Index

Abacavir, 73, 241Abbreviations, listing of, 223�224ABC transporters, 86, 111, 123, 218AB-8�2

constituents in, online structurecharacterization of,584�598

defined, 582flavonols in, 603�605identification research, 583profiling the integral metabolism,

598Ab initio analysis, 47Absorption, see Absorption,

distribution, metabolism, andexcretion (ADME)

active metabolites and, 245bioavailability, determinants of,

206�207, 392�393dosing vehicle and feeding state,

207�208of enzymes, 118�119evaluation methods, 208�209influential factors, 128intestinal, 204, 210�211in vivo studies, 208in mass spectrometry, 269prediction of, 206�211rate of, see Absorption rateratio, see Absorption ratio

Absorption, distribution, metabolism,and excretion (ADME)

bioanalysis studies, 366�367,518�519

clinical studies, 555�556drug discovery studies, 110,

152�155, 230, 236, 238, 246, 387drug-drug interactions, 185drug development process and, 152,

528enzyme-transporter interplay, 185experimental models, 157�184ex vivo models, 169�170high-resolution mass spectrometry,

438high-throughput assays, 398�399human, 558in silico models, 152in situ models, 168�169interindividual differences, 185in vitro-in vivo discrepancy, 184in vitro models, 109, 152, 157�168,

372in vivo models, 152, 170�171,

173�176key transporters, 110�118, 122metabolic pathways, influential

factors, 185�186preclinical models, 171, 173�175profiling, 122, 236

Mass Spectrometry in Drug Metabolism and Disposition: Basic Principles and Applications,First Edition. Edited by Mike S. Lee and Mingshe Zhu.r 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

727

BINDEX 1 March 2011; 10:31:29

COPYRIG

HTED M

ATERIAL

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

quadrupole-linear ion trap massspectrometry, 484�485, 518

radiolabeled, 568research studies, 3�4, 7, 84�86, 155small-molecule drugs, 615species differences, 184

Absorption rate, 102, 109, 207Abundance

abundant proteins, 633�634isotopic, 326�327relative, 368

Accelerator mass spectrometry(AMS), metabolite studies

biochemical tracing, 526clinical aspects of, 238, 553�554comparative resolution of LC

measurements, 540�545instrumentation, 528�531, 535liquid chromatography, see Liquid

chromatography-acceleratormass spectrometry (LC-AMS)

new metabolite studies enabled by,558�560

overview of, 525�528quantitation, 527, 530, 532�536quantitative extraction and

recovery, 545�550reactive metabolites analysis,

554�555sample contamination sources, 554sample definition and interfaces,

531�532species metabolite comparison,

555�558Accelorators, electrostatic, 528Accelrys metabolism, 312Acceptors, 183. See also Michael

acceptorsACD/MS Fragmenter program, 309Acetaminophen, 38, 45, 47, 50�51,

69�70, 73, 91, 97, 116, 178,243�244, 511, 555

Acetate esters, 44Acetic acids, 59, 66, 322, 598Acetone, 88Acetonitrile, 269, 323, 325, 355�356,

360, 362, 514, 617, 622, 697�698Acetylation, 51, 65, 153, 292, 423,

598�599Acetyl-carnitine, 714Acetylcholine, 714Acetyl groups, 294�295, 598Achiral separations, 369Acidic glycoprotein (AGP), 211Acidic groups, 265Acoustic drop ejection, 463Acrolein, 61, 654Active drugs

biotransfofrmation reactions, 39oxidative reactions, 22

Active metabolitescharacterized, 237, 292detection during drug discovery,245�246

early screening, 244potential assessment, overviewof, 243�246

Active transport, 209Acyclovir, 116, 156�157Acylation reactions

amino acid conjugation ofcarboxylic acids, 34

chemical, 34�35primary amines and hydrazines,33�34

Acylcarnitine, 295Acyl coenzyme A, 239Acyl glucuronidation, 65�67Acyl glucuronides, 30Acyl halides, 62�63Acylium ion, 330Acylthiourea, 58Additives, mobile phase, 322Adduct ions, formation of, 322�325.

See specific types of adductsAdenisone 50

-monophosphate (AMP), 33

728 INDEX

BINDEX 1 March 2011; 10:31:29

-triphosphate (ATP), 123�124,466, 634

ADMET (absorption, distribution,metabolism, elimination, andtoxicity), 450, 467

ADMET-pharmacokinetics studies,450�451

Adriamycin, 555Adverse drug reactions (ADRs), 6, 14,

44�45Aerospray, 267Affinity, dye-based, 635Affinity capture methods, 658Affinity-labeling agents, 60Affinity tagging, 627Aflatoxin B, 87, 89Aglycone, 583�584, 598, 603, 605, 607Agranulocytosis, 64, 71�72Agricultural chemicals, 526AIP1, 92Albumins, 634�635, 659, 662Alclofenac, 59Alcohol dehydrogenases

biotransformation reactions,22�23, 26

oxidative reactions, 22�23reductive reactions, 26

Alcohols, 32, 88, 91, 545Aldehyde dehydrogenases, 22�23, 86Aldehyde oxidase (AO), 22, 86, 162Aldehydes

characterized, 17, 46, 58, 62, 65,638, 653, 659�660

oxidative reactions, 21reductive reactions, 26

Alfentanil, 98Algae, blue-green, 125Alignment, chromatographic,

707�709Aliphatics, 15�16, 37, 656Aliskiren, 112Alkaloids, 325Alkenes, 25Alkylamines, 20Alkylation, 59�60, 619, 656

Alkyl groups, 49, 423Alkylphenols, 47�48Alkyls, 15�17, 499Alkynes, 59�60Allegra. See FexofenadineAllometric scaling, 199Alpidem, 57�58, 68�69Alprazolam, 98Alprenolol, 203Alternating current (ac),

273�274Alzheimer’s disease, 660�661Amadori rearrangement, 66Ambien. See ZolpidemAmbient desorption techniques, 259Ambient gas, 268Ambient ionization, 451Ames test, 59Amidase, 156Amides, 27�28, 30�33Amidines, 25Amindes, 325Amines

alkylation reactions, 33biotransformation reactions, 18,

30�31, 33�34, 36functions of, 306, 312, 422, 554methylation of, 36oxidative reactions, 20�21primary, 33�34quaternary, 30reactive metabolites, 46sulfation reactions, 32�33

Amino acids, 4, 31, 34, 46, 90, 118,292, 308, 620, 624, 659, 698�699

2-Aminoanthracene, 90Aminobenzotriazole, 106, 234, 2466-Aminochrysene, 87, 892-Aminofluorene, 90Aminoglycosides, 325Aminophenols, 19, 47, 50Amiodarone, 106Amitriptyline, 87Ammonia/ammonium, 266, 267Amnoside, 583

INDEX 729

BINDEX 1 March 2011; 10:31:29

Amodiaquine, 24, 50�51Amprenavir, 98, 106Analgesics, 244, 366. See also

AminocetaphenAnalog proteins, 626Analysis of variance, 713Anaphylactic reactions, 45Anemia, 48Anesthetics, inhaled, 62�63Anilines, N-hydroxylation, 54�55Animal in-life study, 169Animal studies

absorption, 207bile-duct canulation (BDC), 171,

174, 233�234, 245, 485, 510drug-drug interactions, 90high-resolution mass spectrometry,

427�428liquid chromatographic

separations, 369LLC-PK1 cells, 120mass spectral imaging, 469MDCK cells, 120pharmacokinetics, 199quantitative drug metabolism,

557reactive metabolites, 50, 242vehicle control, 715

Animal testing, 44Anionization, 452Annotation, data, 711Anserine, 660Antiangiogenesis agents, 168Antiarrhytmic agents, 473Antiasthmatic drugs, 53Antibiotics, 64, 168, 209, 258Antibodies, 63, 96, 238, 618�619,

631�632, 655�656Anticancer drugs, 168, 178Anticholinergics, 310Anticoagulants, 533Antidementia drugs, 214Antidepressants, 70�71, 339�340Antiepileptic drugs, 87, 452Antigens, 620Anti-HIV drugs, 168

Antihypertensives, 55, 72Antioxidants, 45, 72�73Antipeptides, 631�632Antipsychotic agents, 47�48, 53,

63�64, 312Antipyrine, 98, 203Antitrypsin, 634Antituberculosis drugs, 55Antivirals, 111, 1151,8,9-Antrancetriol (dithranol), 271Apixaban, 174�175Apolipoprotein A-I (apoA-1), 620,

661�662Apricitabine, 116AQ4N prodrug, 465�466ARA9 protein, 92Arachidonic acid, 89, 652, 663,

666�667, 714Area under the curve (AUC), 94, 98,

101, 104, 107�108, 112�116,170, 172, 200, 205, 214�215,219�220, 536, 621

Arene oxides, 25, 56�57, 68, 239Arginine, 619, 714Argon, 456Aromatic(s)

characterized, 18hydroxylation, 16oxidative reactions, 20reductive reactions, 26rings, 46�54, 311, 422�423

Artificial intelligence, 713Artificial neural networks, 713Aryl amines, 23, 87, 91, 662Aryl hydrocarbon receptor (AhR),

92Aryl hdyrocarbon receptor-aryl

hydrocarbn receptor nucleartranslocator (AhR-ARNT)pathway, 85, 87

Ascorbic acid, 660Aspartate, 27Astemizole, 198Asthma, 53, 654Astragalin, 583, 585, 587, 591Atazanavir, 112�113, 115

730 INDEX

BINDEX 1 March 2011; 10:31:29

Atenolol, 63Atherosclerosis, 661�662Atmospheric pressure, impact of, 473Atmospheric pressure chemical

ionization (APCI), 616, 646Atmospheric pressure chemical

ionization (APCI) massspectrometry, 267�269,321�323, 325, 328, 367, 390, 661,699�700

Atmospheric pressure desorption-massspectrometry (APD-MS), 690

Atmospheric pressurephotoionization (APPI), 269

Atomic mass, 259Atomic mass units (AMUs), 126Atorvastatin, 66�67, 112, 114,

117�118Atorvastatin, 98ATP/ATPase activity, 123�124, 464,

634AUC pooling, 556. See also Area

under curve (AUC)Automatic gain control (AGC), 277Automation, drug transporter

evaluationcell maintenance systems, 126robotic liquid-handling systems,

126�127Autoradiography

features of, 475MALDI-MSI compared with,

465�466whole-body (WBA), 466�469, 515

Avogadro’s number, 9Azithromycin, 106, 112, 114

Background, 451�453Background, generally

distribution studies, 451�453interference, 299, 310noise, 300, 655, 701signals, 491, 701subtraction, 294�295, 301�303,

305, 428, 439, 552, 702Backup drugs, marketing of, 84

BacteriaERYF, 182Escherichia coli, 650TERP, 182

Bacterial artificial chromosome(BAC), 177, 180

Bacterial CYPs, 182BADRs. See Idiosyncratic adverse

drug reactions (IADRs)Baohuoside I, 581Base excision repair (BER), 651BCRP (breast cancer resistance

protein) transporter, 111�112,123, 125, 127, 167, 218

Beads, immunocapture, 632�633Beclomethasone, 10Benoxaprofen, 336Benzdioxole groups, 70Benzene, 47, 543Benzene oxide, 25Benzenoid, 19Benzo[a]pyrene, 56Benzodiazepine receptors, 68Benzoic acid, 325Benzoquinone, 48, 53Benzoylecogonine, 572�573Benzylic in, 330Bergamottin (GF-I-2), 106β-adrenoreceptor antagonists,

55, 63Beta carotene, 549Betaine, 698, 714β-glucuronides, 29β-lactam antibiotics, 209β-lactoglobulin, 626Betanaphthoflavone (BNF), 90Bile, generally

acids, 90�91, 559, 699excretion of, see Biliary excretionin rats, 595�603salts synthesis, 170samples, preparation of, 361

Bile-duct cannulated studies, 171, 174,233�234, 245, 485, 510

Biliary excretionclearance, 124, 214, 216�217

INDEX 731

BINDEX 1 March 2011; 10:31:29

Biliary excretion (continued )implications of, 239, 292, 549index (BEI), 124, 166

Bilirubin levels, 90Biller-Biemann algorithm, 302Binding affinity, 184Binding sites, 129Bio-MICADAS (MIniature CArbon

DAting Spectrometer),528�530

Bioactivationof drugs, 44�45pathways, 309structural alerts, 45thiazolidinedione ring, 60�61toxicophores, 45

Bioanalysischiral, 366�370high-throughput, 363liquid chromatographic separation

in, 361�370using QTRAP instruments,

487�488quantitative, 634sample preparation, 354�360

Bioavailability (BA)absorption, 392�393determinants of, 206�207drug discovery process, 156�157,

230, 234influential factors, 152, 210, 214, 220metabolic clearance, 233oral screening tool, 381

Biochemistry phase in drugdevelopment, 5, 526

Biogenic background, 553Biology phase in drug development,

5�7Biomarker(s)

bioanalysis, 637development of, 637discovery studies, 506functions of, 633, 646measurement, 638of oxidative stress, 665�670peptide, 659�660

protein, 638validation, 614

Biomedical research environments,555

Biopharmaceuticals, 5581-Biotinamido-4-(40-

[maleimidethylcyclohexane]carboxamido)butane (BMCC),656

Biotinylation, 656�657Biotransformation

in drug metabolism process, 4, 7of inert chemicals, 44in vivo, 245�246oxidative, 239pathways, 291, 300, 312, 336Phase I, 421�422, 425�426Phase II, 423, 426reactions, see Biotransformationreactions

Biotransformation reactionsacylation, 33�35glucuronidation, 29�31glutathione conjugation, 36�38hydrolytic, 27�28methylation, 35�36overview of, 14�15oxidative, 15�24reductive, 24�27sulfation, 31�33types of, 292

Birefringence, 469Bisphosphonate, 208Bis-[ p-nitrophenyl] phosphate

(BNNP), 234Blood

AMS metabolite studies, 554anemia, 48drug concentration in, 198�199flow, 202, 211�212, 214flow rate, 199�200samples, preparation of, 359�361

Blood-brain barrier (BBB), 111, 115,118, 121, 124�125, 168, 183

Blood-to-plasma partitioning, 152BM-3 bacteria, 182

732 INDEX

BINDEX 1 March 2011; 10:31:29

Bond breakage, 306p-Boronphenylalanine-fructose

(BPA-F), 452Bosentan, 117, 260Bromide, 63Bromine, 259, 261, 310, 326�327,

329�330Bromobenzene (BB), 359Bromoethylamine (BEA), 706Bromofenac, 336Budesonide, 98Bufuralol, 95, 97Buprenorphine, 112Bupropion, 95, 97Buspirone, 47, 97�98, 106, 425Butylcholinesterase, 27

13C, 37414C

accelerator mass spectrometry(AMS), 526�528, 532�536, 543,545�546, 555�558

characterized, 7drug disposition, 174�175mass spectral interpretation (MSI),

344metabolic activation, 56metabolite identification, 428, 467oxidative stress, 653

Caco-2 cells, 119�121, 127, 167, 208,387, 394�395, 570

Caffeine, 87Calcitriol, 10Calcium, 124, 323, 706CAM

bacteria, 182kinase (CK) inhibitors, 93

Cancer(s)carcinogenesis, 85, 157anticancer drugs, 168, 178biomarkers of, 654, 672bladder cancer, 90, 92BCRP (breast cancer resistance

protein) transporter,111�112, 123, 125, 127, 167, 218

breast cancer, 91

colorectal cancer, 91, 167, 657lung cancer, 90, 92procarcinogens, 89�90prostate cancer, 91skin cell carcinoma, 92

