INDEX

abacavir (ABC), 340, 561, 564abbreviated new drug application (ANDA), 9absence of reference standard, 452–8absolute carryover (AC), 268absorption, 6–7, 45, 85, 166, 194, 327–8accelerated solvent extraction (ASE), 301accelerator mass spectrometry (AMS), 7acceptability of batch run, 111acceptance criteria, 8, 11, 23, 26, 44, 48–51, 67, 80, 85, 106, 219,

222, 288–9, 303–4, 361–2, 531accumulation, 5, 7, 59, 135, 327, 329, 423acetaminophen, 265, 381, 587acetazolamide, 134acetylcholine (Ach), 436, 441acetylcholinesterase, 436acid-catalyzed methanolysis, 472acidification, 441, 508, 512–3acoustic disruption, 300active metabolite, 5, 77, 307, 337, 509acylglucuronide, 52, 53, 154, 447–8adaptive focused acoustics (AFA), 300additive, 144, 396adduct, 239, 346, 398, 400, 481–4, 567, 570, 629adefovir, 561adenine, 560ADME, 4, 6–7, 16, 45, 71–2, 74, 77–8, 141, 194, 327, 329, 426adsorbent, 580adsorption, 140, 145–6, 151–2, 259, 262–6, 282, 307–15, 365adverse trend(s) and event investigation, 111aerosol, 79, 156–7, 264, 278, 300agitation, 153, 277, 300aglycone, 42, 447–58albutenol, 371–2aldehyde, 5, 240–2, 448, 462, 479, 483

aldosterone, 576alkylation, 479, 481, 604alkyl silica analytical column, 563amdoxovir, 564amide, 153, 479, 482aminophenzone, 134amprenavir (APV), 340–1analogue, 509, 562, 578, 657analysis of variance, 405–6analytical procedure (AP), 113, 362, 651analytical run, 32–4, 106, 194, 230, 236, 362analyzer, 205–13androgen, 398, 477, 574–5, 587–8androstenedione, 575androsterone, 241, 473, 573, 579animal care and use protocol (ACUP), 640animal facility, 129, 143, 148antiadsorption agents, 311–2antibiotics, 9, 166, 345, 462antibodies, 11, 176–7, 535–6, 539, 601antibody-drug conjugate (ADC), 11anticoagulant, 41, 44, 66, 118, 142–6antigen, 176–7, 539, 603antioxidant, 145, 270, 462–3, 484, 495, 498–9, 513antisense, 614, 619, 623ANVISA, 30, 40–3, 83–6, 110, 219, 231, 370, 375–6, 471, 491apricitabine, 561archival facilities, 19, 24archive, 18–20, 24, 34, 104–5area under the curve (AUC), 75–7, 80, 83, 83, 110, 134, 249, 481Arrhenius equation, 44arylesterase, 155, 431, 435arylsulfatase, 472ascorbic acid (vitamin C), 495, 499

Handbook of LC-MS Bioanalysis: Best Practices, Experimental Protocols, and Regulations, First Edition. Edited by Wenkui Li, Jie Zhang, and Francis L.S. Tse.C© 2013 John Wiley & Sons, Inc. Published 2013 by John Wiley & Sons, Inc.

673

674 INDEX

asenapine, 371–3aspartic and glutamic acid, 481aspiration, 135, 277–8, 330aspirin, 154assay batch, 11, 218, 220assay development, 26assay selectivity, 11, 42, 68, 185, 201, 649–50assay sensitivity, 11, 384assay specificity, 8, 118, 363, 583–4assay validation, 5, 8, 11, 26, 309, 360–6, 384, 437Association of Southeast Asian Nations (ASEAN), 30asymmetry, 233atazanavir (ATZ), 340–2, 346atmospheric contamination, 264atmospheric pressure chemical ionization (APCI), 53, 192, 211–3atmospheric pressure ionization (API), 213, 346atmospheric pressure photoionization (APPI), 211, 213, 396atomic absorption spectroscopy (AAS), 629atorvastatin, 370–1, 506–7authentic analyte, 355authentic matrix, 355automation, 156, 168–71, 275–89auxiliary gas, 6433-azido-3-deoxythymidine (AZT), 345

backflush, 594–8, 635BA organization chart, 20barbiturates, 134barcode, 157, 277, 279, 289baseline, 186, 214, 288, 392, 524, 526, 528, 530basic statistics, 403, 405BBR3464, 630bead-beating, 300bendroflumethiazide, 492benzene, 243, 310, 483benzoxadiazole, 242, 244, 485betamethasone acetate, 440betamethasone phosphate, 440bile, 327–32bile sample collection, 329–30bile sample preparation, 331binding affinity, 135, 310, 322, 608–9bioanalysis process map, 17bioanalysis-related statistics, 403–14bioanalytical data flow, 97–100bioanalytical guidance, 29, 30, 109bioanalytical laboratory, 15–27, 89, 91, 97–107, 109–24bioanalytical method transfer, 65, 66bioanalytical method validation, 40, 67, 91, 109bioanalytical workflow, 98bioavailability (BA), 4–5, 16, 29–30, 83, 89bioequivalence (BE), 4, 16, 29–30, 83, 91biofluid, 5, 250, 327, 331, 649–51, 653–4, 655–7biohazardous, 19, 312biological matrix, 145, 356, 360biological specimen, 165biomarker, 4–5, 8, 193, 353–66, 535, 551, 604, 607, 649–57biomolecule, 191, 200, 214, 239, 608, 623

biopharmaceuticals, 10, 151, 165–6, 601bioresearch monitoring (BIMO), 113, 116, 261biosensor, 318, 494biosynthesis, 243, 355, 362, 365, 506, 621biotransformation (BT), 58, 78, 193, 329, 420–2, 426, 479bis(4-nitrophenyl)-phosphate (BNPP), 436Bland–Altman plot, 50blank matrix, 11, 251–2, 301, 577blank sample, 234, 260–61, 263, 269, 315, 387blood-brain barrier (BBB), 8blood collection, 140–6, 433–4, 443, 498, 640blood/plasma distribution, 129–36blood stability, 11, 129–37, 153–6, 387, 433–9BMS-068645, 439BMS-068645-acid, 439bovine serum albumin (BSA), 151, 152, 310, 312, 314–5, 356,

