7577reversed-phase columns for, 7577

    Polar metabolites, structural elucidation of, 140

    Poly(ethylene glycol) (PEG), 164, 165. See also PEG- entries

    Polymerase chain reaction (PCR). See qPCR techniques; Q-RT-PCR methods; RT-qPCR entries; siRNA qPCR concentrations

    Polymeric sorbents, 58, 59Pooled incurred samples, 81Pooled placebo samples, 119Pooling, of biological samples, 135136. See

    also Sample poolingPorous graphitic carbon (PGC), 7576Posaconazole (SCH 56592), degradation

    products of, 198201Positive electrospray (ESI) selected

    reaction monitoring (SRM), 6162Positive ESI, 83Positive ESI response, 75Positive ion mode, 410, 412Positive/negative mode electrospray

    analyses, 394Positive neutral loss scan technique, 62Positive precursor ion scan technique, 62Positron emission tomography (PET), 304Positron-emitting nuclides, 304Post-acquisition data filtering, 121

  • INDEx 453

    Post-acquisition data processing software, 40

    Post-acquisition data processing software tools, 121

    Post-analysis processing software tools, 121, 142

    Post-column analyte addition, 60Post-column infusion system, 60Post-ion/ion trap CID spectrum, 371. See

    also Collision-induced dissociation (CID)

    Post-run data mining, 123Postsource decay (PSD), 284Post-transcriptional gene regulation,

    357358Post-translational modifications (PTMs),

    150, 180. See also PTM analysisin proteins/peptides, 203

    Potassium adducts, 3Prakash, Chandra, x, 115Pramanik, Birendra N., x, 239Pravastatin, 74Pravastatin lactone, 74Preclinical ADME programs, investment in,

    131. See also Absorption, distribution, metabolism, and excretion (ADME) entries

    Precursor ion approach, 346347Precursor ion mode, 1617, 23Precursor ions (PIs), 20isolation of, 22isolation window of, 24mass measurements of, 26

    Precursor ion (PI) scans, 22, 23, 62, 120, 346347

    Primary sequence characterization, 151158Principal component analysis (PCA), 391,

    392Principal component analysis (PCA)

    followed by discriminant analysis (DA) (PCA-DA), 293

    Pristatsky, Pavlo, x, 149Probe-specific analysis, 99Prodrugs, 133instability of, 56, 57

    Product ion mass spectra, 194, 195, 197, 201203. See also Product ion spectra

    Product ion mode, 16Product ions, 16, 22Product ion selection, at high resolution,

    420Product ion spectra, 205206

    Profile data, 419420ProMass software, 377378Proof-of-concept LESA-MS analysis, 232Proof-of-concept (POC) studies, 129Property assays, 98Prostate tissue marker, 289Protein affinity selection mass spectrometry,

    261Protein aggregation, 210Protein A strategy, 178179Protein binding assays, 106Protein characterization, 192Protein degradation, 279in tissues, 295296

    Protein denaturing, urea for, 211Protein drug candidates, preclinical stage of,

    150Protein drug discovery/development,

    149150Protein drugssample denaturing for dissociating, 178therapeutic properties of, 171

    Protein exclusion mechanism, 59Protein folding defects, 210Protein glycosylation, 158Protein heterogeneity, analysis of, 151Protein identification, 283284MALDI and, 22

    Protein ions, fragmented, 156Protein modification analysis, ECD/ETD in,

    177Protein oxidation, 206207Protein precipitation (PPT), 57, 58, 133,

    134Protein profiles, from lung tumor tissue,

    288Proteinprotein interactions, 210Protein quality, evaluating, 150Protein quantification, mass spectrometry

    for, 177Proteins. See also Peptide entries; Proteins/

    peptidesdeamidation of, 168170detected in situ, 283disulfide bonds in, 160HDx in, 172imaging and identifying, 285imaging mass spectrometry of, 277302isoAsp in, 167168modifications/degradations of, 167, 202204

    MS analysis of, 149190

  • 454 INDEx

    quantitative workflows for larger, 404RISC core, 358therapeutic, 151

    Protein signals, identifying, 284Proteins/peptidesaffinity-based enrichment of, 210post-translational modifications in, 203

    Protein structures, 210Protein therapeutics, characterizing, 176Protein therapies, 4345Proteolytic degradation, 279Proteomic experiments, 283284Proteomics, 388Proton exchange, 9Proton transfer ion/ion reactions, 370PseudoMS/MS data sets, 348. See also