Canine studies, 172�173, 185,214�215

Capillary electrophoresis (CE), 699Capillary electrophoresis-mass

spectrometry (CE-MS), 690�691Capsofungin, 118Captopril, 56�57Carbamate groups, 62Carbamazepine, 17, 57�58, 203Carbenes, 48Carbohydrates, 91Carbon(s), see specific carbons

acidic, 31biotransformation reactions, 38dating, 527, 531functions of, 49, 259�260,

262�263, 310�311, 326, 374,551, 647, 706

oxidative reactions, 17�18sp, 56�57, 60

Carbon-carbon epoxidation, 16�17Carbon dioxide (CO2), 531Carbonium ion, 330Carbon monoxide, 15Carbonyls, 26, 61�62, 86, 660Carboxylesterases, 28Carboxylic acids, 23, 34, 63, 65�66,

183, 239, 312, 421, 664Carcinogenicity, 44, 172Carcinogenics, 336Carcinogens, 87, 172Cardiotonic agents, 54Cardiovascular diseases, 672Cardiovascular drugs, 67Carnitine, 295�296, 714Carnosine, 660Carprofen, 116Carvedilol, 112�113, 436�437Caspfungin, 117Cassette-accelerated rapid rat screen

(CARRS), 393�394

INDEX 733

BINDEX 1 March 2011; 10:31:29

Catalysis, 57Catechol(s)

biotransformation reactions,19, 35

functions of, 47�48, 72,336�337, 603

groups, 604-O-methyltransferase (COMT), 35,

86, 603�605, 607oxidative reactions, 19reactive metabolites, 47

Cationization, 452Cefaclor, 116Cefmetazole, 116Cefonicid, 116Cefoxitin, 116Celiprolol, 112Cell maintenance systems, automated,

126Cell proliferation, 152Cemetidine, 98Central nervous system (CNS), 118Cephalexin, 116Cephalosporins, 115Cephradine, 116Ceramides, 331Cerebrospinal fluid (CSF), 374, 634,

660Cerivastatin, 84, 112Cervical epithelial carcinoma, 649Cesium, 323, 456Cesium chloride, 323Cetirizine, 112�113, 243Cetuximab, 632Charge remote fragmentation, 331Charge residue model (CRM),

266�267Chemical acylation, 34�35Chemical derivatization strategies,

311�313, 342�343, 658Chemical inhibitors, 95�96Chemical ionization (CI), 258,

267�268, 322Chemical noise, 704Chemical reactions, 44

Chemiluminescent studies, metabolitequantitation, 569

Chemistry phase in drugdevelopment, 4�5

Chemodeoxychlic acid, 714Chinese hamster ovary (CHO)

cells, 111Chinese herbal medicine

chemical constituents in,characterization of,583�598

integral metabolism, profiling,598�608

overview of, 579�583, 608�609Chiral separations, 366�367, 369Chlorides, 18, 62�63, 706Chlorination, 23Chlorine, 62, 259, 261, 310, 326�327,

329�330, 428Chloroamphenicol, 622-(3-Chlorobenzyloxy)-6-

(piperazin-1-yl)pyrazine, 49Chloroephedrine, 106Chloroethylene oxide, 652Chlorzoxazone, 88, 95, 97Cholesterol levels, 661Cholic acid, 714Choline, 714Cholinesterase, 234Chromane, 72Chromatograms, 8Chromatographic separation, 258Chromatographic studies,

development of, 4�5. See alsospecific types of chromatography

Cialis. See TadalafilCigarette smoke

cessation drugs, 129response biomarkers, 669�670,672�661

Cimetidine, 106, 112, 115�116Cisapride, 106Citalopram, 370Citrate, 696Citrulline, 714

734 INDEX

BINDEX 1 March 2011; 10:31:29

Clarinex. See DesloratadineClarithromycin, 97�98, 106, 112�113Clearance

in drug discovery process, 232�235estimation of, 200, 212�218hepatic, 203, 205�206hepatic intrinsic, 200, 204�205,

212�217, 221human, prediction of, 232�233implications of, 152, 200, 212in vivo, 214intrinsic, 202, 233, 238, 391metabolic, 232�235metabolic stability and, 388�389,

391organ, 199permeability-limited, 205�206renal, 200, 217�218

Clearance-limited drugs, 212Click chemistry, 658Clinical trials, see specific medications

adverse drug reactions, 44candidate drop-outs, 198

Clonidine, 10Clopidgrel, 67�68, 106Clotrimazole, 92, 114Clozapine, 53�54, 63�64, 71�72, 87,

368, 473, 507Clusin, 106Cluster ion beams, 456Clusters, isotopic, 325�328Coating, in MALDI-MSI, 463Cobalt, 269Cocaine, 464, 572Codeine, 88, 98, 574Coenzyme A, 239Coenzymes, 159Colchicine, 300�301Collapsibility, 207Collision-activated dissociation

(CAD), 615Collision cells, 274�275Collision energy (CE), 304, 306,

361�362, 490, 493Collision energy spread (CES), 490

Collision-induced dissociation (CID),275, 278�279, 286, 306, 330, 454,471, 500, 503�504, 506�507, 662

Colorimetric analysis, 671�672Column chromatography, 4�5, 121Comparative proteomic studies, 627Complementary deoxyribonucleic

acid (cDNA), 4, 94�95, 122, 177Component detection algorithm

(CODA), 704Component object model (COM), 704Computer software/programs, see

DatabasesAmerican Standard Code of

Information Interchange(ASCII), 704

AnalysisXML, 704bond disconnection approaches,

435chemical structure inspection, 45data processing, 302�303, 305, 312in vivo DDI predictions, 108MassHunter, 706metabolite identification, 309metabolite prediction lists, 312Microsoft Excel spreadsheets, 389Microsoft Excel Visual Basic, 713mzData, 704mzXML, 704netCDF, 704plotting programs, 537Sieve, 706statistical, 537

Confounding factors, 179�180Conjugated metabolites, 295Conjugation reactions, 44, 243�244Constant neutral loss (CNL)

scanning, 294�299, 303�306,313

Constant-pressure flow splitter, 363Constitutively active receptor (CAR),

87�89, 92�93Contact research organizations

(CROs), 127Contamination sources, 554

INDEX 735

BINDEX 1 March 2011; 10:31:29

Contribution ratio, determination of,218�220

Copper (Cu), 660Corona discharge, 269Correlation analysis, 96�97Cotrimoxazole, 116Coulombic, generally

explosions, 267, 571repulsion, 266

Coumarin, 87, 95, 97, 179Counterelectrodes, 265Counterions, 265Covalent binding

drug toxicity, 68�71functional group metabolism,

55�56implications of, 50, 499reactive metabolite studies, 46, 58,

68�71, 240structural alerts and, 65�66

COX-2, 651�652, 663. See alsoCyclooxygenases (COX)

CP-493,715, 112CP2C8, 174, 396CP2D6, 95�96, 106, 177Cpr gene, 176�178CPY1A, 106C-reactive protein, 620Cre/LoxP technology, 180Creatine, 714Creatinine, 661, 671�672, 695�696, 714Cremophor, 113Crigler-Najjar syndromes, 90Cross-correlation analysis, 430�431,

436Cross-linking, 658, 661Cryopreservation, 164, 212Crystallization, 4, 461�464C-trap, 285Cutoff filters, 634Cyanide, 46Cyanide, 503Cyano-4-hydroxycinnamic acid

(4-HCAA), 271, 462�463Cyclodextorin, 207

Cyclooxygenase (COX), 23, 50, 59,646, 651, 666

Cyclophosphamide, 61, 87, 98Cyclopropylamine, 64�65Cyclosporins, 89, 98, 111�115,

117�118, 128, 210Cyclotron motion, 283�284CYPs

CYP1A, 106CYP1A1, 93CYP1 family, 85, 87CYP1A2, 85, 87, 93, 95�96,174, 177�178, 182�183,396�397

CYP1B1, 85, 87CYP2, 87CYP2A, 93CYP2A5, 93, 178�180CYP2A6, 93, 95�96, 177, 179�180,396

CYP2B, 92�93, 183CYP2B6, 87�88, 92, 95�96, 106,166, 396

CYP2C, 88, 93CYP2C8, 84, 92, 95�96, 106,117, 183

CYP2C9, 92, 95�96, 106, 174, 183,396�397, 512�514

CYP2C18, 181CYP2C19, 95�96, 106, 165, 174,181, 396�397

CYP2D6, 88, 106, 160, 162, 165,179, 182, 186, 396�397

CYP2E1, 88, 93, 95�96, 177�179,396

CYP2F1, 89CYP2g1, 180CYP2j, 177CYP2J2, 89, 174CYP3, 89CYP3A, 93CYP3A4, see CYP3A4CYP3A5, 89, 93, 96, 174CYP3A7, 89�90CYP4, 90

736 INDEX

BINDEX 1 March 2011; 10:31:29

CYP4A11, 170CYP7A1, 170

CYP3A4bioactivation, 72drug disposition studies, 160, 162,

174, 177�178, 180�183, 186drug-drug interactions, 84, 89,

92�98, 106�109early drug metabolism screening,

396�397metabolic activation 59, 66, 69, 72pharmacokinetics, 210�211, 214,

219Cysteine

conjugation, 302functions of, 27, 56, 68, 423,

506�507, 60, 655�657, 662-glycine, 307groups, 655

Cystolic GSTs, 91Cystosine, 46Cytidine, 714Cytochrome P462 (CYP), see specific

CYPsbacterial, 183biotransformation reactions,

15�20, 24�26cDNA-expressed, in human

studies, 94�95drug discovery, 387, 396�397, 485drug-drug interactions, 84�85enzymes, 11, 177�178evaluation of NCEs, 109�110functional group metabolism,

50�60, 62�63functions of, 15�20, 152human, regulation of, 92�93IADRs and, 72inhibition, 98�102, 159�160, 386,

512, 514mapping, 161mechanism-based inhibitors, 106oxidative reactions, 15�20phenotyping studies, 164reaction phenotyping, 93�98

reductase, 86reactive metabolites, 44�45reversible inhibition, 98�102types of, 85, 87�90

Cytokines, 93, 169Cytosol, 162�163, 212, 662Cytosolic β-glucosidase (CBG), 603Cytotoxicity, 152

Daidzein (DZ), 162�163Dalton, 260Danshen injection fluid, 580�581Dansyl chloride, 311�312Dansyl-glutathione (dGSH), as

trapping agent, 507�509Dapsne, 55

Data acquisition, 8, 412, 415Data analysis guidelines, 702�713, 715

DatabasesBioCyc, 712BioSpider, 712chemical, 711GenBank, 619Golm, 712human metabolome (HMDB), 712

KEGG, 712Madison Metabolomics

Consortium, 711MassBank, 712metabolic, 711METLIN, 712MMCD, 712

Data-dependent product ion scanning(MS2), 304�305, 454, 488, 584,599

Data interpretation factorsdrug-drug interaction, 185enzyme-transporter interplay,

185

interindividual differences, 185in vitro-in vivo discrepancy, 184species difference, 184

Data mining, 236, 238, 495�496, 703Data processing systems, 302�303,

305, 312, 339, 412, 417

INDEX 737

BINDEX 1 March 2011; 10:31:29

Dealkylation, 17, 49, 62, 292, 303, 421Deamination, 292, 334�335, 421Debenzylation, 421Debrisoquine, 179Debromination, 422Decarboxylation, 60, 115, 422�423Decay counting techniques, 526�528,

554Dechlorination, 64, 422Decision making process, 239Decision trees, 235, 568Decomposition, 268, 330, 340Deconvolution, 706Decoupling, 456Deethylation pathways, 244Deferoxamine, 649Defluorination, 422, 434Deglycosylation, 604�605, 607De-glutathionylation, 663Dehalogenation, 17�18, 429Dehydration, 60, 421�422Dehydrogenases, 19�20, 22�23, 62Dehydrogenation, 24, 53, 300, 302, 420Delavirdine, 106Deletions, 94, 179 182Demethylation, 48, 52, 96, 186, 242,

300, 302, 420, 434Denaturation, 619, 622Deoxycholic acid, 714Deoxygenation, 336Deoxyribonucleic acid (DNA)

adducts, 651�652, 672DNAzol, 649functions of, 270, 554, 646, 663, 686mass spectral interpretation,

336�338-reactive metabolites, 46recombination, 122

Depletion kits, 634�635Depurination, 336�337DEREK software, 45Derivatization, in drug metabolism, 4.

See also Chemical derivatizationstrategies

Desaturation, 421, 423

Descriptive studies, metabolicprofiling, 231

Desethylamidarone, 106Desfluorane, 62Desloratadine, 85, 243Desmethyldiltiazem, 106Desolvation, 268Desorption, 272, 452Desorption electrospray ionization

(DESI)applications of, 259, 273, 451,457�458, 460, 473

-mass spectral imaging (DESI-MSI), 473

-multiple reaction monitoring(DESI-MRM), 515

-tandem mass spectrometry (DESI-MS/MS), 457, 515�516

Desorption/ionization on poroussilicon (DIOS), 270

Detector, in mass spectrometers, 263Detoxication/detoxification 14,

44�45, 56, 58, 68�70, 72, 170Deuterium, 311, 342�345, 428Dexamethasone, 89, 93, 113Dextromethorphan, 88, 95, 97, 573Dextrorphan, 97, 574Diabetes, 654, 670Dialysis methods, 638Diazepam, 88, 98, 203Diazine, 56Diazonium, 56Dibenzodiazepine derivatives, 63�64Dicarboxylic acids, 694Diclofenac, 51�52, 97, 106, 295Dicloxacillin, 113, 116Difluoromethoxy group, 63Digestion

enzymatic, 622�623, 625, 638proteolytic, 655trypsin, 660

Diglucuronide, 605Digoxin, 98, 111, 113, 117�118,

127�128Dihydralazine, 45, 106

738 INDEX

BINDEX 1 March 2011; 10:31:29

Dihydroclusin, 106Dihydrocubebin, 1062,5-Dihydroxy benzoic acid (DHB),

271, 462�463Dihydroxybergamottin (DHB), 106Diiminoquinones, 53�54Diltiazem, 89, 97, 106, 112�113Dimers, 23, 92�93, 106, 324�325Dimethyl sulfoxide (DMSO),

396�397, 648Dimines, 23Diols, 19. See also specific types of

diols9,12-Dioxo-10(E)-dodecenoic acid

(DODE), 652�653, 664Dipeptide transporters, 209Direct analysis in real time (DART),

273, 398Direct current (dc), 273�274, 279,

337, 489Direct injection-mass spectrometry

(DI-MS), 690�691Disaccharides, 598Disease biomarkers, 374Dispersion model, clearance

relationships, 202�204Dispositional studies, experimental

modelsADME, 154�176engineered mouse models, 176�184in vivo, 199overview of, 152�154, 186�187physiological pharmacokinetics, 199typical model systems, 154

Dissociation constant, 104Distribution studies

drug efficacy and protein bindingrelationship, 211�212

MALDI, 462�465mass spectrometric imaging,

451�474plasma protein binding, 211significance of, 152, 186, 450,

474�475tissue imaging techniques, 450�451

volume of, 201�202Disulfides, 56�57, 68, 663Disulfiram, 88Dityrosine, 661Diuretics, 58, 517Docetaxel, 113Dofetilide, 116Donors, 183Doripenem, 116Dosage

clearance studies, 200dose size, 9�10drug discovery phase, 231hepatotoxicity and, 70�71multiple ascending dose (MAD),