526, 528, 544, 651bradykinin B1 receptor antagonist peptide, 539–40butylatedhydroxyanisole (BHA), 499butylatedhydroxytoluene (BHT), 499butylcarboxylesterase, 436butyldimethylamine (BDMA), 618butyldimethylammonium bicarbonate, 618BW284c51, 435–6

caffeic acid phenethyl ester, 440caffeine, 194, 233, 465calcium, 142–4, 355, 432, 508calibration curve, 43–4, 85, 122, 406calibration range, 43, 85, 259calibration standard (Cs), 32, 43, 301, 380camptothecin drug, 509candidate selection, 5capillary electrophoresis (CE), 348, 521, 551, 607capillary LC, 199, 211, 604, 611capillary zone electrophoresis (CZE), 520captive spray ionization (CSI), 80carboplatin, 629–35carboxylesterase, 155, 431, 435–6carboxylic acid, 56, 68, 130, 174, 282, 356, 398, 447–8, 450, 452,

497carcinogenicity, 6carryover, 11, 45, 194–5, 259–71catechins, 495catecholamine, 355, 495, 498cationic lipid, 592, 595–9cell counting, 338cell lysis, 337–40, 342, 344, 346, 348cell separation, 338cellulose, 57, 320, 438, 527, 643, 645Centers for Disease Control and Prevention (CDC), 577Central Drugs Standard Control Organization (CDSCO), India, 30,

43, 46central nervous system (CNS), 193, 199, 495centrifugation, 148cerebrospinal fluid (CSF), 8, 141, 168–9, 441certificate of analysis (CoA), 22–3, 41, 106, 232, 244, 304, 506Cetero case, 113

INDEX 675

21 CFR part 11, 101–3charcoal, 8, 356, 577, 585, 587charged aerosol detection (CAD), 79chelating, 142, 144, 436, 508, 631chelator, 195, 498chemical analogue, 221, 578chemical reactivity, 447–9chenodeoxycholic acid, 244, 327, 576chiral column, 186, 521, 523, 526, 528–30chiral compound, 520, 522chiral derivatization, 520–3, 529, 531chiral drugs, 232chiral interconversion, 156chiral separation, 199, 201, 513, 519–32chiral stationary phase, 521, 523–4, 526–30chiral supercritical fluid chromatography, 529chirobiotic stationary phase, 524–6chlordiazepoxide, 134ρ-chloromercuribenzoate, 436chlorpromazine, 134, 156, 461–3chlorthalidone, 134, 5123-([3-cholamidopropyl]dimethylammonio)-2-hydroxy-1-

propanesulfonate (CHAPSO), 152, 3123-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate

(CHAPS), 152, 312cholane, 573, 576cholestane, 573, 576cholesterol, 240, 253, 327cholesterol esters, 254cholic acid, 327, 576choline, 253, 255, 441cholinesterase, 144, 155, 431, 436, 441chromatographic data systems, 18cisplatin, 629–31, 634citrate, 144clearance (CL), 249cleavage, 142, 208clinical laboratory, 10, 264, 353, 582, 584clinical protocol, 149–50clinical trial, 16, 89, 91, 281, 361clot formation, 145clozapine, 461, 466–7clozapine-N-oxide, 467–8Cmax, 9, 49, 55co-administration, 194coagulation, 142–4, 524codeine, 134Code of Federal Regulations (CFR), 16, 21, 29, 90, 101, 109, 111coefficient of variation (CV), 42, 50, 67, 86, 253, 408co-elution, 59, 220, 250, 253, 255, 332, 570, 612co-extraction, 250, 254collision cell, 263, 393, 395, 419–21, 537, 643collision energy (CE), 194, 393, 423, 451, 477, 594, 597, 599, 618,

633, 636, 643collision exit potential (CXP), 620collision-induced dissociation (CID), 207, 240, 253, 398, 579,

613, 617column dead volume, 200

column efficiency, 186–91, 199, 521, 523, 538column heater, 18column lifetime, 194, 196, 198column switching, 331, 528column volume, 199, 271co-medication, 42, 223, 250compensation voltage (COV), 391–2compliance check list, 160compliance program guidance manual (CPGM), 109, 116, 124composite sampling, 639–40computer system validation (CSV), 101–3concentration ratio (CR), 133, 167, 262–3conductivity, 135, 265, 396–7, 618cone, 212, 263, 282, 452, 455–6, 524, 621confidence interval, 133, 410–2configuration, 102, 176, 252, 277, 511, 519consistency in data reporting, 122contamination, 17–8, 57–8, 112, 116, 194, 235, 259–71contract research organization (CRO), 16, 25, 65, 370control matrix, 357, 361, 498cordycepin, 553corona discharge, 212–3, 239, 251, 396, 583corrective and preventive action (CAPA), 111, 121, 269corticosteroid, 320, 322, 330, 640corticosterone, 575cortisol, 282, 322, 576–7, 584cortisone, 584cotinine, 464–6cotinine-N-oxide, 464–6counter-ion, 174, 567, 570, 616, 618covalent binding, 153, 193CRO site audits, 25cross validation, 40–1, 49–50, 66–7, 123Crystal City Bioanalytical Workshops, 29cultured cells, 344–5, 348curtain gas, 212, 477, 594–5, 599, 620, 633–4, 636cyclodextrin, 153, 200, 310, 312, 524cyclodextrin stationary phase, 524cyclohexane, 271, 396, 450cyclophosphamide, 484cyclosporine A, 10, 134, 338–9cysteine, 155, 481, 483–5, 495, 499, 604cytarabine, 551, 553–5, 559cytidine, 155, 568cytochrome P450, 9, 474cytosine, 553, 560, 568–9, 608

dansyl chloride (Dns-Cl), 344, 578–9, 585–6dansyl hydrazine (Dns-Hz), 241data archival system, 18data backup, 98, 102, 104data integrity, 8, 20, 22, 26, 84, 97, 104, 110, 113–5, 329data processing, 10, 98, 103, 197, 573data quality, 230data review, 26data transfer, 26data warehouse system, 105daughter ion, 393, 570, 585

676 INDEX

daunorubicin, 492dead volume, 191, 196, 198, 200dealkylation, 461–2, 492deaminase, 155, 553declustering potential (DP), 332, 451–2, 620, 633, 636, 643decomposition, 68, 154, 260, 432, 564deconjugation, 4722,2-defluorodeoxycytidine (gemcitabine, dFdC), 5652,2-defluorodeoxyuridine (dFdU), 565degradation, 154–6, 384, 432–3, 435, 438–42, 448–50, 472,