    Tandem mass spectrometry (MS/MS)Pseudo neutral loss approach, 346347Pseudo-Rayleigh ion release (PRIR), 5Pseudo-SRM, 404. See also Selected

    reaction monitoring (SRM) entriesPTM analysis, 155, 167170. See also

    Post-translational modifications (PTMs)

    Pulmonary granulomas, 291292Pure ion evaporation (PIE), 5Purity analysis, 243245

    Q Exactive, 26qPCR techniques, 361. See also Q-RT-PCR

    methods; RT-qPCR entries; siRNA qPCR concentrations

    QqQ instruments. See Triple quadrupole (QqQ, QQQ) instruments

    QQQ mass spectrometers, 115. See also Triple quadrupole (QqQ, QQQ) instruments

    QqTOF instruments, 281, 283. See also Quadrupole-time-of-flight (QqTOF, Q-TOF) instruments; Time-of-flight (TOF) entries

    Q-RT-PCR methods, 44. See also qPCR techniques; RT-qPCR entries; siRNA qPCR concentrations

    Q-TOF MS, 46. See also Fast scanning Q-TOF MS/MS systems; Mass spectrometry entries; Quadrupole time-of-flight (Q-TOF)

    Q-trap instrument, 120QTRAP mode, 1920Quadrupole CID spectra, 1920

    Quadrupole fields, 14Quadrupole instruments, operation of, 408Quadrupole (3D) IT mass spectrometers,

    120Quadrupole ion trap (QIT) mass

    spectrometer, 17Quadrupole ion traps (QiTs, QITs), 16,

    1720, 344. See also Linear quadrupole ion trap

    in qualitative analysis, 18Quadrupole mass analyzer modes, 1617Quadrupole mass analyzers, 14, 15, 407408Quadrupole mass filters, 17Quadrupole settings, 16Quadrupole time-of-flight (Q-TOF), 40. See

    also Q-TOF MSQuadrupole-time-of-flight (QqTOF,

    Q-TOF) instruments, 22, 23, 255, 344. See also QqTOF instruments

    schematic of, 23Qualitative analysisof biological drugs, xiiof drugs/metabolites, 414

    Qualitative/quantitative (Qual/Quan) workflows, 40. See also QUAL/QUAN workflows

    in drug metabolism, 3841Quality control (QC) samples, 56, 80, 82, 85Qual/Quan experiments, 41QUAL/QUAN workflows, 28. See also

    Qualitative/quantitative (Qual/Quan) workflows

    QuanOptimize, 100Quantification, mass resolving power as

    influencing, 416419Quantification strategy, best, 408Quantitative analysisof biological drugs, xiiof peptides, xii, 403of peptides using mass spectrometry, 403425

    Quantitative bioanalysisHRMS instruments for, 414role of HRMS in, 421

    Quantitative data, response factors for obtaining, 127129

    Quantitative HPLC-MS/MS bioanalysis, research activities in, 85. See also Tandem mass spectrometry (MS/MS)

    Quantitative informationcapturing analyte, 394derived for imaging data, 329

    Proteins (contd)

  • INDEx 455

    Quantitative mass spectrometry, in a regulated environment, 5595

    Quantitative methods, for peptide drug candidates, 412

    Quantitative whole-body autoradiography (QWBA), 221222. See also QWBA analysis

    Quantitative whole-body autoradiography imaging, 321

    Quaternary ammonium glutathione analog (QA-GSH), 351

    QuickQuan, 100, 102QWBA analysis, 323. See also Quantitative

    whole-body autoradiography entries

    Radial ejection, axial ejection vs., 19Radioactive detector, HPLC-MS coupled

    with, 136Radioactive samples, biotransformation

    analysis of, 136, 137Radiochromatograms, 138Radiochromatographic profiles, 136Radio frequency (RF), magnetic field

    produced via, 14. See also RF entriesRadiolabeled ADME studies, 130. See also

    Absorption, distribution, metabolism, and excretion (ADME) entries

    Radiolabeled compounds, 130Radiolabeled drug products, testing, 131Radiolabeled drugs, 116Radiolabeled drug studies, 136Radiolabeled material studies, 117Radiolabeled peptides, as internal

    standards, 178Radiolabeled samples, for estimating

    metabolites, 128129Radiolabeled studies, uses for, 130Radiolabeled test articles, metabolite

    profiling in studies with, 130141Radiolabeled trapping agents, 351Radiometric detector technology, 139Radioprofiles, 130RAM-based online extractions, 59RapidFire system, 103, 106schematic of, 104