175pharmacokinetic studies, 171significance of, 8�10, 71�72, 186single ascending dose (SAD), 175

Dosing vehicles, 207�208Double-bond equivalency (DBE),

329�330Down-regulation, 92Doxorubicin, 113�114, 555DPC 693, 106Dplot, 537Drug absorption and permeability

assays, 392�396Drug candidates

high-quality, 247metabolic pathways, 292optimization, 234screening, 244selection, 231

Drug concentration, significance of,198�201

Drug design, structural alerts, 63�68Drug development

components of, 85, 152fit-for-purpose strategy, 636�637,

639mechanistic investigation studies,

153pharmacokinetics, 172, 198, 222quantitative bioanalysis, 628

INDEX 739

BINDEX 1 March 2011; 10:31:29

Drug discovery, see Drugdevelopment

ADME strategy, 154�176, 230animal-to-human in vitro

correlations, 158�159chiral bioanalysis, 368�369data interpretation, 184�186exploratory stage, 220�222issue-driven strategy, 155�157mechanistic investigation studies,

153metabolic clearance, 232�235metabolite identification, 94, 305metabolite profiling/mass balance

studies, 235�237pharmacokinetic studies, 172, 485preclinical, 129process overview, 44, 47, 71, 85,

152, 230�232, 246�247, 388quantitative bioanalysis, 628reaction phenotyping, 238�239research, see Drug discovery

research studiessafety testing, 237�238sample preparations, 359step-by-step strategy, 154�155toxicology assessment, 239�243transporters and, 110

Drug-drug interactions (DDIs)ADME studies, 152adverse clinical, 129backup drugs and, 84clinical, 104, 107, 186components of, 72, 85cytochrome P462 (CYP) assays,

396, 514drug discovery phase, 231enzyme kinetics analysis, 512�513enzyme reaction phenotyping,

metabolizing, 513�514human, 104in vitro studies, 127, 512�514metabolism-based, seeMetabolism-

based DDIsmetabolite identification, 292

OAT-mediated, 115�118, 122�123OCT-mediated, 115�116, 123pharmacokinetic-related, 98�102,218�220, 485

potential, 185prediction of, 104, 107, 218�219significance of, 84, 244victim drugs and, 84

Drug eliminationclearance, 200�201velocity of, 206

Drug exposure, 152, 170, 185, 245Drug-food interactions, 231Drug metabolism (DM), generally

dose size, 8�10experimental design, 3historical phases of, 4�7industrial, 7metabolite quantitation, 8�9new regulatory expectation, 7significance of, 3�4, 229�232,246�247

technological challenges, 7�8Drug metabolism and

pharmacokinetics (DMPK)research, 153, 158, 183, 186, 374,484�485, 488, 519, 615

Drug-metabolizing enzymes (DMEs)CYPs, see CYPs; CYP3A4drug-drug interactions, 85, 98glutathione-S-transferases (GSTs),86, 91�92, 162, 662

major, 86sulfotransferases, 31�32, 86, 91,161�163, 234, 603

UDP-glucuronosyltransferases(UGTs), 29, 44, 86, 90�91,161�162, 185, 603

Drug resistance, 111Drug transporters, see TransportersDual-pressure LIT, 279Duplications, 94Duration of drug, 152, 185Duty cycle, 9, 277Dwell time, 540, 543�544

740 INDEX

BINDEX 1 March 2011; 10:31:29

Dynamically linked libraries (DLLs),704

Dynamic fill time (DFT), 489Dynamic-flow RFD, 373Dynamic range, 415, 440, 491, 559,

617, 633Dynamic SIMS, 456�457

Early drug metabolism (EDM)assays, 398in vivo ADME screens, 399phase, 386

Ecstasy, 106Efavirenz, 157Efficacy

biotransformation reactions, 39in drug metabolism process, 6, 94pharmacokinetics, 222preclinical determination, 244research studies, 198�199,

211�212, 222Efflux, generally

influential factors, 128ratios (ER), 119transporters, 175

Eicosanoids, 647, 668Elacridar, 114�115Electron-capture atmospheric

pressure chemical ionization/mass spectrometry(EC-APCI-MS), 669

Electron donating, 47Electron impact (EI) ionization, 258,

261, 264, 268Electron spin resonance studies, 55Electron volts (eV), mass analyzers,

275Electron withdrawal, 47Electrophiles/electrophilicity, 44, 46,

336, 651�652, 655�659, 663Electrophoretic studies

capillary electrophoresis (CE), 699capillary electrophoresis-mass

spectrometry (CE-MS), 690�691denaturing gel electrophoresis, 658

sodium dodecyl sulfatepolyacrylamide gelelectrophoresis (SDS-PAGE),634�635

two-dimensional (2D) gelelectrophoresis, 655

Electrospray, standard-freemetabolite quantitation,570�571, 574

Electrospray ionization (ESI)applications, 259, 263, 303, 307,

321�323, 345, 363, 367�368,457, 617, 619, 646 (ESI), 649, 661

-Fourier transform-ion cyclotronresonance mass spectrometry(ESI-FTICR-MS), 329

-liquid chromatography-massspectrometry (ESI-LC-MS), 270,698�699

-mass spectrometry (ESI-MS)analysis, 322�325, 328, 343�344,367, 373, 595�597, 667, 702�703

-multistage scanning (ESI-MSn), 582-tandem mass spectrometry (ESI-

MS/MS), 582Electrospraying, 463Electrospray-quadrapole time of

flight (ESI-QTOF) spectrometry,272

Electrostatic(s), generallyaccelerators, 528field, 285mirror, 281painting, 264

Eltrombopag, 117Embryonic stem (ES) cells, 177, 179EMTPP, 106Emtriva, 168Enal, biotransformation reactions,

37�38Enalapril/enalaprilat, 156Enantiomers, 366�367, 369�370Endogenous metabolites, liquid

chromatography-massspectrometry (LC-MS), 686

INDEX 741

BINDEX 1 March 2011; 10:31:29

Endoplasmic reticulum (ER), 90, 657,660

Enflurane, 88Enhanced mass spectrometry (EMS),

490, 515Enhanced mass spectrometry-

enhanced product ion (EMS-EPI) scan, 495�499, 516, 518

Enhanced multiply charged (EMC)scan, 490

Enhanced product ion (EPI) scan,280, 490, 507, 516, 518

Enkephalin, 124Enone, biotransformation reactions,

37�38Enthalpy, 268Environmental considerations

environmental exposure, 554pesticides, 124pollutants, organic, 518wastewater treatment, 517�518

Enzyme(s), see also specific enzymesconjugating, 211digestio, 622�623, 625, 638drug discovery process, 234drug-metabolizing, 4�6, 45, 212,

219enzymatic reactions, 44expressed, 159�162inhibition, 68, 99, 101metabolic, 185�186molybdenum-containing, 25recombinant, 214transferase, 239

Enzyme immunoassay (EIA)techniques, 516

Enzyme-inhibitor (EI) complex, 99,103

Enzyme-linked immunosorbent assay(ELISA), 539, 615, 620�621,632, 668

Enzyme-substrate (ES) complex, 99EPI-hNE4 protein, 617�618, 628, 630EPIC (Elucidation of Product Ion

Connectivity), 435�436

Epimedim A/Epimedim B/EpimedimC, 581

Epimedium koreanum, 581Epitopes, 96Epoxidation, 16�17, 57�60, 69, 423Epoxide(s)

biotransformation reactions, 27, 37drug discovery and developmentprocess, 239

drug-drug interactions, 86, 91hydrolases, 27�28metabolic activatio, 46metabolite identification, 309oxidative stress, 656, 658pharmacokinetics, 499reduction of, 25

Epoxyeicosatrienoic acids (EETs), 89Erbitux, 632�633Er:YAG lasers, 458Erythromycin, 89, 98, 106, 112, 114Esomeprazole, 85Esterases, 27�28, 86, 156, 211, 239Esters, 27�28, 44Estone sulfate, 117Estradiols, 59�60, 87, 98, 106, 163,

336Estrogens, 60, 336�338Estrone, 125, 336Etacrynic acid, 37Ethanol, 88, 93, 554Ethinyl estradiol, 98, 106, 163Ethoxybenzomide, 2037-Ethoxycoumarin, 124Ethylenediaminetetraacetic acid

(EDTA), 545, 696Ethyl esters, 486Etizolam, 98Etoposide, 114, 125Evaporation, implications of,

266�267, 463Everolimus, 98, 114Evolutionary programming, 713Exactive, 418Excimer lasers, 458Excretion

742 INDEX

BINDEX 1 March 2011; 10:31:29

bile/biliary, 212, 239, 292, 549fecal, 559pharmacokinetics of, 212�218renal, 212, 217�218urine/uurinary, 239, 292

Exposure. See Drug exposure;Environmental considerations,environmental exposure

Extinction coefficients, 236Extractants, isotope coded, 627Extracted in chromatography (EIC)

process, 439, 496�497Extracted ion chromatograms (XICs),

438, 591�592, 599, 601, 604�605Extraction methods

accelerated mass spectrometry,545�549

chemical, 549hepatic, 234liquid-liquid (LLE), 355, 348�359,

362, 369, 409, 572�573, 618, 668,694

solid-phase (SPE), 355�348,359�362, 374, 409, 559,617�618, 620, 630�631,694�698 tissue samples, 460

turbulent flow, 394Extractive electrospray ionization

(EESI), 273Ex vivo studies, 169�170Eye cataracts, 661Ezetimibe, 245

Famotidine, 116Fast atom bombardment (FAB), 258,

270, 322, 582Fast evaporation, 463Fatty acids, 331, 409, 659, 699Fa2N-4 cell line, 166FDA regulations. See U.S. Food and

Drug Administration (FDA)Feces

fecal samples, preparation of, 361quantitative extraction and

recovery, 549

Feeding conditions, significance of,208

Felbamate, 61�62, 70�71Femtomole, 526Fentanyl, 114Fermentation, microbial, 168Fexofenadine, 85, 112, 114, 116, 118,

243Filters/filtering

high-resolution mass spectrometry,417, 428�429

isotopic, 428�429mass analyzers, 274mass defect (MDF), 294, 302�303,

305, 313, 373, 419�426, 715mass spectrometry, 293metabolite detection, 439neutral loss (NLF), 372, 495�496noise, 704, 707product ion (PIF), 495�496quantifiability in data analysis,

709�710, 713RF/DC, 489

Fingerprinting, 374, 580, 688�690,693, 706, 710

First-in-man studies, 231, 238, 568First-pass effect, 206�207, 212First-pass metabolism, 245FlashQuant, 398Flavenoids, 581Flavin, generally

adenine dinucleotide (FAD), 634functions of, 634monooxygenases (FMOs), 20�21,

86, 161�163, 233reductive reactions, 26

Flavonols, 582�584Florfenicol, 332�333Flow scintillation detectors, 540Flp-Int, 122Flp recombination target (FRT), 122Fluconazole, 97�98Fluorescent studies, 10Fluorine, 18, 62, 259, 266, 295,

325�326, 330�331, 374, 706

INDEX 743

BINDEX 1 March 2011; 10:31:29

4-Fluoroaniline, 306Fluorofelbamate, 61�62Fluoroquinilones, 64�654-Fluoro-7-sulfamoylbenzofurazan

(ABD-F), 665Fluoxetine, 106Flutamide, 54, 505Flutamine, 502Fluticasone, 84Fluvastatin, 117�118Fluvoxamine, 95Formaldehyde, 48Formamidopyrimidines, 650�651Formate, 48, 266Formic acid, 322, 696Formoterol, 10Fourier transform (FT), generally

implications of, 261, 285ion cyclotron, 278ion cyclotron resonance-mass

spectral imaging (FTICR-MSI),455

ion cyclotron resonance massspectrometry (FTICR MS),279, 284, 328�329, 337, 339,415, 419, 455, 470�471,691�692, 700

ion trap, 415mass spectrometers, 293mass spectrometry (FTMS),

283�286, 303, 307, 338Fractional mass filtration, 419�420Fractional resolution, in accelerated

mass spectrometric analysis,538�540, 544

FragmentationChinese herbal medicines and, 582of GSH conjugates, 500high-resolution mass spectrometry,

417�418mass spectral imaging (MSI),

458�460, 470reactions, 330�332, 340�342, 345tandem mass spectrometry

(MS/MS), 691

triple-quadrupole linear ion massspectrometry, 490�494, 498

Fragment Identifier, 435Free radicals, 55Fuel atomization, 264Fullerene, 531Full mass spectrometric (MS)

scanning, 293�294, 301�305,312, 368, 389, 416, 439, 485, 584,646, 658, 686, 691

Full peak width at half-height(FWHH), 262

Full peak width at half-mass(FWHM), 262, 274, 285,411�413, 415, 440, 538, 541,543�544

Full tandem mass spectrometric (MS/MS) scans, 454, 658

Functional group activation, toreactive intermediates

anilines, N-hydroxylation of,54�55

carbonyl compounds, unsaturated,61�62

carboxylic acids, 63epoxidation of sp2 and sp centers,56�60

haloalkanes, 62�63hydrazines, 55�56reduced thiols, bioactivation of, 56thiazolidinedione ringbioactivation, 60�61

two-electron oxidation on electron-rich aromatic ring systems, 46�54

Functional groups, characterized,265, 292, 311

Functionalization reactions, 244Furafylline, 106Furanocoumarin, 106Furans, 58, 652�653Furosemide, 116FuzzyFit, 300

Ganciclovir, 116Gas chromatography (GC)

744 INDEX

BINDEX 1 March 2011; 10:31:29

-accelerated mass spectrometry(GC-AMS), 532

characterized, 471, 699-mass spectrometry (GC-MS), 258,

292, 516, 668, 688, 690�692, 712Gas-phase

ionization phase, 268ions, 264�267

Gas transfer, 531Gastric disorders, 68Gastrointestinal (GI) tract, 168, 174,

206, 233, 242Gaussian distribution, 537�538, 543,

552Gefitinib, 98Gemfibrozil, 106, 117�118GenBank database, 619Gene-drug interactions, 85General unknown screening (GUS),

516Genetic algorithms, 713Genetic polymorphisms, 91Genetics phase of drug development,

5Genistein (GS), 162Genotoxins, 554, 651Gestodene, 106Gilbert’s disease, 90Ginkgo, 112, 114Glabridin, 106Glaucoma, congenital, 87Glibenclamide, 112Glomerular filtration rate (GFR),

217Glucathione (GSH) conjugation

reactionscarbon atoms, saturated and

unsaturated, 38conjugated enone/enal and similar

systems, 37�38epoxides, 37heteroatoms, 38metabolite identification, 299�300,

306�307overview of, 36�37

Glucocorticoid receptor (GR), 92�93Glucocorticosteroids, 326Gluconobacter oxidans, 168Glucopyranoside, 571�572Glucose, 714Glucosidation, 296Glucosides, 583, 585, 588�589, 591Glucurnidati, 302Glucuronic acid, 239, 605Glucuronidation reactions

amines and amides, 30�31drug discovery and development

processes, 244drug disposition, 174drug-drug interactions, 86, 90�91hydroxy groups, 29�30metabolic activation, 66, 69metabolite identification, 296, 302,