491–501, 505dehydroepiandrosterone (DHEA), 575dehydroepiandrosterone sulfate, 575deionization, 265delavidine, 339demethylation, 80, 420, 422, 525denature, 155–6, 169, 604, 621deoxyadenosine, 552, 559–60deoxycorticosterone (DOC), 573, 575, 58411-deoxycortisol, 576, 587deoxycytidine, 552, 559, 570deoxyguanosine, 551–2, 570deoxyribonucleic acid (DNA), 551, 608deoxyribonucleoside, 566deoxyribose, 551, 559–60derivatization, 239–45, 484–6, 521, 578–9derivatization reagents for amines, 245derivatization reagents for carboxylic acids, 243derivatization reagents for ketones and aldehydes, 241derivatization reagents for phenols and alcohols, 242design qualification (DQ), 288desolvation, 212, 251, 610, 618, 621deterioration, 165, 525determination of metabolites, 45deuterium, 130, 217, 221, 255, 357, 466, 523, 578, 585, 602,

653dextromethorphan, 194, 381, 474–7dextrorphan, 286, 474–7dextrose, 118, 144dialysate, 10diastereomer, 506, 511, 519–22diatomaceous, 285, 313, 463, 5802,2-dichlorovinyl dimethyl phosphate (dichlorvos, DDVP), 145,

155, 432, 436, 442diclofenac, 154, 447, 449didanosine, 340, 342–3, 345, 551, 561, 564didanosine triphosphate, 344diethylamine, 525, 566diethyldithiocarbamate (DDTC), 631, 636diethylenetriaminepentaacetic acid (DTPA), 499differential mobility spectrometry (DMS), 391digoxin, 134dihydrotestosterone (DHT), 574, 579, 587diisopropylamine, 617diisopropylethylamine, 243, 617diisopropyl fluorophosphate (DIFP/DFP), 155, 435–6, 443dilution integrity, 11, 67, 379, 386, 466dimethylbutylamine, 617dimethyl sulfoxide (DMSO), 151, 280, 310, 443, 456–7, 643

dipropylamine, 617disaster recovery plan, 104, 158dispersion, 174, 302, 392displacement, 134, 136, 276–81, 286–7, 289, 318disposable pipette extraction (DPX), 176disposal of samples, 23disposition, 7, 121, 327, 329, 477disulfide bond, 384, 484–5, 5402,5-ditert-butyl-hydroquinone (DTBHQ), 4995,5-dithiobis-(2-nitrobenzoic acid) (DTNB), 436dithiothreitol (DTT), 604divert valve, 196documentation, 16dopamine, 495dorzolamide, 134dosage, 4–5, 73, 75dose range-finding (DRF), 6dosing vehicle, 49, 131, 249, 252doxorubicin, 492, 592draflazine, 134dried blood spot (DBS), 10, 57–8, 156, 178, 198, 379–87, 438,

639–45dried matrix spot (DMS), 379dried plasma spot (DPS), 639droplet, 212–3, 239, 251, 616, 640drug binding sites, 134drug-drug interaction (DDI), 4, 7, 9, 16, 49–50, 329, 551, 564, 583drug metabolism (DM), 7, 71, 77, 417–26drug safety assessment, 5drug substance, 3, 266, 484drying time, 156, 380, 382, 385, 387, 438

eddy diffusion, 187edge effect, 321efavirenz (EFV), 340, 339, 341, 343electronic audit trails, 22electronic data, 22electronic data management system (EDMS), 101electronic laboratory notebook (ELN), 18, 34, 98, 100–1, 104–6electronic records, 110electrophiles, 479–80electrospray ionization (ESI), 80, 212, 613elimination, 6–7, 249–56eluate, 136, 212–3emtricitrabine, 561, 564enantiomer, 200–1, 511–3, 519–31endogenous baseline (EB), 653endogenous compound, 331, 361, 585endogenous deoxyribonucleoside triphosphate, 566endogenous hepcidin peptides, 540–2endogenous ribonucleoside triphophate, 566enrichment of antibody drug, 603entecavir, 551, 561enterohepatic circulation, 327–8, 330entrance potential (EP), 620, 643Environmental Protection Agency (EPA), USA, 89enzymatic instability, 154enzyme, 155, 360, 431, 438, 601enzyme activity assay, 360

INDEX 677

enzyme digestion, 610, 621enzyme inhibitor, 144, 437enzyme-linked immunosorbent assay (ELISA), 8, 40, 276, 364,

366, 536, 539epimer, 511epimerization, 511epirubicin, 492epoxidation, 471equilibration, 114equilibrium dialysis, 136, 318–22erythrocyte, 133–5, 144, 152, 317, 435, 481, 485, 561erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA), 553eserine (physostigmine, erserine), 436esterase, 431esterase inhibitor, 130, 145, 384, 432, 434, 436, 438, 441, 443esterase labile compound, 432estimated carryover influence (ECI), 262estradiol (E2), 243, 322, 329, 573–4, 580, 585–6estriol (E3), 574, 585estrogen, 574estrone, 328–9, 574–5, 585ethinylestradiol (EE), 242–3ethopropazine, 436ethylenediaminetetraacetic acid (EDTA), 143, 432, 499European Bioanalysis Forum (EBF), 49–51, 57–8, 129, 143, 379,

383–7European Federation of Pharmaceutical Industries Association

(EFPIA), 260European Medicines Agency (EMA), 11, 21, 24, 29, 84evaporative light scattering detection (ELSD), 337expression of nucleotide concentrations, 563extraction efficiency, 49, 173, 364, 382–3, 472, 500, 577, 650extraction procedure, 42, 166, 177, 185, 249, 297, 562, 630extraction recovery, 171, 221, 285, 313–5, 356, 379, 381–4

failure investigations, 22fast atom bombardment (FAB), 211, 419fatty acid, 240, 244–5, 270, 318, 357, 359, 362, 365FDA letter, 112FDA mock inspection, 123FDA 483 observations, 114FDA untitled letter, 114fecal collection, 147feces, 141, 147–8, 159, 327–8, 422, 462fibrin, 142–4, 375fibrinogen, 140, 142–4, 146, 278, 283filtrate, 320, 463filtration, 7, 255, 344, 463, 465firmware, 18, 103, 289first-in-human (FIH), 6, 49, 73, 146, 259, 437, 479fit-for-purpose, 4, 8, 67, 75, 302–4, 353, 360flow diversion, 594–7, 599, 632–3, 635–6fluorescence, 186, 214, 245, 337, 364, 484fluoride, 1444-fluorobenzyl chloride, 486fluorouracil, 551, 559fluoxetine, 285, 525–6fluvastatin, 506fluxoamine, 371