    Rapid mass analysis, 18Rapid metabolic clearance, 258Rapid oligonucleotide sequencing, 378Rapigest surfactant, 211Raw HRMS spectral data, transformation

    of, 419420. See also High-resolution mass spectrometry (HRMS)

    Rayleigh limit, 4Reaction monitoring mode, 20Reactive iminium ions, cyanide-trapped, 350Reactive intermediate formation, 258Reactive metabolite formation, 352quantitation of, 351

    Reactive metabolitesclassification of, 340, 343detection and characterization of, 341detection and identification of, 352in vitro trapping of, 340

    Reactive metabolite screening, xii, 339355challenges of and future perspectives on, 351352

    LC-MS/MS approaches for, 340343mass-based data mining tools for, 345351

    Reactive metabolite screening workflow, 123

    Reactive species, 339Real time (RT). See Direct analysis in real

    time (DART); Q-RT-PCR methods; RT-qPCR entries

    Real-time dynamic background subtraction, 123

    Reconstitution solvents, 85Reduced mAbs, mass analysis of, 153, 154.

    See also Monoclonal antibodies (mAbs)

    Reducing agents, 212Reference standards, 128Reflectron, 21trajectories in, 21

    Reflectron mode ISD (reISD), 166. See also In-source decay (ISD)

    Reflectron technology, 344Regulated environment, quantitative mass

    spectrometry in, 5595Regulatory authorities, 116Reily, Michael D., x, 387Relative standard deviation (RSD), 85Renal elimination studies, 119Research and development (R&D), 239DESI role in, 308309MS role in pharmaceutical, 303

    Resolution (R), 27. See also Mass resolution; Resolving power

    in DESI imaging, 311increasing, 21in MALDI imaging, 311Orbitrap, 26transient time and, 25

  • 456 INDEx

    Resolving power, 416419. See also Resolution (R)

    defined, 416effect of, 44of experiments, 396minimal, 419

    Resonant mass ejection, 18Responseconcentration relation, 5960Response factorscalculating, 128for obtaining quantitative data, 127129

    Response normalization techniques, 124127

    Restricted access media (RAM), 59Reversed-phase (RP) chromatography,

    6265, 7475. See also Flow-injection RP-HPLC-MS technique; RP entries

    Reversed-phase (RP) columns, for polar analytes, 7577

    Reversed phase (RP)-HPLC separation, 151152, 396397

    Reyzer, Michelle L., x, 277RF/DC potentials, 15, 17, 19. See also Radio

    frequency (RF)RF mode, 16RF-only mode, 22RF voltage, 15modulated, 22

    Ricin A-chain (RTA), 165166RISC core proteins, 358. See also RNA-

    induced silencing complex (RISC)Rising-multiple-dose (RMD) studies,

    117119Rising-single-dose (RSD) studies, 117119RNAi biology, advances in, 378RNA-induced silencing complex (RISC),

    357358RNA interference (RNAi) mechanism,

    357358RNAi therapies, complete sequence

    coverage of, 370371RNA oligonucleotides, sequence coverage

    of, 370RP-HPLC-MS, 152, 153. See also High-

    performance liquid chromatographymass spectrometry (HPLC-MS); Reversed-phase (RP) entries

    RP phase modifications, 75RT-qPCRbased assays, 361. See also qPCR

    techniques; Q-RT-PCR methods; siRNA qPCR concentrations

    RT-qPCR hybridization technique, 367

    Rule of five, 246, 249Run-to-run assay, 66

    Safety, of drug candidates, 116. See also Drug safety

    Safety risks, 45Sample analysis, using HPLC-MS/

    radiometry, 136139Sample collection, 131132based on a stability profile, 119in in vivo AME study, 131

    Sample denaturing, for dissociating protein drugs, 178

    Sample extraction, phospholipid removal during, 6669

    Sample extraction methods/techniques, 66, 133135

    Sample instability, 5657Sample pooling, 104. See also Pooled

    entries; PoolingSample preparation, 56, 132135for imaging mass spectrometry, 278280for MALDI, 365366for mass spectrometry imaging, 313315in metabolomic experiments, 390refinements in, 178