420oxidative stress, 670relatively acidic carbon atoms, 31thiols and thiocarbonyl

compounds, 31Glucuronides, 44, 184, 295, 297�298,

311, 336, 398, 412, 423, 430,604�605, 607, 647

Glutamate, 27Glutamic acid, 292, 295, 714Glutamine, 714Glutaric acid, 694, 714Glutathione (GSH)

adduct screening, 486�487,499�501, 662�665

biotransformations, 423�424conjugation, see Glutathione

(GSH) conjugatesdepletion, 665detection of reactive metabolites,

45�48, 240�241, 499�510ethyl ester (GSH-EE), 506functional group metabolism,

50�54, 56�56, 58�61IADRs and, 72liquid chromatographic detection,

372

INDEX 745

BINDEX 1 March 2011; 10:31:29

Glutathione (GSH) (continued )mass spectrometric techniques, 368metabolite identification, 292,

295�296, 299, 309�30metabolite profiling, 336oxidative stress and, 646quantification, 665reductase, 665

Glutathione (GSH) conjugatesall-in-one data analysis, 429�430mass spectral analysis, 337metabolite identification, 302, 310reactive metabolite screening,

499�510triple quadrupole-linear ion mass

spectrometry, 491, 493Glutathione disulfide (GSSG), 646,

663, 665Glutathione-S-transferases (GSTs),

86, 91�92, 162, 662Glyburide, 98, 112, 425Glycerol, 269Glycine, 292, 296, 423, 558, 698Glycocholic acid, 714Glycolipids, 31, 331Glycoproteins, 31Glycosides, 258, 325, 584, 604�605Glycosyl, 599Glycosylases, 650Glycosylation, 583, 598, 603Glycoursodeoxycholic acid, 714Gold, 456Gomisin C, 106Good laboratory practices (GLPs),

370, 615Gossypium herbaceam L., 582, 584Grapefruit juice, 113�114Grapher, 537Guanidines, 25Guanine, 46, 647�648

Halides, 46, 325, 499Haloalkanes, 27, 62�63Halogens, 38Halohydrin, 18

Haloperidol, 88Halothane, 45, 62�63, 87�88Haptenization, 45Haptoglobin, 634“Hard” electrophiles, 46Heat shock proteins (HSPs), 92, 655Heavy atom bonds, 435Helium, 276Hemizygotes, 179Hemoglobin, 662Hemoproteins, 15, 44HepaGR cell line, 166Heparin, 545Hepatic metabolism

clearance, in vitro-in vivo scaling,214�215

implications of, 212Hepatocyte sandwich cultures, 124Hepatocytes, in sample preparation,

408�409Hepatotoxicity, 45, 47, 55, 336HepG2 cells, 64, 89Heptanone-etheno-20-

deoxyguanosine DNA (HγdGu),646, 651�652, 672

Heteroaromatics, 19, 57�58Heteroatoms

biotransformation reactions, 18, 38mass spectral imaging, 330oxidative reactions, 18

Heterodealkylation, 299Heterodimers, 92�93Hexobarbital, 203Hierarchical clustering analysis, 713HighChem Mass Frontier program,

309High-clearance drugs, 204�205High-collision energy, 417, 429High-dose drugs, 242High-density lipoproteins (HDLs),

661High-energy scans, 411Higher energy collision dissociation

(HCD), 418�419, 440High mass pass filter, 274

746 INDEX

BINDEX 1 March 2011; 10:31:30

High-molecular weight, implicationsof, 45, 258, 270, 634

High-performance liquidchromatography (HPLC)

-accelerated mass spectrometry(HPLC-AMS), 534, 541�544

-ARC (HPLC-ARC), 540�541, 544-atmospheric pressure chemical

ionization-tandem massspectrometry (HPLC-APCI-MS/MS), 390

biomarker discovery research, 699,702

characterized, 4�5, 361�362, 364,373�374, 575

Chinese herbal medicine and, 593-diode array detection (HPLC-

DAD), 516drug discovery and development

processes, 235drug disposition, 173drug-drug interactions, 121earlydrugmetabolismscreening,385-electrospray ionization mass

spectroscopy (HPLC-ESI-MS),385�386

fluorescence analysis, 507-Fourier transform ion cyclotron-

mass spectroscopy (HPLC-FTICR-MS), 581

-liquid scintillation counting(HPLC-LSC), 540�541, 544

mass spectral imaging, 322, 329,334, 336�337

-mass spectrometry (HPLC-MS),269, 293, 580�581, 586�590

oxidative stress and, 653protein therapeutics, 593, 628-tandem mass spectrometry

(HPLC-MS/MS), 337�338, 389,391�392, 394, 396�399

-TOP COUNTt, 540�541-ultraviolet spectra (HPLC-UV)

spectroscopy, 234, 236, 398,569, 591

-ultraviolet spectra-tandem massspectrometry (HPLC-UV-MS/MS), 390

High-resolution scansfull scanning, 301liquid chromatography mass

spectroscopy (LC-MS), 334, 475mass spectrometers, 298, 339mass spectrometry (HRMS),

300�302, 307, 309, 313, 369, 410,470�471, 487, see High-resolution spectrometry, drugmetabolte identification process

High-resolution spectrometry, drugmetabolite identification process

all-in-one data analysis, 429�431background subtraction, 428control comparison, 427�428full-width at half maximum

(FWHM), 411�413future directions for, 440�441instrumentation, 413�419isotope filtration, 428�429localization of, 435�438mass defect filtration, 419�426novel metabolites, rationalization

of, 431�433postprocessing strategies for data

sets, 426�427product ion spectra using accurate

mass, 433�435quantitative/qualitative in vivo

pharmacokinetic data fromsingle injection per sample,438�440

sample challenges, 408�409specificity/selectivity advantage of,

410�411High-throughput applications

assays, 397�399imaging, 236screening, 245, 311, 517

HILIC, 699Hinokinin, 106Hippocrates, 687

INDEX 747

BINDEX 1 March 2011; 10:31:30

Hippuric acid, 702�703Histidines, 27, 619, 655, 659�662, 714Holistic perspective, of drug

metabolism process, 5�6Homeostasis, 558Homocarnisone, 660Homogenization, 123, 450Homologs, 637�638Homology modeling, 182�183Homoscedastic analysis, 551, 553Homozygotes, 179Hormones

estrogen, 60, 336�337nuclear, 246recombinant growth hormone

(rhGH), 622steroid, 92, 168testerone, 95, 97

Hot spots, 235, 243HPETE, 663�666, 668H368 cells, 649Human CYP-transgenic mouse

models, 176�182Human ether a-go-g related gene

(hERG) inhibition, 152Human Genome Project, 110Human immunodeficiency virus

(HIV), 59Human leucocyte antigen B (HLA-B),

73Human liver microsomes (HLM)

cytochrome P462 (CYP) assays,396, 512

enzyme kinetics, 512experimental models, 186expressed enzymes and, 159�161hepatic intrinsic clearance,

212�213, 221mass spectral interpretation, 340metabolism-based DDIs, 105reaction phenotyping, 94�95,

513�514reactive metabolites, 502

Human serum albumin, 659. See alsoAlbumins

Human studiesADME, 175drug discovery, 157, 172drug toxicity, 68�71functional group metabolism,56�58, 62

hepatic intrinsic metabolicclearance, 214

intestinal metabolism, 210mass spectral interpretation, 339metabolic stability, 390�391quantitative drug metabolism,556�558

quantitative extraction andrecovery, 547

quantitative MALDI-MS, 464reactive metabolites, 50, 59�62, 242structural alerts in drug design,64�65

transporters, 124Hydralazine, 55�56Hydrastine, 106Hydration, 302, 422, 581Hydrazides, 657Hydrazines, 33, 55�56Hydrocarbons, 15�16, 56, 259�261Hydrogen, 17�18, 50, 60, 63, 183,

259�260, 262, 310�311, 326,330, 343�345, 374, 419, 435, 647,706

Hydrogen/deuterium (H/D)exchange, 311, 313, 342�345

Hydrolysis, 4, 55, 60, 62, 292, 299,333, 422, 581

Hydrolytic reactions, 27�28Hydroperoxyflavin, 204-Hydroperoxy-2(E)-nonenal

(HPNE), 651Hydrophilic compounds, 244,

547�548, 550Hydrophilicity, 156, 292Hydrophobic compounds, 547�548,

550Hydrophobicity, 115Hydroquinones, 19, 26, 47

748 INDEX

BINDEX 1 March 2011; 10:31:30

Hydroxides, 2030-Hydroxyacetanilide, 69Hydroxyamides, 17, 32�33Hydroxylamines, 20, 32�33Hydroxylation, 47�50, 61, 94�95,

174, 292, 306, 336, 420�423Hydroxy-butamide, 573Hydroxyeicosatetraenoic acids

(HETEs), 669�6704-Hydroxy-2(E)-nonenal (HNE), 651,

655, 657�660, 6644-Hydroxyesterone, 3364-Hydroxyestradiol, 87, 336Hydroxy groups, 29�325-Hydroxyindole, 524-Hydroxypicolinic acid (HPA), 271Hydroxyl groups, 49, 242, 295, 345Hydroxyphenobarbital, 5735-Hydroxytryptamine (5-HT), 49, 203Hyperbilirubinemia, 90

Ibufenac, 65�66, 336Ibuprofen, 65�66, 518IC50, 99, 101, 118, 127, 396�397Idarubican, 112Idiosyncratic adverse drug reactions

(IADRs)defined, 44dosage and, 71�72drug toxicity and, 69, 71frequency of, 44genetic factors, 73life-threatening, 44predictors of, 45, 68�71, 73safety of, 63

Imatinib, i98Imidazlinedione, 61Imines, 18, 21, 23�24, 52�54, 64Imipramine, 87Immobilized artificial membrane

(IAM), 121Immunoaffinity

chromatography, 668implications of, 632, 668purification, 632

Immunoassays, 616, 636�637Immunoblotting, 655Immunocapture, 631�624Immunodepletion methds, 635Immunogens, 45Immunoglobulin A (IgA), 634Immunoglobulin G (IgG), 634Incident beam, 258Indinavir, 59, 98, 425, 432Indole-3-carbinol, 87Indomethacin, 52, 116, 167Inert chemicals, 44Information-dependent acquisition

(IDA), 487, 489�490, 494, 715Infrared (IR) spectroscopy, 690�691Infrared lasers, 458Inimium, electrophilic, 46Injection technique, staggering, 395Inkjet printing, 460, 463Insect cells, 123, 212In situ studies, 168�169Instrumentation, high-resolution

spectrometry, 411, 413�419Insulin levels, 168Intensity-dependentMS/MS scan, 439Interferon-γ, 93Interleukins, generally

IL-1β, 93IL-4, 93IL-6, 92�93

International Conference onHarmonisation (ICH)

Guidances from, 7�8, 10, 237�238Guidance Q2B Validation of

Analytical Procedures, 551International standard (ISTD)

drug development, 637protein quantitation, 615, 620, 622,

625�630sensitivity enhancement, 632

International TransporterConsortium (ITC), 110�111

Inulin, 124Investigational New Drugs (INDs),

173, 615

INDEX 749

BINDEX 1 March 2011; 10:31:30

Invitrogen, 649In vitro-in vivo, generally

correlations (IVIVC), 109,128�129, 158, 171, 233

discrepancy, 184extrapolation (IVIVE), 107qualitative/quantitative studies,

438�440scaling studies, 214�215

In vitro metabolism studies, 94, 109,127, 152, 157�168, 208, 372,498�508, 512�514

In vivo metabolism studies, 108, 152,170�171, 173�176, 199,214�215, 233�234, 244�245,399, 409, 508�512, 570

Iodide, 18Iodine, 325�326, 706Iodoacetamide (IAB), 628, 656�657Ion cyclotron resonance (ICR), see

specific types of ion cyclotronresonance mass spectrometry

mass analyzers, 415mass spectrometer, 262, 283

Ion evaporation model (IEM),266�267

Ion exchange, 356Ionization, 156, 263, 273, 295, 322,

410, 456�460. See alsoElectrospray ionization;Extractive electrospray ionzation(EESI); Matrix-assisteddesorption laser ionization(MALDI)

Ion mobility spectrometry (IMS)defined, 471liquid secondary (LSIMS), 322mass spectrometry (IMS-MS)

studies, 417, 472tandem mass spectrometry (IMS-

MS/MS) studies, 472-TOF mass spectrometer, 417

Ion statistics, 415Ion suppression, 570, 690Ion trap (IT)

FTICR analyzer, 415ion cyclotron resonancespectrometer, 259, 284

mass spectrometers, 235�236, 264,304, 646

technique, 2583D, 278time-of-flight (TOF) massanalyzers, 415

time-of-flight (TOF) massspectrometry, 417

time-of-flight (TOF) spectrometer,259

Ipomeanol, 106Irinotecan, 90, 106Iron/iron groups, 531, 706Irradiation-matrix-assisted laser

desorption ionization (IR-MALDI), 458, 473

Isobutene, 267Isocyanate, 60Isofezolac, 116Isofluorane, 62Isoforms, 90�91, 95Isoleucine, 714Isomers, 366, 369, 390Isoniazid, 55�56, 88, 106Isoprostanes (IsoPs), 646,661,665�670Isoquercetrin, 583, 585, 587, 591, 604Isorhamnetin, 583, 591, 603�604, 607IsoScore algorithm, 436Isotope(s), see Decay counting;

Radioisotopesabundance and mass of, 259, 326characterized, 300decay, 530distribution, 711drug metabolite identification,428�429

patterns of, 711stable, 309�311, 313, 626�627,631, 647, 649, 668, 670�671

Isotope pattern filter (IPF), 439Isotope ratio mass spectrometry

(IRMS), 527�528

750 INDEX

BINDEX 1 March 2011; 10:31:30

Isoxazole, 25Isozymes, 45, 60, 96, 159�160,

162�163, 182, 219, 396Issue-driven studies, drug discovery,

155�157Istradefylline, 112Itraconazole, 97�98, 112�114Ivermectin, 124

JMP, 537

Kaempferol, 583, 589�592, 598�599,604�605, 607

Kaleidagraph, 537Keap1 protein, 654Ketenes, 60, 598Ketoconazole, 89, 95�98, 112�114,

172, 174, 234, 246Ketoglutarate, 115Ketones, 17, 19, 26, 421�422kinact values, 103�106, 164Kinetic isotope effect, 311Kinetics

clearance-limited, 204drug absorption, 208significance of, 5time-dependent inhibition, 103ursodiol, 559

Knockout mice,Cyp- models, 176�180Ki values, 99�101, 103�106, 164Kruskal-Wallis test, 713Kuppfer cells, 169Kynurenine, 714

Labeling, stable isotope clusters,310�311

Lactase-phlorizin hydrolase (LPH), 603Lactone, 28Lactoperoxidase, 23Lamotrigine, 91Laniquidar, 113Lapatinib, 112Large-scale clinical trials, 7Laser ablation electrospray ionization