F4-neuroprostanes, 495focusing potential (FP), 620Food and Drug Administration (FDA), USA, 11, 30, 48, 83, 260fourier transform ion cyclotron resonance (FTICR), 206, 210–1freedom of information act (FOIA), 114free reactive compound, 483free testosterone (FT), 322freezer temperature logs, 23full width at half maximum (FWHM), 419fused-core particle, 200

gas chromatography-mass spectrometry (GC-MS), 40, 205, 246,276, 483

generic drug, 4, 9, 86, 113, 122genotoxic compound, 481genotoxicity, 260, 479, 485Global Bioanalytical Consortium (GBC), 31, 35, 370glucuronidation, 193, 422, 447, 477, 520glucuronosyltransferase, 471glutamine, 655–6glutathione, 209, 420, 471, 479, 499glycerophosphatidylcholines, 254glycerophosphocholines, 254glycerophosphoethanolamines, 254glycerophosphoserines, 254glycine, 327, 580glycoprotein, 136, 201, 343β-glucuronidase, 472–3, 475good automated manufacturing practice (GAMP), 101–3good clinical practice (GCP), 16, 65, 84, 89, 91, 101, 103, 109–10,

150good laboratory practice (GLP), 5, 11, 89, 109–10good manufacturing practice (GMP), 84, 110gradient elution, 188–91grinding, 300guanine, 560guard column, 192, 196, 528, 566, 632

halo, 643halogen, 218, 255, 512Hamilton pooling, 76Hamilton Star, 157, 278, 580health authority, 11, 42, 66, 348, 437Health Canada, 40, 45, 47–8, 86Health Products and Food Branch (HPFB), Canada, 30, 110height equivalent of a theoretical plate (HETP), 199, 201hematocrit (HCT), 57, 130, 135, 379–85, 641hemoglobin, 130, 134–5, 327, 369, 371, 374–5, 480–5, 499hemolysis, 57–8, 115, 135, 140–1, 144, 146, 148, 369–76, 380,

449heparin, 142–4, 432, 499, 508hepatic impairment study, 7hepatocytes, 72, 327, 329, 477hexafluoroisopropanol (HFIP), 616, 619–20, 622hexylamine, 564, 566, 617hexylammonium acetate (HAA), 611high field-asymmetric waveform ion mobility spectrometry

(FAIMS), 391–2, 394high performance liquid chromatography (HPLC), 40, 68, 185

678 INDEX

high-resolution mass spectrometry (HRMS), 73, 77–9, 191,210

high resolution MSn, 206high-throughput screening, 4high-turbulence liquid chromatography (HTLC), 574, 579,

581–2histidine, 481homogenate, 197, 283, 301, 538, 568homogeneity, 32–3, 57, 111, 198, 303, 379, 381, 385–6homogenization, 6, 147–8, 297–303homogenizer, 18, 299–300, 302hormone, 573, 577, 584–5, 587, 602human ADME study, 7human blood, 155, 434–5, 441–3, 468, 484, 512, 583human serum albumin (HSA), 153, 317, 448, 483hybrid ion-trap (IT)-FTICR, 211hydrazide, 240, 5782-hydrazino-1-methyl-pyridine (HMP), 2412-hydrazinopyridine (HP), 241hydrochloric acid (HCl), 499hydrocortisone, 322, 576, 580hydrogen peroxide, 301, 552, 566hydrolysis, 471–4, 582hydrophilic interaction liquid chromatography (HILIC), 188, 190,

201, 506, 582hydrophobicity, 242, 396, 538, 609, 616hydroxycinnamates, 49516α-hydroxyestrone (16α-OHE1), 585hydroxylamine, 241, 484, 578–9, 587–8hydroxylation, 80, 327, 47117α-hydroxyprogesterone (17OHP), 587hydroxytoluene, 145, 495, 499

ibuprofen, 154, 513ice bath, 330, 345, 375, 514, 553, 631imatinib, 344imidazole, 242–3, 617imipramine, 134, 424, 426, 461–2immunoaffinity (IA) extraction, 538–9immunoassay, 10–1, 276, 481, 577, 601, 607immunoprecipitation, 603impurity, 130, 265, 479, 611–2inactivation, 156, 381, 432inadequate investigation, 112inadequate method validation, 117incubation, 360, 582incurred sample accuracy (ISA), 47, 60–1incurred sample reanalysis/reproducibility (ISR), 45, 47–51, 84,

110, 412, 464incurred sample stability (ISS), 47, 58–9, 437Indian Department of Health, 85indinavir (IDV), 340, 341induction, 5, 9, 16, 481, 519inductively coupled plasma mass spectrometry (ICP-MS), 612,

629, 630industry regulations, 20infrastructure, 16inhibition, 9, 16, 144–5, 329, 360, 498, 509, 519, 641

injection valve, 165, 195, 263injection volume, 189, 194, 198–9injector, 195, 200, 234–5, 259, 265–6, 271, 566inner diameter (ID), 198in-source fragmentation, 53, 68, 392, 451–3, 455, 537inspection, 94, 109–23inspector, 20, 91, 261installation qualification (IQ), 18–9, 24, 101–4, 229, 263, 288–9Institutional Animal Care and Use Committee (IACUC), 640instrument qualification, 18, 21, 84, 229–31, 269, 288intellectual property, 7, 25, 101interconversion, 55, 68, 139, 154, 156, 472, 506–14, 529interconvertible compound, 505–15interference, 7, 52, 122, 260, 393, 601internal standard (IS or ISTD), 11, 122, 165, 217–24, 261, 356, 382International Conference on Harmonization (ICH), 20, 30, 45,