    Sample pretreatment, for imaging mass spectrometry, 278279

    Samples, reanalysis of, 129. See also Biological samples; Blood samples; Dosed samples; Fixed tissue samples; Formalin-fixed paraffin embedded (FFPE) samples; Fresh frozen tissue samples; Incurred samples; In vitro ADME assay samples; In vitro ADME samples; Metabolic activity samples; Minimally fixed tissue samples; Placebo samples; Plasma sample entries; Pooled incurred samples; Pooled placebo samples; Quality control (QC) samples; Radioactive samples; Radiolabeled samples; Spiked QC samples; Steady-state plasma samples; Tissue samples; Toxicological samples; Untreated water-rich biological samples; Urine samples

    Sample stabilization, common approaches for, 133, 134

    Scanning MS, metabolite screening using, 255256. See also Mass spectrometry entries

    Scan numbers, comparison of, 102

  • INDEx 457

    Scan/scanning modes, 16, 255Scan types, 115SCH 56592. See Posaconazole (SCH 56592)Screening assaysfor reactive metabolites, 339355targetligand, 259262, 263, 264

    Sealing surface sampling probe (SSSP), 9Secondary ion mass spectrometry (SIMS),

    306307application to tissue imaging, 307for drug and metabolite, 307imaging via, 277MALDI vs., 312

    Secondary ions, 306Secondary metabolites, 291Segmented post-column analyte addition,

    60Selected ion monitoring (SIM), 404Selected reaction monitoring (SRM). See

    also SRM entriesfor peptide quantification, 407414TOF-based approaches vs., 420421

    Selected reaction monitoring (SRM) mode, 13, 16, 17, 77

    Selected reaction monitoring (SRM) technique, xi, 37, 4041, 43, 223, 342, 404

    Selective sample extraction, 55Selectivity, in HRMS experiments, 405(Semi)-preparative LC/SFC, 242243. See

    also Liquid chromatography (LC); Supercritical fluid chromatography (SFC)-MS

    Semi-quantitative imaging technology, 304Separation techniques, 161Sequence mass ladders, 368369Sequencing. See De novo sequencing;

    Metabolite sequences; Oligonucleotide sequencing entries; Primary sequence characterization; siRNA sequencing

    Sequential window acquisition of all theoretical fragment-ion spectra (SWATH), 28, 41

    Serum, siRNA degradation in, 374375Serum sample enrichment strategies,

    178179SFC-MS system, 243. See also Supercritical

    fluid chromatography (SFC)-MSSFC-UV chromatogram, 244. See also

    Ultraviolet (UV) entriesSFC-UV system, 243, 244Shipkova, Petia, x, 387

    Shotgun lipidomic approaches, liquid extraction surface analysis and, 229

    Shou, Wilson Z., x, 97Signature peptides, 404Silica-based RP columns, characterizing,

    7475. See also Reversed-phase (RP) entries

    Silica-based sorbents, 5859Simple Oligonucleotide Sequencer (SOS),

    378SIMS imaging, 306307, 329. See also

    Secondary ion mass spectrometry (SIMS)

    SIMS isotope images, 308Single ion monitoring (SIM), 16Single MS mode, 22. See also Mass

    spectrometry entriessiRNA analysis, future trends for, 378379.

    See also Small interfering RNAs (siRNAs)

    siRNA applications, mass spectrometry for, xii

    siRNA degradation, in serum, 374375siRNA duplexes, 361362, 373375collision-induced dissociation of, 364, 369370

    siRNA duplex intensities, measured by MALDI-MS, 368

    siRNA hydrophobicity, ESI efficiency and, 364

    siRNA metabolites, 44, 376characterizing duplex, 373375

    siRNA molecules, characterizing, 44siRNA qPCR concentrations, 44. See also

    qPCR techniques; Q-RT-PCR methods; RT-qPCR entries

    siRNA quantitation methods, 360siRNA-related LC-MS techniques, 366368siRNA sequencing, by mass spectrometry,

    368372siRNA stability, 360siRNA strands, elucidating, 378siRNA therapeutic formulations,

    accumulation of, 373siRNA-type oligonucleotides, desalting, 365Six sigma initiative, 240Size-exclusion chromatography (SEC), 208,