(LAESI), 451

Laser desorption ionization (LDI), 452Laser desorption ionization-triple

quadruple (LDI-QqQ) massspectrometer, 452

Laser microprobe mass analyzer(LAMMA), 452

Lasers, types ofinfrared wavelength, 458matrix-assisted laser desorption

ionization (MALDI), 269�272,454

Nd:YAG, 458nitrogen, 270, 458wavelength, 458

Lead candidate, 171, 245Lead identification, 154Lead optimization, 154�155, 171,

229, 243�245, 392Leucine, 714Leukotrienes, 27Leurpein, 106Levenberg-Marquadt algorithm, 543Levofloxacin, 116Licensing, 122Lidocaine, 89Ligand binding, 343Lignocaine, 203Limit of detection (LOD), 534Linear discriminant analysis, 713Linear ion trap (LIT)

mass analyzer, 278�280, 285�286,453, 455, 469, 473, 491

mass spectrometers, 293-Orbitrap, 471tme-of-flight-mass spectrometry

(LIT-TOF-MS), 279Linear scale plots, 556Lineweaver-Burk plot, 100, 104�105Linoleic acid, 663�664Lipid(s)

accelerator mass spectrometricanalysis, 551

bilayer barrier, 119biomarkers, 665�670biotransformation reactions, 27

INDEX 751

BINDEX 1 March 2011; 10:31:30

Lipid(s) (continued )in distribution studies, 461, 464, 472hydroperoxide, 661�662hydroperoxides, 662metabolism, 182in metabolite identification, 409oxidative stress and, 646peroxidation, 310, 646�647,

653�654, 661Lipinski’s “rule of five,” 156Lipitor. See AtorvastatinLipodomic profiling method, 647Lipophilic compounds, 244Lipophilic drugs, 236�237Lipophilicity, 127, 156, 167, 174Lipoxygenase (LO), 646Liquid chromatography, see specific

types of liquid chromatographydistribution studies, 471fast separations, 364�366flow, 363flow scintillation detectors, 540instrumentation, 258, 268-microplate scintillation counting

(LC-MSC) analysis, 373�374normal-phase (NP), 367

Liquid chromatography-acceleratormass spectrometry (LC-AMS)

background, 550�553drug metabolite analysis, 536�540,

544, 555, 560sensitivity, 550�553

Liquid chromatography-atmosphericpressure chemical ionizationtandem mass spectrometry (LC-APCI-MS/MS), 292, 336, 651,661, 672

Liquid chromatography-electron-capture atmospheric pressurechemical ionization/massspectrometry (LC-ECAPCI/MS), 669

Liquid chromatography-electron-capture atmospheric pressurechemical ionization/multiplereaction monitoring/mass

spectrometry (LC-ECAPCI/MRM/MS), 668, 670

Liquid chromatography-electrosprayionization-tandem massspectrometry (LC-ESI-MS/MS),336, 617, 662

Liquid chromatography-massspectrometry (LC-MS), seespecific types of liquidchromatography-massspectrometry

drug discovery and developmentprocess, 239

DNA biomarkers, 649�650, 686enzyme kinetics in drug-druginteractions, 512

full scan, 305�306, 312herbal medicine profiling andcharacterization, 592, 600,608�609

historical perspective, 9instrumentation, 276, 280mass spectral detection,697�700

metabolite characterizationstrategies, 342�345

metabolite identification, seeMetabolite identification

metabolite profiling, 686�687metabolite quantitation, 569metabonomics, data processing andanalysis, 700�713, 715

mobile phase, 322nanospray, 441, 573profile, anatomy of, 701�702proteins in drug development,636�638

samples, 516, 695standard-free metaboliteestimation, 573

Liquid chromatography-multiple-reaction monitoring-massspectrometry (LC-MRM-MS),649, 662

Liquid chromatography-nuclearresonance imaging mass

752 INDEX

BINDEX 1 March 2011; 10:31:30

spectroscopy (LC-NMR-MS)analysis, 374�375, 593

Liquid chromatography radio-flowdetection (LC-RFD) massspectrometry, 373

Liquid chromatography tandem massspectrometry (LC-MS/MS), seespecific types of liquidchromatography tandem massspectrometry

biomarkers for oxidative stress,658, 662, 667

Chinese herbal medicine and, 580,582

distribution studies, 473drug discovery and development

process, 232�233, 235, 246,636�639

drug disposition, 159�160, 173drug-drug interactions, 121, 125instrumentation, 258mass spectral imaging, 333�334,

336, 342matrix effect, matrix suppression/

enhancement, and recovery,628�631

metabolic activation, 46metabolite identification, 311�312metabonomics, 711pharmacokinetic research, 213, 222,

509, 518protein bioanalysis, 614protein concentration

measurement, 638protein quantitation by, 615�625protein therapeutics, 614, 639sensitivity enhancement via

depletion of abundant proteins,633�636

sensitivity enhancement viaimmunocapture/purification,631�633

techniques, overview of, 368,374

Liquid chromatography-TOPCOUNTt, 544

Liquid chromatography-ultravioletspectra-mass spectrometry (LC-UV-MS), 371�373, 389, 441,495, 582, 591

Liquid-liquid extraction (LLE), 355,348�359, 362, 369, 409,572�573, 618, 668, 694

Liquid-phase microextraction(LPME), 348

Liquid scintillationcounting (LSC), 374�375,

540�541techniques, 373

Liquid secondary ion massspectrometry (LSIMS), 322

Lithium chloride, 323Liver, see Hepatocytes

hepatic intrinsic clearance,212�217

perfusion, 168�169LLC-PK1 cell line, 120, 127Loperamide, 112Lopinavir, 98, 113, 115Loratadine, 85Losartan, 98Lovastatin, 89, 125Low-clearance drugs, 204Low-collision energy, 417, 429Low-density lipoprotein (LDL), 659,

661Low-dose drugs, 8�9, 71, 242Lower limit of quantitation (LLOQ),

534�535, 538, 543, 545,547�553, 558�559, 614, 617,619, 630, 635

Low-flow electrospray, 267Low mass pass filter, 274Low-molecular weight, generally

compounds (LMWC), 270�272pharmaceuticals, 45, 217, 312, 362,

457, 615Low-resolution mass spectrometry,

300, 313LTQ

-FTICR mass spectrometer, 416,419

INDEX 753

BINDEX 1 March 2011; 10:31:30

LTQ (continued )Orbitrap mass spectrometry,

285�286, 329, 340, 368�369,416, 418�419, 658, 700

Lung-selective enhancers, 90Lupus syndrome, 56Lyophilization, 549Lysines, 46, 50, 66, 619, 655, 659, 714

Macromolecules, 240, 258�259, 267,499, 528

Macrophages, 661, 665Madison Metabolomics Consortium,

711Magicangle spinning (MAS)NMR,374Magnesium, 706Magnetic resonance imaging, 450Malaria, 452Mann-Whitney test, 713Mardin-Darby canine kidney II

(MDCK II) study, 214, 216Market withdrawal of drugs, 84Mass accuracy, 412, 415Mass analyzers, in mass spectrometry

function of, 263, 273, 280�286,453�456

ion trap, 276�280linear ion trap, 278�280triple quadrapole, 273�278types of, 453�456

Mass balance equation, 201Mass balance studies, 235�237, 568Mass defect filtering (MDF), 294,

302�303, 305, 313, 368�369,373, 417, 419�426, 715

MassFragmenter, 435Mass-mass spectrometry, 238Mass measurement accuracy (MMA),

261�262, 328�329, 337, 341,345, 432�435, 711

Mass reflectron, 281�282Mass resolution, 262Mass resolving power (MRP), 262�263Mass spectral correlation, 300Mass spectral interpretation

applications, 332�345common fragmentation reactions,330�332, 340�342, 345

molecular weight and empiralformula interpretation, 322�330

significance of, 321Mass spectrometers, see specific types

of mass spectrometrycomponents of, 263�264types of, 264

Mass spectrometric imaging (MSI)background, 451�453localizing drugs and theirmetabolites, verifying targeteddrug distribution, 465�474

methodologies, 453�464Mass spectrometry, see specific types

of mass spectrometryconcepts and thery of, 257�263historical perspective, 4, 8�11,257�259

instrumentation, see Massspectrometer

ion sources, 264�273isotopes, 259�263mass analyzers, 264, 273�286mass spectral interpretation,321�345

metabolite profiling, 334�342MS3, 464, 470, 490�491, 494MSe, 411, 439performance improvementtechniques,

sample preparations, see Massspectrometry samples,preparation of

signal intensity, 265�266single-stage, 369

Mass spectrometry samples,preparation for

blood, 359�361for bioanalysis, 354�360fecal tissue, 361liquid-liquid extraction (LLE),348�359

754 INDEX

BINDEX 1 March 2011; 10:31:30

for metabolic profiling andidentification, 360�361

plasma, 359�361protein precipitation, 355solid-phase extraction (SLE),

355�356turbulent flow chromatography,

356�348urine, 360�361

Mass-to-charge ratio (m/z)biomarker identification, 617, 698,

700, 702, 708mass spectral interpretation and,

322, 324, 331�332, 334, 340, 342,344

metabolite identification, 297�298,306, 308, 411�412, 417, 429, 435

pharmacokinetics and, 489significance of, 257, 262, 276�277,

280�281, 283, 285Mathematical models, 202�204MATLAB, 591Matrix effect, 628�629Matrix suppression/enhancement,

628�629Matrix-assisted laser desorption

ionization mass spectrometry(MALDI-MS)

early drug metabolism screening,398

-Fourier transform-ion cyclotronresonance mass spectrometry(MALDI-FT-ICR MS), 339

instrumentation, 258, 263�264,269�272, 280�281

-LIT/Orbitrap mass spectrometer,456

low-pressure, 461�462MALDI-QqQ mass analyzer, 454MALDI-QqTOF, mass spectral

imaging, 465mass spectrometric imaging,

distribution studies, 451, 453,458�460

matrix deposition, 462�463

matrix selection, 462orthogonal (o-MALDI), 282quantitative, see Quantitative

MALDI-MS-time of flight (MALDI-TOF)

spectrometry, 272, 454tissue samples, 461tissue washing, 463

Matrix-enhanced (ME)(SIMS), 457Matthieu’s equations, 277MDCK cell line, 120MDL metabolite, 312MDR transporters, 164Mechanism-based inhibition (MBI),

102Medicinal chemistry

carbonyl compounds, 61metabolic activation, 43�73metabolite identification, 309profiling experiments, 236structural alerts, 66

Medium-throughput screens, 246Mefloquine, 98Membrane

immobilized artificial (IAM), 121-protein interactions, 5vesicle systems, transporter,

123�124Mephenytoin, 88, 95, 97Mercapturic acid, 56, 61�62Messenger RNA (mRNA), 93, 125META, 312MetabolExpert, 312Metabolic activation, organic

functional groupscovalent binding, 68�71, 73defined, 44dosage considerations, 71�72reactive intermediates, 46�63reactive metabolites, detection of,

45�46structural alerts and drug design,

63�68trapping, reactive metabolites,

68�71, 73

INDEX 755

BINDEX 1 March 2011; 10:31:30

Metabolic clearance, 232�235. Seealso Clearance

Metabolic diseases, 654Metabolic instablity, 244Metabolic profiling

biomarker identification, 690drug discovery and development

processes, 235�237, 243in vitro species, 371, 498liquid chromatographic detection,

372�375liquid chromatographic separation

technologies, 370�371-mass balance studies, 235�237mass spectral interpretation,

333�342metabolite identification, 300, 302metabolite levels, 570in metabolite quantitation, 569metabolic soft spot determination,

495�498metabolic stability analysis, 494�495nonradiolabeled compounds, 371radiolabeled compounds, 371sample preparation, 360�361

Metabolic quantitation, in absence ofsynthetic standards, 568�570

Metabolic stabilitydrug discovery and development

process, 243, 245drug disposition and, 152early drug metabolism screening,

387�392pharmacokinetics and, 494�495screening strategies, 234�235

Metabolism, influential factors, 128Metabolism-based DDIs

clinical DDI prediction from CYPinduction, 107�109

experimental models, 186reaction phenotyping, 93�98reversible CYP inhibition, 98�102,

106�107time-dependent inhibition (TDI),

102�105, 107, 165

Metabolite(s), generallybiomarkers, see Metabonomicscharacterization by LC-MS,342�345

identification, see Metaboliteidentification (MET ID)

quantitation, 8�9, 568�570safety testing, see Metabolite insafety testing (MIST)

Metabolite identification (Met ID)detection strategies, 293�303drug disposition, 155future research trends, 312�314sample preparations, 408�409significance of, 291�293, 408in silico tools, 312in vivo, 409structure elucidation, 291, 304�312

Metabolite identification bycomparison of correlated analogs(MICCA), 436

Metabolite in safety testing (MIST)accelerator mass spectrometry(AMS), 526, 528, 545, 555�556

ADME studies, 175�176, 185Metabolome

defined, 686measurement of, 686�687

Metabolomics/metabonomicsbiomarker identification, 687�688,715�716

data processing and analysis,700�713, 715

experimental designs, 692�700fingerprinting methods, 688�690nontargeted, 690�691, 693, 710,714

pharmacokinetics and, 506targeted, 691�692, 710, 714technology, 73web-based, 711

MetaDrug, 312Metal-assisted (MetA)(SIMS), 457Metal-catalyzed oxidation (MCO),

660

756 INDEX

BINDEX 1 March 2011; 10:31:30

Metal ions, 325METEOR, 312MetFast assay, 389Metformin, 115�116Methadone, 98Methane, 267, 434Methanol, 323, 360�361, 390, 547,

620, 623, 696�698Methides, 19Methimazole, 56�57Methionine, 620, 659�662, 714Methotrexate, 124�125Methoxychlor, 87Methoxylamine, 46Methoxymorphinan, 186Methylation, 35�36, 70, 292, 599, 603Methylbenzotriazole (MBA), 953-Methylcholanthrene (3MC), 87, 90Methylene, 49, 421�423Methyl groups, 19, 68�69, 603Methyl-histidine, 7143-Methylindole, 53, 89Methyl methanesulfonate (MMS), 649Methylprednisolone, 1124-Methylpyrazole, 95Metoclopramide, 106Metoprolol, 63, 88MetWorks, 303Metyrapne, 92Mibefradil, 97�98, 106Michaelis-Merten (MM)

equation, 213, 233kinetics, 99

Michael reactionsacceptors, 46, 499, 656addition, 37, 47, 62, 336, 653, 656,

658, 664Microarray analysis, 64Microbial systems, 168Microcrystals, mass spectral imaging

(MSI), 469�470Microcystin-LR, 125Microdosing studies, 222Microflora, intestinal, 27Microphotography, 457�458

Microplate scintillation counting(MSC), 373

Microsomal stability assays,388�389, 570

Midazolam, 89, 94�95, 97�98, 106,179�180, 210

Mifepristone, 59, 92Milk thistle, 114Minoxidil, 32�33Mirtazapine, 98Mitochondrial amidoxime reducing

component (mARC), 25Mitoxantrone resistance (MXR)

protein, 111Moclobemide, 260Modern, accelerated mass

spectrometryclinical aspects, 554equivalent definitions of, 533�535LC-AMS background and

sensitivity, 551�552neonatal studies, 558�559

Molecular ions, 263Molecular oxygen, 660, 666Molecular weight (MW), see High-

molecular-weight; Low-molecular-weight

implications of, 9, 235, 260, 276,453, 475, 492, 552, 599

nitrogen rule, 328Molybdenum hydroxylases, 22, 86Mometasone furoate, 326�328, 330Monoamine oxidases (MAOs)

biotransformation reactions, 21�22disposition studies, 162drug-drug interactions, 86inactivators, 55

Monoatomic ion beams, 456Monoclonal antibodies (MAb), 96,

615, 619�620, 625�628,631�632, 636

Monooxidation, 507Montelukast, 95, 102Morphine (GUT2B7), 91, 112, 116,

574

INDEX 757

BINDEX 1 March 2011; 10:31:30

Mouse studiesADME studes, 173, 176�182C57BL/6 strain, 179�180, 652CYP gene, 176drugdiscovery anddevelopment, 172drug disposition, 178engineered models, 176�182mass spectral imaging, 467mass spectral interpretation,