71–2, 80, 147, 193, 260, 479interrupted run, 122intestine, 143, 298, 327, 462intravenous (IV), 192, 249, 255, 314investigational new drug (IND), 6, 45, 72, 80, 89, 198in vivo sample collection, 141ion abundance, 10, 213, 620ion exchange chromatography (IEC), 188, 191, 347, 608ion mobility spectrometry (IMS), 391ion pairing (IP), 397, 450, 560, 609, 622ion source, 208, 210–3, 392, 396, 419–20, 423ion suppression, 219–21, 224, 249–53, 255, 372–3ion trap (IT), 205–6, 208, 210–1ionization efficiency, 240, 396–7, 618ion-pairing buffer, 611, 618ion-pairing chromatography, 347, 564–5, 610ion-pairing reagent, 250, 564ion-trap-Tof (IT-Tof), 206, 210–1irinotecan, 510isobaric compound, 363–4, 392isocratic elution, 188–9, 456isomer, 193, 198, 448, 512, 525isomerization, 154, 196, 492, 512–3isopropanol, 174, 271, 310, 397, 465, 529, 596, 598isothiocyanate, 245, 482, 522–3isotope dilution, 217, 322, 649–51isotope dilution mass spectrometry (IDMS), 217isotope labeled peptide, 539ISR failure investigations, 51, 58

juvenile blood, 380

ketoconazole, 173α-ketoisocaproic acid (KIC), 651ketoprofen, 447, 529Korea Food and Drug Administration (KFDA), S. Korea, 30KR-62980, 441

laboratory information management system (LIMS), 17–8, 22–4,98, 100–6, 151, 644, 657

lactone, 130, 154, 193, 355–6, 384, 431, 441, 506–11, 514lactonization, 506–8, 514

INDEX 679

lamivudine, 340, 561, 564large unilamellar vesicle (LUV), 591LC-radioactivity detection (RAD), 73LC-UV assay, 10, 80, 187, 608Leap Technologies, 265, 643levonorgestrel (LN), 685licorice, 205–7limit of detection (LOD), 348linearity, 11, 85, 220, 303, 384, 531linear regression, 51, 133, 219, 362, 403–7, 410, 655–7lipemia, 369, 375–6lipemic plasma, 6, 376lipids, 591lipids associated with matrix effect, 254lipophilicity, 134, 167–8, 172–3lipoprotein, 136, 317, 320, 356, 375liposomal drug, 591–2liposome, 220, 591–2, 599, 610liquid handler, 18, 175, 279–83, 285, 313liquid-liquid extraction (LLE), 170–2liquiritigenin, 207–9lithium, 143–4, 149lobaplatin, 630log D, 167–8log P, 167–8longitudinal diffusion, 187–8, 191lopinavir (LPV), 340–1, 343lovastatin, 506–9lower limit of quantification (LLOQ), 5, 67, 194, 259–61, 269,

308, 408, 653low resolution MSn, 206lumen, 327lysine, 481lysophosphatidylcholine, 253–5

macromolecule, 3, 50–1, 169, 175, 200, 329, 447–8, 479–81, 485,519, 630

macrophage, 214, 564manifest, 134, 260, 474manifold, 57, 212, 277, 279, 281, 285, 581manipulation, 78, 112–3, 114–5, 156, 276, 277–9, 283, 286, 289mass-balance, 6, 7mass defect filter (MDF), 45, 75, 420, 423–4Mathieu equations, 209matrix effect (ME), 42, 73, 117, 192, 221, 249–55, 356, 361, 364,

384, 650–1matrix factor (MF), 42–3, 234, 252matrix requirement, 41maximum concentration difference (MCD), 268MDS case, 112Medicines and Healthcare Products Regulatory Agency (MHRA),

UK, 89mefloquine, 134membrane, 136, 147, 317–21, 329–30, 591membrane-based protein precipitation (PPT) filter plate, 170mercaptoethanol (2-ME), 499mesalamine, 371metabolic pathway, 447, 559

metabolism-mediated toxicity, 5metabolism of N-oxide, 462metabolite profiling, 71–2, 74–80, 147, 170, 477metabolites, 193metabolites in safety testing (MIST), 4, 16, 71–6, 78, 80, 212, 447metaphosphoric acid (MPA), 499methadone, 526methazolamine, 134methionine, 481method development (MD), 7, 11, 15, 41–2, 52, 58, 91method modification, 66–7, 223, 371method transfer, 49, 65–8, 172, 230method validation (MV), 30, 39, 40, 61, 66, 81, 84–6, 89, 109methylation, 51, 53, 4772-methyl-cytidine-triphosphate (2’-Me-Cy-TP), 568mevalonic acid (MVA), 651, 657microbore, 191, 196, 199, 384, 639–45microextraction, 166, 176, 302, 320microextraction by packed sorbent (MEPS), 176microflow, 384, 639–40, 642, 644microfluidic flow control (MFC), 641microsampling, 57, 145, 178–9, 198, 639–44microseparations, 198microsome, 72, 417, 420–4, 454, 461, 477, 528midazolam, 194, 423–5Millipore, 322, 604Ministry of Health and Family Welfare (MHFW), India, 30Ministry of Health and Labor Welfare (MHLW), Japan, 30missing peak, 122MIST decision tree, 72mixed-mode anion-exchange (MAX), 539mixed-mode cation-exchange (MCX), 174, 331, 468, 525mobile phase velocity, 187–8molecularly imprinted polymer-solid phase extraction (MIP-SPE),

177molecular weight cutoff (MWCO) membrane, 136monitored air displacement (MAD), 278monoclonal antibody, 51, 544, 601monolithic column, 200, 575morphine, 332, 371, 471MSn, 210–1MS signal enhancement, 396multichannel verification system (MVS), 280multicharge, 241multilamellar vesicle (MLV), 591multiple ascending dose (MAD), 4, 6–7, 16, 73, 75–6, 78multiple reaction monitoring cubed (MS3), 391, 393, 395multiple reaction monitoring (MRM), 75, 193, 220, 332multiplexing, 185, 189, 192, 200multiplier, 419Multiprobe, 281, 283, 286–7, 313, 315, 468, 580multisite study, 21, 92

nedaplatin, 630nafamostat, 441nanospray ionization (NSI), 79–80naphthalene, 396, 578–9naphthylisothiocyanate, 245

680 INDEX

National Committee for Clinical Laboratory Standards (NCCLS),265

National Health Service (NHS), 141, 147National Health Surveillance Agency (ANVISA), Brazil, 85, 375,