    210211, 261Skin penetration, for nonsteroid

    glucocorticoid receptor agonists, 316317

    Small cations, effects of, 60

  • 458 INDEx

    Small interfering RNAs (siRNAs). See also siRNA entries

    ADME properties of, 364analytical methodologies for, 360361chemical modifications of, 358360complete sequencing of, 364de novo sequencing of, 369double-stranded characteristic of, 361362extracting from biological matrices, 365366

    isolation from biomatrices, 364MALDI-MS of, 368mass spectrometry of, 357385qualitative and quantitative analyses of, 372376

    quantification of modified and unmodified, 373

    tandem mass spectrometry fragmentation and, 364

    of UPLC-MS/MS, 370371Small interfering RNA (siRNA) therapies,

    4345Small molecule degradation products,

    characterization of, 198201Small molecule impurities, characterization

    of, 193198Small molecule metabolites, 387388Small-molecule pharmaceuticals/biologics,

    impurities and degradation products in, 191220

    Small molecule quantification, HRMS and, 405

    Small molecules, LC-MS/MS analyses of, 372

    Sodium adducts, 3Soft electrophiles, 340Soft nucleophiles, 340Softwareadvancement of, 376378for metabolomic studies, 390

    Software development, 108Software ease of use, 3940Software tools. See also Statistical toolsdevelopment of, 106107for post-acquisition data processing, 121for post-analysis processing, 142

    Solid-phase extraction (SPE), 57, 58, 66, 68, 103104, 134, 229, 366. See also SPE entries

    Solid-phase extraction (SPE)-NMR, 262, 263, 264

    Solid-state lasers, 282

    Solid-supported LLE, 58Solubility, defined, 250Solubility assay methods, 250Solution phase hybridization, 361Solventsin drug extraction, 224225reconstitution, 85

    Sonic spray, 4Sorbents, 5859Spatial resolution, 305of LESA, 224

    Special-isotope-requirement technologies, 304305

    Specialized phases, 7576Spectrometers, for intact mass analysis, 151SPE method, 412. See also Solid-phase

    extraction (SPE) entriesSPE systems, 103Sphingomyelin (SM) phospholipid class, 61,

    62Sphingomyelins (SMs), 60, 61Spiked QC samples, 80. See also Quality

    control (QC) samplesSporulation delaying protein (SDP), 291Sporulation killing protein (SKP), 291Spotted arrays, for imaging, 281, 282SRM analysis, 100. See also Selected

    reaction monitoring (SRM) entriesSRM assays, 37SRM-based method development, for

    peptides, 408SRM chromatograms, 408409in negative ion mode, 413

    SRM conditions, optimized, 102SRM development, solutions for, 100102SRM LLOQ chromatograms, 409. See also

    Lower limit of quantitation (LLOQ)SRM methods, 177for metabolomics, 397

    SRM mode, 372SRM systems, 46SRM transitions, 80, 83, 84, 104105, 254,

    409, 410SRM workflow, 405Stability indicating, development of, 252Stability profile, sample collection based on,

    119Stability testing regimen, 85Stabilizing reagents, 57Staggered parallel approach, 102103Standalone linear ion trap, 19Standard assays, 260

  • INDEx 459

    Standard-free quantitative techniques, 129STAT3 compound, 326, 327Static extraction process, 234235Stationary phase screening, 7475Statistical tools, 391Steady-state plasma samples, analyzing, 118Stress-testing methods, 198Structural elucidation, 139140chemical derivatization for, 140141

    Structureactivity relationships (SARs), 46, 246

    Structureliability relationship (SLR), 97Structureproperty relationships (SPRs),

    246Subtraction routines, 46Sulfate metabolites, 7173Supercritical fluid chromatography (SFC)-

    MS, 242, 243Supernatants, 134Super oxide dismutase (SOD), 164, 165SUPREx (stability and unpurified proteins

    from H/D exchange) method, 260261Surface analysis, 13application of MS to, xii

    Surface enhanced laser desorption/ionization (SELDI), 13

    Surface sampling ionization MS platforms, 305

    Synapt G2 ion mobilityTOF mass spectrometer, 39. See also Time-of-flight (TOF) entries