337�338mdr 1a model, 124regulatory mechanism, 93sample preparation, 359tissue imaging of drugs, 515�516transgene inducibility, 181transgenic, see Transgenic mice

MPP+, 115MPTP (1-Methyl-4-phenyl-1,2,3,6-

tetrahydropyridine), 21MS total useful signal (MSTUS), 709MS209, 113Multicollinearity, 713Multidrug and toxin compound

extrusion (MATE), 218Multidrug resistance-associated

protein (MRP/MRP2)characterized, 214, 216, 218transporters, 164, 167

Multiple affinity removal system(MARS), 634

Multiple ascending dose (MAD), 175Multiple-drug resistance (MDR1),

111, 125, 128Multiple ion monitoring (MIM)

-enhanced product ion (MIM-EPI),486, 492, 494, 496, 498�499, 518

metabolite identification, 299�300,304, 313

-multiple reaction monitoring(MIM-MRM) scan, 497

-multiple reaction monitoring-enhanced product ion (MIM-MRM-EPI) scan, 497

pharmacokinetic studies, 490,493�494, 498

Multiple-reaction monitoring (MRM)biomarker identification, 700-enhanced product ion (MRM-EPI), 486, 514�515, 517�518

metabolite identification, 298�300,304, 313

oxidative stress, 647pharmacokinetic studies, 485�486,490�492, 498, 500, 503�504,507�509, 511�512, 514�515,517�518

-tandem quadrupole massspectrometry (MRM-TQMS), 692

Multistage scanning (Mn)biomarker identification, 711Chinese herbal medicine, 580, 582,598�599, 605

distribution studies, 453, 455�456,464, 469

mass spectral interpretation, 329metabolite identification, 306�309,418, 436

Multitarget screening (MTS), 517Muraglitazar, 174, 433Mutations/mutagenesis, 85, 157, 337Myeloperoxidase (MPO), 23�24,

64�65, 239, 661Myoglobin tryptic peptides, 622�625My13, 632

N-acetylcysteine, 296N-acetylglucosomine, 296N-acetyl-L-cysteine (NAC)

adducts, 486, 510�511as trapping agent, 506�507

N-acetyl-para-benzquinone imine(NAPQI), 50

N-acetyltransferases (NATs), 33, 56,86, 162�163

NAD(P)H-quinone oxidoreductase(NQO), 26

NADH, 23, 26�27Nafcillin, 116Nalidixic acid, 116Nanoelectrospray, 267, 398

758 INDEX

BINDEX 1 March 2011; 10:31:30

Nanoflow liquid chromatography, 267NanoMate, 572, 576Nanospray, 574Nanospray ionization (NSI), 646Nanospray mass spectrometry

DNA analysis, 672equimolar response, 570�572, 576estimating metabolite levels,

572�575Naphthflavone, 95Naphthalene, 56�57, 89Naproxen, 116Narrow-window extracted ion

chromatograms (nwXICs),426�427, 429

National Institute of Standards andTechnology (NIST), 529, 532,712

Nefazodone, 47, 52�54, 98, 339�342,425, 432, 504

Negative chemical ionization (NCI),267

Nelfinavir, 106, 112, 114Neohesperidose, 584Neonates, AMS studies, 558�559Nephrotoxicity, 157Nernst equation, 664�665Neurodegenerative diseases, 654Neurokinin I receptors, 344Neurotensin, 572Neurotransmitters, 91Neutral loss (NL)

-enhanced product ion (NL-EPI)scan, 486, 490, 499, 503,506�507, 510, 518

filter (NLF), 439fragmentation reactions, 330, 332high-resolution mass spectrometry,

434scans, 276, 417, 430, 490�491, 494,

500, 506, 510, 515, 580Neutropenia, 90Neutrophils, 64New chemical entities (NCEs)

biotransformation pathways, 292

dosing considerations, 122drug discovery phase, 231�232,

239, 332drug-drug interactions, 84, 127drug metabolism phases, 4�5evaluation of, 109inhibition potential, 129metabolic clearance, 232, 238metabolite identification using LC-

MS, 291Pg-p substrates, 120pharmacokinetic distribution,

124�125reactive metabolites, 239, 246screening process, 85, 99

New Drug Application (NDA),173, 615

New drug candidates, screeningof, 205

NF-KB pathways, 663Nicardipine, 106Nickel, 706Nicotinamide, 714Nicotinamide adenine dinucleotide

(NAD+), 634Nicotinamide adenine dinucleotide,

23Nicotinamide adenine dinucleotide

phosphate (NADPH), 15, 23�24,26�27, 46, 49, 56, 159, 163, 232,663

Nicotine, 36, 87Nifedipine, 89, 92, 97�98Nimesulide, 54N-in-one, 394Nitrenium ions, 499Nitric oxide, 24Nitroaromatics, 26�27Nitrobenzenes, 50�51, 54Nitro groups, 38, 50Nitrogen

biomarker identification, 706biotransformation reactions,

17�18, 20, 22mass spectral interpretation, 326, 330

INDEX 759

BINDEX 1 March 2011; 10:31:30

Nitrogen (continued )mass spectrometric studies,

259�260, 262�263, 265,360, 374

in metabolic activation, 51�52, 54metabolite identification, 310, 312,

433metabolite levels and, 569oxidative reactions, 17�18, 20, 22oxidative stress, 647rule, 328, 711

Nitrones, 18Nitrosamines, 87p-Nitroanisole, 96Nitrotyrosine, 661�662NNK ([4-(methylnitrosamino)-1-(3-

pyridyl)-1-butanone)], 87, 89NOAEL, 172Nonlabeled drugs, 360Nonparametric testing, 713Nonsteroidal anti-inflammatory

drugs (NSAIDs), 52, 58�59, 65,67, 88

Norephedrine, 36Normal distribution, 553�554Normalization, in data analysis,

708�709Normalized liquid chromatography

nanospray ionization massspectrometry, 575

Normorphine, 574Nortriptyline, 106Norverapamil, 106Notations, listing of, 223�224Novel metabolites, 433N-oxides, reductive, 24Nrf2 protein, 654�655NtprBNP protein, 632Nuclear hormone receptors, 246Nuclear magnetic resonance (NMR),

374�375Nuclear magnetic resonance (NMR),

591�592Nuclear magnetic resonance (NMR)

spectroscopic studies

biomarker identification, 688, 690,711

historical perspectives, 4, 8, 10-liquid chromatography-massparallel dynamic spectroscopy(NMR/LC-MS PDS), 591�593

mass spectral interpretation, 313,334

metabolite quantitation, 569�570oxidative stress, 664

Nucleic acids, 6Nucleophiles, 46, 49, 53, 58�59, 62,

240, 499, 655, 658Nucleophilic groups, 20�21, 29, 35Nucleotide(s)

chemistry, 4excision repair (NER), 653polymorphisms, 670

Nutrient metabolism, 526

Obesity, 88Octanediol, 652OC144�093, 113Odd-electron ions, 264Off-target toxicity, 231, 242�244Ogg1, 650Olanzapine (OLZ), 71, 116, 467�468,

470�471Olefins, 59Oligodeoxynucleotides (ODNs), 337Oligonucleotides, 4, 271Oltipraz, 106Omeprazole, 67�68, 85, 87�88, 98,

113, 311“One-molecule” concept, 9Optical imaging, bioluminescence and

fluorescence, 450Oral bioavailability screening,

392�394Orbitrap mass analyzer/spectrometer

biomarker identification, 692, 700characteristics of, 259, 278,285�286, 368�369

distribution studies, 456in trap, 259

760 INDEX

BINDEX 1 March 2011; 10:31:30

mass spectral interpretation, 328,339�341

metabolite identification, 292�293,301, 306, 313, 415�416,418�419, 438, 440�441

oxidative stress studies, 658Organic anion transporters (OATs)

characterized, 115�117in vivo-in vitro correlations, 129transgenic mice, 125urinary excretion, 218

Organic anion transportingpolypeptide (OATP), 164

Organic cation transporters (OCTs),115�116, 129, 218

Organic functional groups, metabolicactivation, see Functional groupactivation

bioactivation of drugs, 44�45detection of reactive metabolites,

45�46dosage considerations, 71�72reactive metabolite trapping and

covalent binding studies aspredictors of idiosyncratic drugtoxicity, 68�71

Organ perfusion model, ADMEstudies, 168�169

Organometallics, 258Ornidazole, 112Oseltamivir, 116, 125Osmolality, 696Ouabain, 117Oxalic acid, 62, 532�533Oxazepam, 243Oxazole, 433Oxazolidinedione, 61Oxidation

impact of, 79, 243, 265, 292,297, 302, 306, 333, 336, 344,410, 432, 435, 438,492, 581

thiols to disulfides, 56�57two-electron, 50, 52�54

Oxidative damage, 649

Oxidative metabolites, 487, 499Oxidative reactions

alcohol and aldehydedehydrogenases, 22�23

cytochrome P462, 15�20flavin monooxygenases (FMOs),

20�21metabolic identification, 292monoamine oxidases, 21�22molybdenum hydroxylases, 22peroxidases, 23�24

Oxidative stress, biomarkers ofaldehydes, 653�654background of, 64, 646�648base propenals, 653�654DNA adducts, lipid-

hydroperoxide-derived,651�653

formamidopyrimidines, 650�651genotoxins, lipid-hydroperoxide-

derived, 6518-oxo-dGuo, 648�650

Oxidoreductase, NADPH, 159Oximes, 18, 20, 422Oxirenes, 59�60, 2398-Oxo-7,8-dihydro-20-

deoxyguanosine (8-oxo-dGuo),646�650

Oxygenin biomarker identification, 706characterized, 259�260, 262�263in metabolite identification, 311,

326, 330, 433molecular, 58

Oxygenation, functional groupmetabolism, 59�60

Oxyphebutazne, 243Oxytocin, 10

Paclitaxel, 113Pantothenic acid, 714PAPS (30-phospho-adenosine-50-

phosphosulfate), 91Parabola spectrograph, 258Paracetamol, 88

INDEX 761

BINDEX 1 March 2011; 10:31:30

Parallel artificial membranepermeability assay (PAMPA),120�121, 167�168, 387,394�395, 398, 518

Parallel tube model, clearancerelationships, 202�204

Paraoxonase, 28Parenteral administration, 246Parkinson’s disease, 185Paroxetine, 48, 70, 106, 113Partitioning, 121Partitioning coefficient, 127PB-responsive elements (PBREMs),

91, 93Peak detection, in LC-MS,

705�706Peak filters based on the Orphan

Survival Strategy (P-BOSS)algorithm, 704

Peglyated proteins, 637�638Pelitrexol, 168Penciclovir, 22Penehyclidine, 310Penicillamine, 56�57Penicillin, 125Pentose, 598Peptidase, 211Peptides, see specific peptides

biomarker identification, 614�615,617, 619�620, 622�624,633�634, 638�639

biotransformation reactions, 27drug-drug interactions, 91functions of, 4, 258, 266,

270�272mass spectral interpretation,

324�325, 329in metabolite identification, 409oxidative stress and, 655�656,

658�660pharmacokinetic studies, 500transporters, 156�157, 209

Peptide transporter 1 (PEPT1),156�157, 209

PEPT1/SLC15A1, 209

PEPT2/SLC15A2, 209Per-Arnt-Sim (PAS) family, 92Permeability

artificial systems, 167�168drug disposition and, 152, 156, 167,183

drug-drug interaction studies, 107,118�120, 127, 129

early drug metabolism studies,394�395

in vitro studies, 208-limited clearance, 205�206in pharmacokinetics, 207

Permeation, 156Peroxidases, 23�24, 51, 53, 53, 337Peroxidation, 310, 646�647,

653�654, 661Peroxides, reduction of, 25Peroxisome proliferator activated

receptors (PPARs), 243Perphenazine, 425Pesticides, 124Pethidine, 203P-glycoprotein (P-gp)

absorption, 208�210drug discovery studies, 155drug-drug interactions, 111�114,118�119, 127

transporter models, 124�125,128�129, 167

transwell efflux assays, 123Phallodin, 125Pharmaceutical industry, safety

concerns, 43�44Pharmaceutical Research and

Manufacturers of America(PhRMA) guidance, 160, 166

Pharmacodynamics (PD)active metabolites, 244�246drug-drug interactions, 84�85influential factors, 129

Pharmacogenetics, 5Pharmacokinetic absorption-

distribution-metabolism-excretion (PK/ADME), 84�86

762 INDEX

BINDEX 1 March 2011; 10:31:30

Pharmacokinetic principles,predictions in drug discovery

absorption predictions, 206�211animal studies, 199development stage, 222distribution, 211�212drug-drug interactions, 218�220drug efficacy and concentration,

198�199exploratory stage, 220�222metabolism and excretion,

212�218physiological pharmacokinetics,

199�206Pharmacokinetic (PK)-

pharmacodynamic (PD),generally

drug discovery studies, 157relationships, 222

Pharmacokineticsactive metabolites, 244�246biomarker identification, 614clinical DDI predictions, 107in drug discovery and development,

484�485influential factors, 129in vivo, 215, 570mathematical models, 202�204metabolite profiling, 370oral bioavailability screening, 393physiological, see Physiological

pharmacokineticssample analysis, 514�515significance of, 5, 7, 9tissue imaging of drugs, 515�516tracing, 533

Pharmacokinetic (PK)-toxicokinetic(TK) studies, drug discovery,157

Pharmacology, off-target/on-target,237

Pharmacophores, 62, 183Phenacetin, 87, 95, 97, 203, 244Phencyclidine, 106Phenelzine, 106

Phenobarbital (PB), 87, 89, 92�93,95, 181, 573

Phenolic groups, 69, 325Phenols, 23, 47, 49�50, 90�91, 306,

312Phenotyping, 93�98Phenylalanine, 714Phenylisocyanate (PIC), 658�659Phenyl isothiocynate, 311Phenyl-piperidinol, 3062-Phenylpropenal, 61�62, 71Phenyls, 56Phenytoin, 87, 203Phosphates, 38, 124Phosphatidylcholine (PC), 121, 46630-Phosphoadenosine-50-

phosphosulfate (PAPS), 31, 163Phospholipids, 331, 515, 699Phosphonium, 312Phosphor imaging, 173Phosphorus, 20, 325�326, 330, 374,

706Phosphorylation, 93, 663Phosphoserine, 627Phthalazine, 56Physiochemistry, 14, 244, 545, 556Physiological pharmacokinetics

clearance, 199�202, 213�214distribution, volume of, 201�202intrinsic clearance and organ

clearance relationship, 202,204�205

model, significance of, 198permeability-limited clearance,

estimation of, 205�206schematic diagram of, 203

Phytoestrogens, 162Pilsicainide, 112�113Pimelic acid, 694Pindolol, 390Pioglitazone, 71�72Piperacillin, 124Piperazine rings, 52, 342Piperidines, 334Pitavastatin, 118

INDEX 763

BINDEX 1 March 2011; 10:31:30

pKa, 127, 266PK model, 184Plasma

adducts, 707AMS quantitations, 535, 546�550isotopic patterns, 706pharmacokinetics, 438protein binding, 211quantitative drug metabolism,

556�558samples, preparation of, 359�361,

696�697Plavix. See ClopidogrelPneumatic electrospray, 267Pneumatic spraying, 463Pneumotoxicants, 89Point-to-point plotting, LC-AMS,