471National Institutes of Health (NIH), 353nebulization, 212–13nebulizer, 213, 477, 583, 594, 597, 599, 633–4, 636nelfinavir (NFV), 340, 341neutralization, 562neutral loss (NL), 209–10, 242–4, 253–4, 332, 417nevirapine (NVP), 340newborn, 244new chemical entity (NCE), 479new drug application (NDA), 8–9, 16, 112, 122new molecular entity (NME), 71–6, 78–80nicotine, 464–6nicotine-N-oxide, 464–6nifedipine, 492–4nitrobenzoic acid, 155, 435–6nitrofurantoin, 134ρ-nitrophenyl acetate (PNPA), 436nonlinear calibration curve, 151nonspecific binding (NSB), 136, 146, 151–2, 307–10, 622nonvolatile acid, 165norclozapine, 460–67norethindrone (NE), 586normal phase liquid chromatography (NPLC), 191nornicotine, 464–6N-oxide, 68, 129, 156, 461–5N-terminal valine, 481nuclear magnetic resonance (NMR), 4, 75, 78–9nucleoside reverse transcriptase inhibitors (NRTIs), 559, 561nucleosides, 551–4, 559–71, 621nucleotides, 559–70, 610, 612

octapeptide, 2503’-O-demethyletoposide, 495OECD principles of GLP monographs, 92Office of Regulatory Affairs (ORA), 90Office of Scientific Investigations (OSI), 109–13olanzapine, 371, 375, 495, 500oligonucleotide, 10, 607–20, 622–3omeprazole, 59, 384on-card stabilization, 384operational qualification (OQ), 288–9opioid peptide, 441oral contraceptive (OC), 583Orbitrap, 206, 210–1, 419–21Organization for Economic Cooperation and Development

(OECD), 11, 20, 40, 89–94, 101, 103, 231orifice, 391–3original equipment manufacturer (OEM), 279oseltamivir, 145, 156, 438, 442outlier, 44, 61, 115–6, 120–1, 123outline, 20–1, 146, 233, 261, 298out-of-specification (OOS), 112, 121outsource process, 25

overestimation, 140, 364, 393, 431, 447, 452, 523, 531, 584–5oxalate, 144–5oxaliplatin, 629–35oxazepam, 513oxidation, 68, 130, 145, 154–5oxyphenbutazone, 134

packed cell volume (PCV), 380palladium acetate, 631paperless bioanalytical laboratory, 106paperless processes, 97paraoxon, 155, 436, 441, 443paraoxonase, 431, 508partial validation, 40–1, 66–7, 116–7, 123particle size, 190, 198–9, 332, 468, 564, 566, 568, 621peak area, 132, 187, 262, 267–8, 364peak capacity, 186, 188, 538peak height, 187peak integration, 34, 197, 392, 643peak tailing, 122, 195–6, 241, 564peak width, 205peek tubing, 263, 266pegylated lipid, 591–2pegylated peptide, 10pellet, 136, 179, 283, 341, 346, 562–3penicillin G, 345peptide, 8, 10–1, 131, 151–3, 199, 535–44, 601–4perchloric acid (PA), 499perforated dried blood spot, 385performance maintenance (PM), 19, 123, 634performance qualification (PQ), 288–9peripheral blood mononuclear cells (PBMCs), 8–9, 199, 338–48,

560–2, 565, 568pH adjustment, 174, 313, 331, 365, 505, 507, 513pharmacodynamics (PD), 5, 31, 85, 133, 178, 297, 360, 519–20,

591, 607pharmacokinetics (PK), 3, 5, 8, 71, 83, 297phase II conjugate, 68, 392, 471–2, 474, 476, 522, 582phase II study, 8pH control, 434phenothiazines, 134phenylbutazone, 134phenylmethylsulfonyl fluoride (PMSF), 152–3, 155, 435–6, 441,

443phenytoin, 134pH instability, 154pH modifier, 383, 434, 437, 439phosphatase, 9, 144, 339phosphate buffered saline (PBS), 177, 281, 321, 338, 356, 510phosphatidylcholine, 192, 253, 255phosphodiester, 559, 613, 618phosphodiesterase, 436, 468phospholipid, 192–3, 234, 253–5phosphorothioate, 608–14, 618–9phosphorylation, 8, 559–60photochemical reaction, 492–3photodiode array (PDA), 462photoionization, 211, 337, 391, 396, 583

INDEX 681

photosensitive compound, 492–4photosensitivity, 154phototoxicity, 6piperidine, 244, 461, 617, 623pipette, 21, 157, 168, 264, 269, 276, 278, 280, 365, 653pivotal study, 260pKa, 167–8placebo, 75–6, 78–9, 259, 264, 267–9, 365plasma preparation, 145plasma protein binding, 16, 136platinum drug, 629–30, 632, 634, 636polarity, 210, 239, 255, 307polycarbonate, 152, 157, 320polyether ether ketone (PEEK), 623polyethylene, 157–8, 310–1, 320polyethylene glycol (PEG), 250, 536, 591polymer, 175, 177, 201, 265, 312, 320, 523, 536, 565polymerization, 177, 592polymorphism, 529polypeptide, 535–47polypropylene, 157–8, 312polysaccharide stationary phase, 527–8polystyrene, 157–8, 308, 310, 312poor chromatography, 122porous graphitic carbon (PGC), 347, 551–2, 565–6portal, 98, 100, 106, 327–8post-approval study, 9post-column infusion, 191, 221, 223, 234, 251–2post-translational modifications (PTMs), 11, 601potassium fluoride (KF), 436, 440potassium oxalate, 144–5, 508pravastatin, 506prazosin, 436precision and accuracy, 11, 61, 67, 280, 362preclinical ADME, 6preclinical study, 185, 437pre-column, 520–2precursor ion, 53, 207–10prednisolone, 322, 577, 584predose, 120, 122, 146, 150, 223–4, 259, 267–9pregnane derivative, 587pregnenolone (Preg), 587–8pressure cycling technology (PCT), 299, 301pressure monitoring pipetting (PMP), 278pre-study validation, 48, 115, 119, 408pretreatment, 169, 329, 346pre-validation consideration, 361preventive maintenance (PM), 19, 280primates, 5, 156, 159principal investigator (PI), 20, 22–3, 25, 91–2, 141pro-drug, 431–43progesterone (P), 241, 575, 587proof of concept (PoC), 7–8, 12, 611propiverine, 467–8propiverine-N-oxide, 467–8propofol, 133proprietary, 9, 83, 105, 152, 280–1, 452, 519, 543propyl gallate (PG), 499

proquazone, 134prostaglandin, 214–5prostanoids, 345protease, 365, 436, 601protein binding (PB), 136, 317protein digest, 602protein precipitation (PPT), 3, 9, 53, 132, 166, 169, 283–4protein stationary phase, 526–7proteomics, 188, 193, 199, 201, 211, 536, 538, 615protocol, 26, 48, 69protocol amendment, 26, 69protonation, 452, 567, 569–70pseudouridine, 551, 615, 623punch size, 381, 384purification, 18, 177–9, 214, 317, 603, 611purine, 462, 559, 614pyridine, 241, 243–4, 461, 486, 579pyrimethamine, 134