    Synthesized compounds, screening, 253Systematic method development, protocol

    for, 8285

    Tandem mass spectrometry (MS/MS), 15, 18, 1920, 44. See also MS/MS entries; Trap MS/MS

    in chemical structure elucidation, 245246oligonucleotide sequencing by, 369, 378

    Tandem mass spectrometry (MS/MS) experiments, 192

    Tandem mass spectrometry (MS/MS) techniques, to monitor phospholipids, 62

    Tandem MS mode, 22. See also Mass spectrometry entries

    Tandem TOF combinations (TOF/TOF), 23. See also Time-of-flight (TOF) entries; TOF/TOF analyzers

    Tandem TOF/TOF geometries, 24Target characterization, 259

    Targeted enhanced multiple charge scanning (tEMC), 405

    Targeted high-throughput screening (HTS) libraries, 239

    Targeted ion parking (TIP), 405Targeted metabolomic analyses,

    endogenous biomarker measurement assays vs., 393394

    Targeted metabolomics, 390, 392394Targeted MS, metabolite screening using,

    254255. See also Mass spectrometry entries

    Targeted profiling, 278Targetligand interactions, 259262, 263, 264kinetics/energies involved in, 260

    Targetligand screening assays, 259262, 263, 264

    Target quantitation, bioanalytical methods for, 78

    Taylor cone, 2TEA/HFIP buffer system, 367. See also

    HFIP/TEA ion-pairing system; Triethylammonium (TEA)

    Terfenadine, 225227, 321LESA-MS-SRM analysis of, 228

    Test compounds, purity of, 244245Therapeutic discovery, antisense

    oligonucleotide, 372Therapeutic mAbs, in drug development,

    177. See also Monoclonal antibodies (mAbs)

    Therapeutic protein characterization, peptide mapping and, 155

    Therapeutic protein drug candidates, 179Therapeutic proteins, 151, 164deamidation of, 168170modifications/degradations of, 202204oxidation in, 170

    Therapeutic proteins/peptides, in drug portfolios, 403

    Therapeutic siRNAs, ADME and PK parameters and, 372

    Thermodynamic assays, 250251Thermogravimetric analysis (TGA), 249Thiol content, reducing, 207Thiolsinvestigating, 179mass spectrometric analysis of, 161

    Three-dimensional (3D) ion traps (ITs), 120Timed ion selector (TIS), 2324Time-of-flight (TOF) analysis, 2024,

    343344. See also TOF entries

  • 460 INDEx

    Time-of-flight (TOF) design, 39Time-of-flight (TOF) mass systems, 2, 13Time-of-flight (TOF) mass spectrometer, 21Time-of-flight (TOF) technology, 78Time-point pooling method, 136Time-to-digital converter (TDC), 344Tiotropium, in vivo transport of, 315. See

    also Inhaled tiotropium (ITP)Tissue, as pharmacological target, 43. See

    also TissuesTissue distribution studies, application of

    DESI to, 309Tissue images, 8, 303Tissue microarrays (TMAs), 293Tissue preservation, 278279Tissuespharmaceutical mapping in, 312protein degradation in, 295296

    Tissue samplesabsolute quantitation from, 233234fresh frozen or minimally fixed, 279

    Tissue sectionsapplying enzymes to, 284identifying protein signals from, 284matrix added to, 280protein identification in, 292293

    Tissues/organs, imaging drugs and metabolites in, 315320

    Tissue surfacesapplying matrix to, 314315drug detection from, 312

    T-L complex, 261TOF-based approaches, SRM vs., 420421.

    See also Time-of-flight (TOF) entriesTOF-based HPLC-HRAMS methods, 78.

    See also High-performance liquid chromatography (HPLC) with high-resolution accurate mass spectrometry (HPLC-HRAMS)

    TOF-based MS systems, quantitative output of, 421. See also Mass spectrometry entries

    TOF instruments, 2122, 105106, 115, 344for quantitative bioanalysis, 414

    TOF mass analyzer(s), 11, 13, 22, 23advantages of, 344

    TOF systems, resolving power of, 27TOF technology, 255TOF/TOF analyzers, 281. See also Tandem