537Poisson processes, 526, 550Polarity switching, 494, 502�504,

506, 508Polyatomic ion beams, 456Polyclonal antibodies, 634Polycyclic aromatic hydrocarbons

(PAHs), 56�57, 85, 87, 89�90,125

Polyenes, 325Polyethers, 325Polyethylene glycol (PEG), 515, 637Polymers, 271Polymorphisms, transporters, 128Polypharmacy, 84Polyphenolic acids, 581Polyunsaturated fatty acids (PUFAs),

659, 664Polyvinylidene fluoride (PVDF), 120Population kinetics, 172Porphyrins, 462Posacnazole, 112, 114Positive chemical ionization (PCI),

267�268Positron emission tomography (PET),

450Posttranslational modifications, 630,

637�638, 661

Potassium, 49, 323, 706Practolol, 55, 63�64Pravastatin, 98, 117�118Prazosin, 71�72Preacquisition optimization, 411Precipitation, in sample preparation,

355, 359. See also Proteinprecipitation (PPT)

Precursor ion-enhanced product ion(PI-EPI), 486, 499, 502�503, 505,510, 518

Precursor ion (PI) scanningmetabolite identification, 276,294�299, 304�305, 311, 313,429�430

pharmacokinetic studies, 490�491,494, 500, 502, 505�506, 508, 510,515

Predictive multiple reactionmonitoring (pMRM), 490,492�495, 506, 510, 518

Predictive multiple-reactionmonitoring-enhanced production (pMRM-EPI), 492, 494, 496,498�499, 502�503, 506�507,510�511, 515, 518

Prednisolone, 98, 113Prednisone, 113Pregnane X receptor (PXR), 87�93Primate studies, 157, 172�174,

185, 369, 371, 373, 628,634�635

Principal component analysis (PCA),688�688, 712�713

Probenecid, 115Probes

drug discovery and development,238�239

mass spectrometry, 268�269, 271nuclear magnetic resonance, 374

Procainamide, 55, 115�116Procarcinogens, 89�90Prodrugs

biotransformation reactions, 39distribution studes, 465�466

764 INDEX

BINDEX 1 March 2011; 10:31:30

mass spectral imaging (MSI),469�470

oxidative reactions, 22pharmacokinetics, 211

Product ion (PI)analysis, 303, 330, 334, 340�341,

344�345, 362filter (PIF), 439scan, 294�299, 304�305, 311, 313,

580spectra, 433�436

Profens, 366Profiling

in drug discovery and development,235�237

kinetic, 122metabolite, by LC-MS, 333�342

proFit, 537Pro-inflammatory cytokines, 169Proline, 619, 714Proline-rich tyrosine kinase inhibitors

(PYK), 54Promethazine, 343�345Propanolol, 88, 203, 390, 473�474,

515�516Propenals, 653Propionic acids, 66Prostaglandins, 23, 666�667Prostate-specific antigen (PSA), 620Protein(s)

binding, 152, 220, 233, 555bioanalysis, 624�625, 639-bound drugs, 213concentration measurement, 638covalent binding (PCB), 240�241degradation, 698drug-drug interaction studies, 91drugs, biotransformation of, 638homologs, 637�638-ligand interactions, 343mass spectrometric analysis,

270�272metabolism, 638metabolite identification, 409microsomal, 213�214

phosphatase (PP), 93precipitation, see Protein

precipitation (PPTprotein-protein interactions, 5quantitation, see Protein

quantitationreactive metabolites and, 45recombinant, 272, 626sequences, 4synthesis, 698therapeutic drugs, 631total and free concentration

measurement, 638Protein precipitation (PPT)

accelerated mass spectrometry,546

biomarker identification, 630, 694,696�697, 706

liquid chromatography massspectrometry bioanalysis,617�618

nanospray, 573in sample preparation, 355,

359�362, 409Protein quantitation

internal standard for, 625�628by LC-MS/MS, 616�619,

624�626, 629Proteomes, mammalian, 630Proteomics

analysis process, 633characterized, 655�656technologies, 73

Protonated ions, 263Protonation, 322Proton-pump inhibitors, 68Protoxicants, 90Pseudo-tandem mass spectrometry

(pseudo-MS/MS), 429Pseudogenes, 88�89p23, 92P2Y12

antagonists, 67receptors, 68

Pulmonary diseases, 654, 672

INDEX 765

BINDEX 1 March 2011; 10:31:30

Purification methods, 375, 631�633,668

Purines, 325Pyrazole, 88Pyridazine, 58Pyridines, 88, 421Pyrimidines, 312, 650�651, 653

Q Trap, 279Quadrupole FTICR analyzer, 415Quadrupole ion trap (QIT) mass

spectrometer, 276�278, 453�455Quadrupole-linear ion trap (QqLIT)

mass spectrometry, 294, 313, 455Quadrupole-linear ion trap (QTRAP)

mass spectrometrydrug interaction studies, in vitro,

512�514instrumentation, 488�490metabolic soft spot determination,

495�498metabolic stability analysis, 494�495methodologies, 486�488oxidative metabolite identification,

in vivo, 499quantification and screening of

drugs and small molecules,514�518

reactive metabolite identification,502, 505�508, 510

scan functions, 490�494, 519species comparison, in vitro, 498

Quadrupole mass, generallyanalyzer, 261filters, 293spectrometry, 617spectrometers, 259, 264

Quadrupole time-of-flight (QTOF),generally

“all-in-one” data analysis, 429mass analyzer, 282�283, 294, 313,

415�417, 432, 435mass spectral imaging, 467, 471mass spectrometry, 328, 337, 700spectrometers, 259

Quality control (QC), 515, 700Quantitative bioanalysis, 628Quantitative clinical metabolite

analyses, 555Quantitative MALDI-MS, 463�464Quantitative NMR spectroscopy, 10Quantitative profiles, 235Quantitative recovery analysis,

accelerated mass spectrometry,545�550

Quantitative structure-activityrelation (QSAR), 183

Quantitative whole-bodyautoradiography (QWBA), 155,171, 173

Quantum chemicals, 47Quenching, 660Quercetin, 114, 583�584, 588�589,

591�592, 598�601, 603�605, 607Quercimeritrin, 583, 585, 587, 591,

604Quetiapine, 63�64, 98, 435Quinidine, 89, 95, 98, 112�114Quinoids, 239Quinoline, 301Quinone(s)

bioactivation pathways, 49biotransformation reactions,23�24, 26

drug-drug interactions, 91formation, 47�48-imine formation, 50�54mass spectral interpretation, 336metabolic activation, 70metabolite identification, 421-methides, 47�50oxidoreductase, biotransformationreaction, 26

pharmacokinetics, 499reactive metabolites, 47�50reductive reactions, 26

Quinonemethides, 91

Rabbit studies, 182�183Radioactive tracing, 532�533

766 INDEX

BINDEX 1 March 2011; 10:31:30

Radioactivitydetection, 373�374metabolic activation and, 46measurement of, 534profiling, 373�375

Radio-flow detection (RFD), 373Radio-frequency (RF) potential, mass

spectrometry, 273�277,279�280, 415, 489

Radioisotopesaccelerator mass spectrometric

studies, 527, 553�554decay counting, 526�528, 540

Radiolabeling/radiolabeledcompounds

accelerator mass spectrometricanalysis, 555

characterized, generally, 8, 10drug discovery and development

process, 235, 238�239drug disposition, 172, 175drug-drug interactions, 91, 119,

123�124mass spectrometric studies, 360, 374metabolic activation, 46, 71metabolite identification, 310metabolite levels, estimation of,

568�569oxidative stress and, 655pharmacokinetics, 515

Radiometric detection, 569Raloxifene, 69�70, 106Raman spectroscopy, 690Ranaolazine, 113Ranitidine, 113, 116Ranolazine, 113RapidFires technology, 126Rat studies

AB-8�2 metabolite analysis inurine, 605�608

active metabolites, 245�246ADME experimental models, 163biliary excretion, 183Chinese herbal medicine, 581,

595�608

drugdiscovery process, 157, 172, 233functional group metabolism,

55�56hepatic metabolic clearance,

214�215mass spectral imaging, 467�468,

471, 473�474metabolic stability, 388, 390�391metabolite identification, 310metabolite profiling, 334metabonomics and, 706oxidative stress, 653, 660�661, 664parent constituents and metabolite

analysis in bile, 598�603plasma, 706�707preclinical ADME models, 171, 175quantitative extraction and

recovery, 547, 550reactive metabolites, 50, 62, 240Sprague-Dawley rats, 467, 471transporters, 122, 124

Rayleigh limit, 266Reabsorption, 217Reaction phenotyping

ADME studies, 174drug discovery and development

processes, 238�239drup disposition and, 162

Reactive metabolite screeningin vitro, 499�508in vivo, adduct analysis, 508�512

Reactive metabolitesAMS metabolic studies, 555formation of, 44screening, see Reactive metabolite

screeningstable isotope clusters, 310�311toxicology studies, 239�242

Reactive oxygen species (ROS),646�647, 649, 651, 660, 664

Recombinant CYPs (rCYPs), 94�95Recombinant human CYP isozymes

(rhCYP), 396Recombinant human growth

hormone (rhGH), 622

INDEX 767

BINDEX 1 March 2011; 10:31:30

Recombination reagents, 94�95Redox chemistry, 48Reduction strategies, 292, 302, 333,

581, 619. See also Reductivereactions

Reductive reactionsalcohol dehydrogenases, 26carbonyl reductases, 26cytochrome P462s, 24�26intestinal microflora, 27molybdenum-containing enzymes,

25quinone oxidoreductase, 26

Reflectron, mass analyzer, 281�282Regression analysis. See Statistical

analysisRegulatory concerns

dose size and, 8expectations and, 7

Relative activity factor (RAF), 161,219�221

Relative molecular mass, 260Remikiren, 261�263Remoxipride, 48Repaglinide, 84, 98, 117Research and development (R&D)

research, 366Resveratrol, 106Retinoid X receptors (RXRs), 92Reverse-phase chromatography,

698�699, 702�703Reverse-phase liquid chromatography

(RP-LC), 367, 375Reverse-phase liquid chromatography

mass spectrometry (RP-LC/MS),367

RH40, 113Rhapontigenin, 106Ribavirin, 310Ribonucleic acid (RNA), functions

of, 662. See also Messenger RNA(mRNA)

Rifampicin (RIF), 87�93, 125Rifampin, 111, 117Ring plus double bode equivalent,

711

Risperidine, 113Ritonavir, 97�98, 106, 112�113, 115,

496rK5 protein, 617, 630�631Robotic systems

metabolic stability assays, samplepreparation, 391�392

microsomal stability assays, 389in transporter assay analysis,126�127

Rocket propulsion, 264R15LO cells, 665Rokach nomenclature systems, 666Ropivacaine, 97�98Rosiglitazone, 71�72, 102Rosuvastatin, 111, 115, 117Rubidium chloride, 323Rutaecarpine, 106Rutin, 583�584, 587, 591, 598�599

S-adenosylmethionine (SAM), 35, 163Safety considerations, seeSafety testing

black-box warnings, 64significance of, 7

Safety profile, 244Safety testing, 237�238, 555,

567�568, 576St. John’s Wort extract, 114Salicylate, 124Salvia miltiorrhiza, 580Sample preparation strategies

for bioanalysis, 354�360in drug development, 637in vitro, 360for metabolite profiling, 360�361tissue, for MSI, 460�462

Samplesaccelerated mass spectrometry(AMS), 531�532, 547�549

biological, 516�517challenges for high-resolutionspectrometry, 408�409

metabonomics experiments,692�697

preparation of, see Samplepreparation strategies

768 INDEX

BINDEX 1 March 2011; 10:31:31

whole-body tissue sections,471�473, 516

Samplingdrug distribution studies, 460�462quality control issues, 515

Sandwich cultures, 124, 165�166Saquinavir, 59, 97�98, 106, 113SAS-Graph, 537Scaling factor, metabolic clearance,

214�216Scanning

constant neural loss (CNL),294�299, 303�306, 313

data-dependent product ion (MS2),304�305, 454, 488, 584, 599

full, 293�294, 301�305, 312, 368,389, 416, 418, 439, 485, 584, 646,658, 686, 691

full mass spectrometry, 291�294,301�305, 312, 368, 389

multiple ion monitoring (MIM),299�300, 304, 313, 490,493�494, 498

multiple-reaction monitoring(MRM), 298�300, 304, 313,485�486, 490�492, 498, 500,503�504, 507�509, 511�512,514�515, 517, 647, 700

multistage (MSn), 306�309, 329,418, 436, 453, 455�456, 465, 469,580, 582, 598�599, 605, 711

precursor ion (PI), 294�299,304�305, 311, 313, 580

SCH49661, 245Schiff base, 46, 66Schisandra chinensis, 114Sebacic acid, 714Secondary ion mass spectrometry

(SIMS) analysis, 258, 451�454,456�458, 460

Secondary metabolites, 244Secretases, 660Selected ion monitoring-electrospray

ionization mass spectrometry(SIM-EI-MS), 631

Selected reaction monitoring (SRM)

biomarker identification, 614, 619distribution studies, 454�455-electrospray ionization mass

spectrometry (SRM-EI-MS), 631instrumentation, 258, 271, 276, 280metabolite identification, 440

Selective seronin reuptake inhibitors(SSRIs), 48

Selectivity analysishigh-resolution mass spectrometry

(HRMS), 410�411, 414, 424liquid chromatography mass

spectrometry (LC-MS), 620mass spectrometric imaging (MSI),

454triple quadruple-linear ion trap

mass spectrometry (QqQ-LIT-MS), 490, 496, 498, 503,510�511

Selenium, oxidative reactions, 20Self-organizing maps, 713Semicarbazide, 46, 72Sensitivity analysis

accelerator mass spectrometry(AMS), 526�527, 544, 550, 555,558, 560

high-resolution mass spectrometry(HRMS), 414

liquid chromatography-massspectrometry (LC-MS), 620

mass spectrometric imaging (MSI),454

metabolite quantitation studies,8�10

nanospray mass spectrometry, 568triple quadrupole-linear ion trap

mass spectrometry (QqQ-LIT-MS), 489, 496, 498, 502�503,510�511

Sensitivity enhanced, proteinquantification

depletion of abundant proteins,633�636

via immunocapture/purification,631�633

Sequential analysis, 73

INDEX 769

BINDEX 1 March 2011; 10:31:31

Serine, 27, 698Sf9 insect cells, 123Signal(s), generally

extraction, 707grouping-related, 706intensity, 461, 700, 704transduction, 664

Signal-to-noise (S/N) ratio, 276,471, 700

Sildenafil, 98, 117Silicon, 326, 330Silver, 266Silybin, 106Silymarin, 114Simcyp software, 108SIM profiles, 236Simvastatin, 98, 106, 113,

117, 210Sinapinic acid (SA), 462�463Single ascending dose (SAD), 175Single nucleotide polymorphisms

(SNPs), 73, 92, 94Single quadrupole mass

spectrometers, 293Sinnapinic acid (SA), 271Sirolimus, 114Sitagliptin, 114, 129SLC family of transporters, 86, 218Small-molecule(s), generally

biomarkers, 715drugs, 615�616mass spectrometry, 614�615metabolites, 715quantification and screening of,