QTof, 206Qtrap, 392, 394–5, 466, 643quadrupole, 206quadrupole linear ion trap (QqQLIT), 418–21quadrupole mass spectrometer, 205–11, 418quadrupole Tof hybrid MS (Qq-Tof-MS), 210–1, 421–3qualified assays, 80qualitative assessment, 32quality assurance (QA), 22quality assurance statement (QAS), 23quality checks, 33quality control (QC), 23, 31, 301, 432, 514quality indicators, 122

racemate, 519, 522–3, 525–6, 529–31racemization, 511–2, 521–3, 526, 531radioactivity (RA), 7, 19, 73–5, 79, 195, 303radiofrequency identifier (RFID), 279radioimmunoassay (RIA), 276, 337randomization, 26, 149–51rapamycin, 10, 193rapid equilibrium dialysis (RED), 319reaction yield, 483, 579, 582reactive compound, 479–87real-time reverse transcriptase polymerase chain reaction

(RT-qPCR), 607rearrangement, 193, 450–2, 454, 456–7reconciliation, 149reconstitution, 169–71, 282recovery (RE), 42, 302, 356, 364, 383red blood cell (RBC), 133, 135, 369reference standard, 23, 32, 42, 73, 132, 218, 304, 650–1regimen, 268, 301, 643, 645regression, 403–7regulated bioanalysis, 39, 97, 230, 371regulatory agency, 9, 20, 26, 30, 44, 61, 86, 89, 104, 109–11, 121,

471regulatory authority, 40–4, 48, 94, 97, 116, 132, 160, 303, 379regulatory citations, 109, 114, 116, 118

682 INDEX

regulatory inspection, 109regulatory requirement, 21, 25, 66, 89, 102, 149, 193, 201, 230,

318, 519reinjection, 236relative carryover (RC), 262–3remediation, 93, 112–3, 278renal impairment studies, 7reproducibility, 47–8reproductive toxicology, 6residue, 90, 120, 170resolution, 450–1, 525resolving power, 210response correction factor, 80response factor (RF), 32, 74, 79, 195, 651–2restricted access material (RAM), 175retention factor, 189reversed-phase liquid chromatography (RPLC), 190–1ribonucleases, 608ribonucleic acid (RNA), 156, 551, 559–60, 608–15, 620–3ribonucleoside, 560, 566ribose, 560riboside, 243ribosomal RNA, 615, 621rifampin, 155, 495, 499risk assessment, 77, 93, 102–3, 114, 481ritonavir (RTV), 340, 341, 343robotic liquid handler, 169, 175, 279–87, 434robustness, 41–2rodent, 5, 7, 72, 155, 264, 369, 417, 432roflumilast, 468rosuvastatin, 506rotation, 148, 287, 511, 519, 530ruggedness, 11, 40, 118, 171, 179, 223, 282, 357, 523, 530run acceptability, 122run size, 45

safety, 4, 12, 18, 45, 71–8salicylic acid and congener, 134salting-out assisted liquid-liquid extraction (SALLE), 172sample collection, 139–40sample dilution, 386sample extraction, 3, 18, 33, 57, 78, 122, 156, 165–80sample identification, 55, 149–50, 160, 438, 634, 656sample management, 16, 20, 23–4, 98–100, 279sample preparation, 165–72, 254, 264, 275, 299, 331, 337, 450saquinavir (SQV), 340, 341, 343satraplatin, 630scientific data management system (SDMS), 98, 101scintillation, 7, 5775-S-cysteinyldopa, 492secondary interaction, 188selected ion monitoring (SIM), 179, 205–8, 241, 611, 647selected reaction monitoring (SRM), 3, 68, 75, 205–214separation voltage (SV), 391serial dilution, 380, 437, 542, 653–4serial sampling, 198, 639–41serine and threonine, 481, 601serine esterases, 155

serine protease, 436serotonin, 654serum preparation, 146sex steroid binding globulin (SSBG), 322sieve effect, 321signal enhancement, 222–3, 391, 396–7signal intensity, 205, 240, 251–2, 384, 396, 464, 584signal peptides, 601signal suppression, 251, 433, 554signal-to-noise (S/N) ratio, 42, 194, 214, 220, 586, 641silanol, 188–90, 195–6simultaneous quantitation and metabolite identification, 417simvastatin, 506–8single ascending dose (SAD), 4, 6–7, 16, 73, 75–6, 365small interfering RNA (siRNA), 614–5small unilamellar vesicle (SUV), 591SN-38, 510sodium arsenate, 436sodium dodecyl benzene sulfonate (SDBS), 152, 310, 312sodium fluoride (NaF), 144–5, 155, 436–7, 508sodium heparin, 371, 588software validation, 18, 103–4, 231solid phase extraction (SPE), 166, 173solid phase microextraction (SPME), 176solubility, 44, 310, 318, 356sonication, 285, 287, 300, 463, 562, 645sonicator, 342, 344–6sparse sampling, 268, 639SPE cartridge, 173, 176, 276, 450, 463, 467, 486, 563, 580, 592,

609–10SPE enrichment of protein, 603sphingosine and sphingosine 1-phosphate, 344spot homogeneity, 381spot size, 385spotting technique, 381spotting volume, 381sputum, 141, 357stability assessment, 58, 130–2, 145, 361–2, 387, 405, 432–4, 436stability of metabolite, 132stabilization, 143–5, 355–6, 437–8stabilizer, 136, 141, 440, 443, 462stable isotope labeled internal standard (SIL-IS), 165, 171, 179,