    TOF entriesTOF trapping instruments, 414415orbital trapping instruments vs., 418

    Top-down mass spectrometry (MS), 174176, 180, 192

    Total adduct burden, 352Total ion chromatograms (TICs), 79, 349,

    363Total ion current (TIC) chromatograms, 415Toxicity, assessing and preventing, 99Toxicity prediction, 45Toxicological samples, LESA-MS applied

    to, 231Toxicology studies, 116117use of samples from, 117119

    Trajectory stability, in Orbitrap, 26Transcriptomics, 388Transient time (T), resolution and, 25Transmission mode, 16Transporter assays, 98Transporter-related liabilities, 99Trap CID spectra, 1920. See also Collision-

    induced dissociation (CID)Trap MS/MS, 18. See also Tandem mass

    spectrometry (MS/MS)Trapped ions, detecting, 344345Trapping agents, 258bromine in, 341radiolabeled, 351

    Trapping assays, 258259Traveling-wave ion mobility mass

    spectrometry (TWIMS), 27Traveling waves (T waves), 174Triethylammonium (TEA), 366367Triethylammonium bicarbonate (TEAB),

    366Trifluoroacetic acid (TFA), 410Triple quadrupole (QqQ, QQQ) instruments,

    13, 1516, 22, 77, 115, 407413fast scanning, 410full scan tandem mass spectrometry with, 22

    QiTs vs., 18schematic of, 16

    Triple quadrupole linear ion trap (QqQLIT), 1920

    operation modes of, 20Triple quadrupole mass spectrometers

    (TQMSs), 37, 40, 110, 120HPLC-MS/MS with, 100105

    Triple quadrupole MS systems, 1, 13, 1417Triple quadrupoles, for metabolomics, 397Tris(2-carboxyethyl) phosphine (TCEP),

    161, 212Trisulfide bonds, detection of, 162

  • INDEx 461

    Trisulfide linkages, 207208Trisulfides, 162164TriVersa-NanoMate robotic ion source, 222,

    223Troglitazone metabolites, 46, 47Trypsin digestion, 212213Tryptic digestion, 156Tumor blood vessel destruction, 319320Tumor margins, IMS studies of, 289290Tumor penetration, by oncology drugs,

    318319T-wave IMMS, 174. See also Ion mobility

    mass spectrometry (IMMS, IMS); Traveling wave entries

    Two-dimensional (2D) ion traps (LTQs), 120

    Two-dimensional (2D) quadrupole field, 14Two-dimensional (2D) trap, 19Tymiak, Adrienne A., x, 191

    Ultrafast ADME sample analysis, 106. See also Absorption, distribution, metabolism, and excretion (ADME) entries

    Ultrafiltration-ESI-MS, 261. See also Electrospray ionization (ESI); Mass spectrometry entries

    Ultra-high pressure liquid chromatography (UHPLC), 102103, 397

    Ultra-high vacuum, 345Ultra-performance liquid chromatography

    (UPLC), 121, 241. See also UPLC entries

    Ultra-performance liquid chromatography (UPLC)-HRMS systems, 40, 42. See also High-resolution mass spectrometry (HRMS)

    Ultraviolet (UV)-based techniques, 129Ultraviolet (UV) detectors, 46Ultraviolet (UV) lasers, 10Unlocked nucleic acids (UNAs), 361Unmodified siRNAs, quantification of, 373Unstable drugs/metabolites, 56Unstable metabolites, 133effect of, 7374

    Untreated water-rich biological samples, analysis of, 10

    UPLC-MS/MS, 405. See also Tandem mass spectrometry (MS/MS); Ultra-performance liquid chromatography (UPLC)

    of siRNA, 370371UPLC technology, 178UPLC-UV assay, 251Urea, for protein denaturing, 211Urine samples, 118119value of, 119

    Vacuum-MALDI, 13. See also Matrix-assisted laser desorption/ionization (MALDI)

    Vaporization problem, 4Veterinary drugs, 40Vinblastine, 321

    Wash step, 66, 67Water washes, 278WBA experiments, 321. See also Whole

    body autoradiography (WBA)WBA imaging, 311Web-based libraries, 395, 396Wei, Hui, x, 191Wet chemistry techniques, 142Whole body autoradiography (WBA),

    309311. See also Quantitative whole-body autoradiography entries; WBA entries

    Whole-body sections, imaging drugs and metabolites in, 321322

    Wide band excitation, 18

    xenobiotics, metabolism of, 339xia, Yuan-Qing, x, 55x-ray therapy (xRT), 318, 320

    Zebrafish, pharmaceutical distribution in, 323324, 325

    Zgoda-Pols, Joanna, x, 115Zhang, Jun, x, 97Zhang, Nanyan Rena, x, 37


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