514�518S9 fraction, 162�163Sodium, 266, 323, 706Sodium dodecyl sulfate

polyacrylamide gelelectrophoresis (SDS-PAGE),634�635

Sodium taurocholate cotransportingpolypeptide (NTCP), 164

Soft-dependent method of classanalogy, 713

Soft ionization, 263Soft laser desorption (SLD),

259Soft spots, metabolic, 45, 235, 243,

486, 495�498, 567, 576Solid-phase extraction (SPE),

355�348, 359�362, 374, 409,559, 617�618, 630�631,694�698

Solubility, significance of, 107, 127,129, 156, 207, 244, 390, 549

Solvents, types ofhalogenated, 358�359organic, 361, 371, 390, 409, 463,545, 622�623, 625, 699

Somatropin, 620, 622, 624�626Sorbents, 356Sorivudine, 198Spatial resolution, 450, 457�460Special populations, AMS studies,

558Specificity analysis

accelerator mass spectrometry(AMS), 555

high-resolution mass spectrometry(HRMS), 410�411

mass spectral imaging (MSI),467�468, 470

Spectral acquisition rates, 415Splitters, liquid chromatography-

mass chromatography (LC-MS),363

Spray-droplet method, 463Stable isotope(s)

accelerator mass spectrometry(AMS) study, 527

biomarker identification, 626�627,631

cluster techniques, in metaboliteidentification, 309�311, 313

oxidative stress, 647, 649, 668,670�671

standards with capture byantipeptide antibodies(SISCAPA), 631�632

770 INDEX

BINDEX 1 March 2011; 10:31:31

Stand-alone linear ion trap, 278�279Standard-free metabolite estimation

current approaches for metabolitequantitation, 568�570, 575�576

future directions for, 575�577nanospray mass spectrometry,

570�575significance of, 567�568

Static SIMS, 456�457Statins, 66�67, 84, 89, 98, 106,

111�115, 117�118, 125, 210Statistical analysis

ADME experimental models, 183biomarker identification, 688, 703,

708, 712�713, 715least-square discriminant analysis,

713least-square regression, 183linear regression, 626multivariate statistical analysis,

706, 710, 713nonlinear regression, 104�105, 183Poisson statistics, 550regression analysis, 96, 104, 183regression coefficient (r2), 96,

626�627, 713standard deviation (SD), 534, 538,

553Staudinger ligation, 658Steady state, pharmacokinetic, 7, 10Step-by-step studies, drug discovery,

154�155Step-plot, LC-AMS, 536�537, 539,

547�548Stereoisomers, 366�367Steroids, 34, 90�91, 269, 331Stop-flow LC-RFD, 373Streptavidin, 657Structural elucidation, 291, 304�312,

343, 437, 495, 506Structural modifications, 663Structure-activity relationship (SAR),

118, 122, 129, 154, 242, 245, 436Structure-metabolism relationship,

236

Structure-toxicity relationships,63�64

Subcellular fractions, 162�164, 232,243

Substance P, 344Substrate-enzyme-inhibitor (SEI)

complex, 99Succinamide, 627Succinic acid, 694, 714Sulfamethoxazole, 55Sulfaphenazole, 95, 514Sulfates/sulfate groups, 38, 44, 295,

301, 423Sulfatin, 65, 296Sulfation reactions

alcohols, 32amines and amides, 33drug discovery and development

process, 244drug disposition, 163, 174drug-drug interactions, 86, 91hydroxyamides, 32�33hydroxylamines, 32�33metabolite identification, 292, 302overview of, 31�32

Sulfenic acids, 56, 58, 60Sulfhydryl groups, 662�663Sulfoglycolithocholic acid, 714Sulfonamides, 121Sulfonic acids, 422Sulfonyl groups, 91Sulfotransferases (SULTs), 31�32,

86, 91, 161�163, 234, 603Sulfoxides, 18, 20, 309Sulfur, 17�18, 20, 259�260,

262�263, 308, 326�327,329�330, 433, 706

Sumatriptan, 21Supercritical fluid chromatography

(SFC)-atmospheric pressure chemical

ionization-tandem massspectrometry (SFC-APCI-MS/MS), 390, 392

characterized, 367�368, 390

INDEX 771

BINDEX 1 March 2011; 10:31:31

Supercritical fluid chromatography(SFC) (continued )

tandem mass spectrometry (SFC-MS/MS), 368�369

Suprofen, 58, 106Surface area, 129Surface charge density, 266Surface-enhanced laser desorption/

ionization (SELDI),271�272

Surface tension, 266�267Systemic circulation, 206�207, 212Systems biology approach, 5�6

Tacrine, 87Tacrolimus, 98, 114, 168Tadalafil, 71�72, 106Tagging proteins, 656Talinolol, 112�114Tamarixetin, 583, 591, 603�604, 607Tamiflu. See OseltamivirTamoxifen, 106, 555Tandem mass spectrometry (MS/MS)

biomarker identification, 711distribution studies, 451, 454�455,

464, 469drug-drug interactions, 126herbal medicines, 580, 591instrumentation, 267, 275�276,

278�280, 282mass spectcral interpretation, 330,

337, 340, 343, 345metabolite identification, 292, 294,

297, 299�300, 304, 310, 415, 439techniques, generally, 368

Tapentadol, 116Taurine, 292, 296, 423, 558, 714Taurochenodeoxycholic acid, 714Taurocholate, 124�125Taurocholic acid, 714Tautomerism, 311Taxol, 88, 95, 97Taylor cone, 265Teniposide, 114Tenofovir, 113

Teratogenesis/teratogenicity, 44, 157Terbinafine, 61�62Terfenadine, 84�85, 198, 467Terpenoids, 325Tertiary amines, 46Testosterone, 95, 97, 5382,3,7,8-Tetrachlorodibenzo-p-dioxin

(TCDD), 85, 90, 93Thalidomide, 366Theophylline, 87Thermospray, 258Thiadiazabicyclo-ONE-GSH-adduct

(TOG), 663�664Thiazoles, 25, 58, 306, 308Thiazolidinedione, 61Thin-layer chromatography, 4Thioamides, 58Thiocarbonyl compounds,

biotransformation reactions, 31Thioesters, 501Thioethers, 20, 493, 500Thiol groups, 46Thiol methyltransferase (TMT), 35Thiols/thiol groups, 20, 31, 35�36,

46, 56�57, 422, 654, 656�657,663

Thiopental, 203Thiophenes, 58Thiopurine methyltransferase

(TPMT), 35�36Thiotepa, 106Thioureas, 58Threonine, 620, 698, 714Thyroids, 90Ticlopidine, 106Ticrynafen, 106Tienilc acid, 45, 58Time-delayed fragmentation (TDF),

490Time-dependent inhibition (TDI),

102�105, 160, 162, 165Time-of-flight (TOF) mass analyzers,

258, 261�262, 270, 278,280�282, 292�293, 411, 413,415, 452�453

772 INDEX

BINDEX 1 March 2011; 10:31:31

Time-of-flight mass spectrometry(TOF-MS), 279, 329, 337, 440,700, 711

Time-of-flight-secondary ion massspectrometry (TOF-SIMS), 454

Time-of-flight time-of-flight(TOF-TOF) mass analyzer,415, 453, 467

Tirilazad, 98, 310Tissue(s), generally

imaging techniques, 450�451necrosis, 44plasminogen activator (tPA), 634samples, see Tissue samples

Tissue samplesexcision of tissue, 460�461preparation of, 361sectioning and monitoring, 461transfer of, 461�462washing, 463

Tizanidine, 84Tolbutamide, 88, 203, 573Tolcapone, 50�51, 260, 428Tolmetin, 66Topotecan, 111, 115Total correlation spectroscopy

(TOCSY), 592Total ion chromatography (TIC),

431, 701Total ion current (TIC), 496�497,

504�505, 509Total radioactivity (TRA), 173Toxic effects, 14Toxicity

biotransformation reactions and,37, 39

dose-dependent, 45drug discovery phase, 246drug-drug interactions, 94, 107drug-induced (DIT),

240�242, 450idiosyncratic, 44, 240impact of, generally, 6, 8metabolic activation, 44�45,

55�56, 68�71

off-target, 244organ, 450pharmacokinetics, 222reactive metabolites, 47

Toxicokinetics (TK) studiescharacteristcs of, 484protein quantitation, 614sample analysis, 514�515

Toxicology assessment methodsdrug discovery research, 172drug disposition, 173off-target toxicities, metabolite

contribution to, 242�243reactive metabolite studies,

239�242validity and, 235

Toxicology potential, 239�243Toxicophores, 45, 66TPGS, 114Tracing/tracers, 553�554, 557Transcription, generally

factors, 181, 184, 654human CYPs, 92�93

Transcriptome technology, 73Transfected cell lines, 121�122Transfection, 214Transferase, 239Transferrin, 634Transflex efflux assays, 123Transgenic mice, pharmacokinetic

distribution of NCEs, 124�125Translation, 93Translycypromine, 95Transplantation, liver, 210Transport clearance, transcellular,

216Transporter(s)

ATP-dependent, 663drug discovery process, 234drug-drug interactions, 85, 110,

128�129hepatic, 109, 214impact of, generally, 5induction, 152inhibition, 152

INDEX 773

BINDEX 1 March 2011; 10:31:31

Transporter(s) (continued )in vitro-in vivo correlations, 109,

128�129key ADME transporters, 110�111,

115, 117�118major, 86P-gp potential, 118, 129sample analysis of, 125�127tools of, see Transporter tools

Transporter toolsabsorption, 118�119Caco-2 permeability, 119�120hepatocyte sandwich cultures, 124membrane vesicles, 123�124PAMPA, 120�121permeability, 118�120transfected cell lines, 121�122transgenic mice, 124�125transflex efflux assays, 123uptake assays, 122�123, 129

Trapping studiesaccelerator mass spectrometry

(AMS), 555drug toxicity, 68�71reactive metabolites, 46, 48, 53, 58,

62, 240Triacylglycerols, 331Triazolam, 89, 98, 106Triazolone, 340�342Tributyric acid, 551Tributyrin, 535Trichloroethanol (TCE), 359Trichloroethylene, 543Tricyclic antidepressants, 88Trifluoroacetic acid (TFA), 322, 462,

619Trimethoprim, 53Triple quadropole (QqQ), generally

-linear ion trap mass spectrometers(QqQ-LIT-MS), 259, 281, 292, 298

mass analyzer, 275�278, 280, 311,313, 453

mass spectrometers, 293, 299, 440,454

mass spectrometry, 392

-tandem mass spectrometer(MS/MS), 389

-time-of-flight (TOF) massanalyzer, 438

Triple-stage quadrupole (TSQ) massspectrometer, 646�647, 672

Troglitazone, 49, 60�61, 72Troleandomycin, 98, 106Tropylium ion, 331Trovafloxacin, 64�65Trypsin, 620, 624�625, 633, 656Tryptic peptides, 626, 628, 634, 658Tryptophan, 620, 714t test, 713Tumor necrosis factor-’, 93Tumors, 554Tumor tissue, mass spectrometric

imaging, 465�466Turanose, 571�572Turbulent flow chromatography

(TFC), 356�359Two-dimensional solid-phase

extraction (2D-SPE), 620, 631Tyrosine, 659�662, 714Tyrosine kinase inhibitors, 54

UDP-glucuronic acid (UDPGA), 232UDP-glucuronosyl transferases

(UGTs), 29, 44, 86, 90�91,161�162, 185, 603

Ultra-high-performance liquidchromatography (UHPLC)

biomarker identification, 691,699�700

metabolite identification, 293,304

-RAM (UHPLC-RAM), 541�542,544

Ultra-pressure liquidchromatography (UPLC)

-accelerated mass spectrometry(UPLC-AMS), 528, 536,540�544, 550, 552�553, 556,559�560

biomarker research, 672

774 INDEX

BINDEX 1 March 2011; 10:31:31

flow rates, 329, 364high-throughput assays, 397�398,

534instrumentation, 535quantitative extraction and

recovery, 546�549-RAM (UPLC-RAM), 543-tandem mass spectrometry

(UPLC-MS/MS), 398Ultraviolet (UV), generally

absorbance, 372�373, 550,556�557

protons, 269Unified atomic mass unit, 260U.S. Food and Drug Administration

(FDA)animal testing, 498DDI guidance, 160, 514Draft Guidance for Industry Drug

Interaction Studies, 110draft transporter guidance

document, 127Guidance for Industry (Safety

Testing of Drug Metabolites),7�8, 10

Guidance for Industry-Bioanalytical MethodValidation, 617

Guidance on BioanalyticalAnalysis, 534

Guidance on BioanalyticalGuidance, 550

Guidance on Metabolite Safety inToxicology (MIST), 526, 528,545, 555�556

permeation studyrecommendations, 208

onP-gp inhibitionpotential, 118, 120proteins and peptides for clinical

use, 615Safety Testing of Drug Metabolites

Guidance, 237, 292, 567�568, 576on uptake transporters, 123waivers for DDI studies, 158White Paper, 222

Unit mass resolution, 260, 262Universal detector response, 569Up-regulation, 663, 670Uptake transporters, 123, 185Ureas, 422Uric acid, 714Uridine diphosphoglucuronic acid

(UDPGA), 29, 163Urine

AMS metabolite studies, 554excretion, 217�218quantitative extraction and

recovery, 549rat, 605�608sample preparation methods,

360�361, 694�696Ursodeoxycholic acid, 117, 714Ursodiol, 558�559U/V ratio, 275

Vacuum chemical ionization, 264Valacyclovir, 116, 156Valence rules, 711Valine, 698, 714Valproic acid, 90Valspodar, 113�114Vaporization problem, 266, 322Varenicline, 129Verapamil, 98, 106, 112�114, 324,

328�329, 430�431Vesnarinone, 54Victim drugs, 84, 98, 101, 107, 117Vinblastine, 472Vincristine, 125Vinorelbine, 114Vinyl fluoride, 652Vitalea spectrometer, 528Vitamins

accelerator mass spectrometricstudies, 526

B12, 258C synthesis, 168

Volatile toxins, 543Voriconazole, 97Vortexing, 546

INDEX 775

BINDEX 1 March 2011; 10:31:31

Warfarin, 88, 124, 512�514Wastewater, pharmaceuticals in,

517�518Water-soluble compounds, 244Well-stirred model, clearance

relationships, 202�204Whole-body autoradiography (WBA)

applications, 450compared with mass spectral

imaging, 473�474quantitative (QWBA), 155, 171,

173Whole-body dosimetry

measurements, 558Whole-body tissue sections, 471�473,

516Whole-cell systems, 164�167Wrong way round, in electrospray

process, 266

Xanthin oxidase (XO), 22, 86, 162XAP2, 92Xenobiotics

biomarker identification, 686, 715drug disposition, 181drug-drug interactions, 90, 111, 124

historical perspective, 4�5mass spectral interpretation, 336metabolite identification, 310metabolic activation, 45, 47oxidative stress, 646, 654, 659response elements (XREs), 90�91

Xenon, 456Ximelagatran, 114X-ray, generally

computed tomography, 450crystallographic studies, 182�183

Yatein, 106YM796, 214�215

Zafirlukast, 53, 106Zalcitabine, 116Zidovudine (AZT), 91, 116Zileuton, 105�106Ziprasidone, 311�312Zolpidem, 68�69, 98Zomepirac, 66, 116, 336Zosuquidar, 113�114Zwitterionicity, 156Zyprexa. See OlanzapineZyrtec. See Cetirizine

776 INDEX

BINDEX 1 March 2011; 10:31:31

BINDEX 1 March 2011; 10:31:31

BINDEX 1 March 2011; 10:31:31