463, 474, 578stable isotope labeled peptide, 602stable isotope labeled protein, 602standard deviation (SD), 60, 467standard free quantification, 73–5, 79–81standard operating procedure (SOP), 21, 49State Food and Drug Administration (SFDA), China, 30, 86, 94,

110, 491statin drugs, 506–9statistics, 51, 133, 403–6, 408, 410, 412stavudine (d4T), 339, 340, 561, 564steady-state exposures, 6stereoisomer, 42, 511, 513–4, 519stereoisomeric interconversion, 511–4stereoselectivity, 519, 525–6steroids, 322, 327, 472, 375, 477, 573–84, 576–88, 657

INDEX 683

stir-bar sorptive extraction (SBSE), 176strong anion ion exchange (SAX), 604strong cation ion exchange (SCX), 538, 543, 546, 604structure-activity relationships, 4study design, 365study monitor, 26submission, 6, 8, 11, 16, 24, 65, 85, 94, 101, 106, 109, 158, 201,

471substitution, 255, 447, 608, 611substrate, 10, 194, 330, 360, 380, 382–3, 417, 421, 423, 431, 473,

524, 609sulfate, 472–3, 582sulfhydryl containing compounds, 484sulfinpyrazone, 134sulfonamides, 134sulfoxide, 280, 310, 456sulphate, 53, 169sunitinib, 492supercritical fluid chromatography (SFC), 524, 529superoxide, 495, 499supported liquid extraction (SLE), 173, 271, 280, 313, 315, 463,

477surrogate analyte, 8, 357–9, 361–2, 366, 650–3, 655–7surrogate matrix, 8, 147, 301, 303, 356–7, 361–4, 366, 433, 577switching valve, 200–1, 331, 475–6, 554, 631–2system suitability, 229–36

tacrolimus, 134tamoxifen, 468tandem Tof (Tof-Tof), 210–1Tee, 251–2, 642tenofovir, 561, 564terbutaline, 396, 525terminology, 39–40tertiary butylhydroquinone (TBHQ), 499test facility, 24, 92–4, 149testosterone (T), 4, 240–1, 243, 317, 322, 392–3, 574–5, 582,

587test specimen accountability, 114, 120tetrahydrofuran (THF), 243, 525, 565–6tetrahydrouridine (THU), 155, 553thalidomide, 156, 512–3thenoyltrifluoroacetone (TTFA), 155, 436, 440therapeutic drug monitoring (TDM), 3–4, 6, 8–10, 213, 275–6,

466Therapeutic Goods Administration (TGA), Australia, 30Therapeutic Products Directorate (TPD), Canada, 30thermal stability, 154thiol, 68, 154–5, 240, 431, 484–5, 513, 522thymidine triphosphate, 341thymine, 560tiered method, 304time-of-flight (Tof), 80, 205–6, 208, 210–1, 346, 419–20, 423–6,

619time-proportional pooling, 76tipranavir (TPV), 340tissue collection, 147tissue digestion, 300–1

tissue distribution, 6tissue samples, 147, 297–304Tmax, 49, 59, 110α-tocotrienols (α-T), 499tolerability, 73, 629tolerance interval, 408–9, 412–3toluenesulfonate, 240, 578Tomtec, 281–3topotecan, 510total aspirate and dispense monitoring (TADM), 278total ion chromatogram (TIC), 205, 207–8, 276, 509, 539–40,

612total parent drugs, 471–7toxicity, 5, 45, 447toxicokinetics (TK), 3–6, 260toxic substance control act (TSCA), 90TP300, 441traceability, 102–3, 265, 362transferase, 471, 474transfer RNA, 614–5trans-3-hydroxycotinine, 464–6transportation, 66, 140, 157–60, 369, 379, 382transporter, 7, 159, 329, 365, 519tributylamine (TBA), 344, 617triethylamine (TEA), 195, 243, 255, 398, 484, 524, 611, 617,

619–21triethylammonium acetate (TEAA), 610, 663triethylammonium bicarbonate (TEAB), 609, 620trifluoroacetic acid (TFA), 190, 241–2, 340, 396–7, 536, 542, 554,

588trimethylammonium (TMA), 240, 253–4triple quadrupole mass spectrometer, 205–15tripropylamine, 617troubleshooting, 266, 314, 553trypsin, 536, 539, 542, 544, 546, 601, 604turboionspray, 586turbovap, 315, 476, 597, 599, 636turbulent flow, 141, 157, 166, 195Tween-20/80, 152, 312two-dimensional chromatography, 188, 528types of mass spectrometers, 206

ultracentrifugation, 136, 320–1ultrafiltrate, 10, 136, 319–22, 630, 633–4, 636ultrafiltration, 136, 317–22ultrahigh pressure liquid chromatography (UPLC), 191, 196,

199–201ultraviolet (UV), 79, 186, 213, 335, 346, 484, 492unbound drug, 136, 318unbound fraction, 133, 136, 317–23unit resolution, 417–8upper limit of quantification (ULOQ), 195, 261, 433uracil arabinofuranoside, 553–5, 560urea, 146, 241, 245, 307, 375, 604uric acid, 344uridine, 447, 471, 474–5, 551–2, 555urinary, 307, 467, 477, 573, 579, 582urine bioanalysis, 307–15

684 INDEX

urine collection, 76, 146, 308–9, 311, 314, 477urine samples, 146user requirements specification (URS), 102

vacutainer, 150, 365, 443, 485validation, 19, 23–6, 39–45, 97, 102–4, 119, 123, 158, 332, 348,

370Van Deemter equation, 187velocity, 148, 187–8, 198–9, 211, 360verapamil, 422–3, 642vicriviroc, 73virus, 156, 551, 559viscosity, 196, 199, 251, 264, 278–85, 312, 320, 396vitamin, 154–5, 244, 304, 356–7, 492, 499, 524

warfarin, 186, 524–5, 528–9Watson, 17, 21, 24, 98, 100, 104, 106, 613, 644, 657weak anion exchange (WAX), 174, 201, 560white blood cell (WBC), 148, 338, 360, 380whole blood stability, 129workflow, 17–8, 73, 76–7, 98–101, 157, 279, 298, 421–3workstation, 100, 115, 169, 276, 284, 468, 475, 554World Health Organization (WHO), 141

zalcitabine, 561, 564ZD0473, 630zidovudine (AZT), 340, 561zidovudine triphosphate, 339zopiclone, 468