Identification and quantification of drugs, metabolites and metabolizing enzymes by LC-MS:
Gespeichert in:
| Format: | Buch |
|---|---|
| Sprache: | English |
| Veröffentlicht: |
Amsterdam [u.a.]
Elsevier
2005
|
| Ausgabe: | 1. ed. |
| Schriftenreihe: | Progress in pharmaceutical and biomedical analysis
6 |
| Schlagworte: | |
| Online-Zugang: | Inhaltsverzeichnis |
| Beschreibung: | XVI, 338 S. Ill., graph. Darst. |
| ISBN: | 0444517103 |
Internformat
MARC
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| 084 | |a CHE 230f |2 stub | ||
| 084 | |a CHE 254f |2 stub | ||
| 245 | 1 | 0 | |a Identification and quantification of drugs, metabolites and metabolizing enzymes by LC-MS |c ed. by Swapan K. Chowdhury |
| 250 | |a 1. ed. | ||
| 264 | 1 | |a Amsterdam [u.a.] |b Elsevier |c 2005 | |
| 300 | |a XVI, 338 S. |b Ill., graph. Darst. | ||
| 336 | |b txt |2 rdacontent | ||
| 337 | |b n |2 rdamedia | ||
| 338 | |b nc |2 rdacarrier | ||
| 490 | 1 | |a Progress in pharmaceutical and biomedical analysis |v 6 | |
| 650 | 4 | |a Chromatography, Liquid |x methods | |
| 650 | 4 | |a Drug Design | |
| 650 | 4 | |a Drugs |x Metabolism | |
| 650 | 4 | |a Enzymes |x Physiology | |
| 650 | 4 | |a Pharmaceutical Preparations |x analysis | |
| 650 | 4 | |a Pharmaceutical Preparations |x metabolism | |
| 650 | 4 | |a Spectrum Analysis, Mass |x methods | |
| 650 | 0 | 7 | |a Enzym |0 (DE-588)4014988-2 |2 gnd |9 rswk-swf |
| 650 | 0 | 7 | |a Arzneimittel |0 (DE-588)4003115-9 |2 gnd |9 rswk-swf |
| 650 | 0 | 7 | |a LC-MS |0 (DE-588)4539813-6 |2 gnd |9 rswk-swf |
| 650 | 0 | 7 | |a Metabolit |0 (DE-588)4138579-2 |2 gnd |9 rswk-swf |
| 689 | 0 | 0 | |a LC-MS |0 (DE-588)4539813-6 |D s |
| 689 | 0 | 1 | |a Arzneimittel |0 (DE-588)4003115-9 |D s |
| 689 | 0 | |5 DE-604 | |
| 689 | 1 | 0 | |a LC-MS |0 (DE-588)4539813-6 |D s |
| 689 | 1 | 1 | |a Metabolit |0 (DE-588)4138579-2 |D s |
| 689 | 1 | |5 DE-604 | |
| 689 | 2 | 0 | |a LC-MS |0 (DE-588)4539813-6 |D s |
| 689 | 2 | 1 | |a Enzym |0 (DE-588)4014988-2 |D s |
| 689 | 2 | |5 DE-604 | |
| 700 | 1 | |a Chowdhury, Swapan K. |e Sonstige |0 (DE-588)185070825 |4 oth | |
| 830 | 0 | |a Progress in pharmaceutical and biomedical analysis |v 6 |w (DE-604)BV010273310 |9 6 | |
| 856 | 4 | 2 | |m HBZ Datenaustausch |q application/pdf |u http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=014770463&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |3 Inhaltsverzeichnis |
| 999 | |a oai:aleph.bib-bvb.de:BVB01-014770463 | ||
Datensatz im Suchindex
| _version_ | 1804135312252731392 |
|---|---|
| adam_text | Contents
Preface v
List of contributors xv
1. LC—MS and drug metabolism: a journey back in time, present trends
and future directions
K.B. Alton
1.1. Introduction 1
References 5
2. Strategies for increasing throughput for PK samples in a drug discovery
environment
W.A. Korfmacher
2.1. Introduction 7
2.2. Strategies for early PK assays 9
2.2.1. Enhanced mass resolution a new analytical tool for
PK assays 18
2.2.2. CARRS an example of an integrated PK assay
strategy 22
2.3. Conclusions 29
References 30
3. Commonly encountered analytical problems and their solutions in liquid
chromatography/tandem mass spectrometry (LC/MS/MS) methods used in
drug development
T.K. Majumdar
3.1. Introduction 35
3.2. Commonly encountered analytical problems and solutions 36
3.2.1. Problems with sample collection and analyte stability 36
3.2.2. Problem with positive controls 37
3.2.3. Carryover problem 38
3.2.4. Problem with retention time shift in HPLC 41
3.2.5. Problems related to the mobile phase composition and
ionization of analytes 43
3.2.6. Problems with ion suppression and matrix effect in the API
interface 43
3.2.7. Problems with stable isotope labeled IS 47
3.2.8. Problem of matrix interference due to the presence of
metabolites or other endogenous compounds 49
viii
3.2.9. The use of gas phase cluster ions for method sensitivity
problem 54
3.2.10. Problem with post column ion source induced changes of
pro drugs and metabolites 56
3.2.11. Problems with both mass spectrometric and chromatographic
resolutions in accurate quantification of parent compound
and metabolites 57
3.2.12. Problem with quantifying an unstable and light sensitive j
compound at ultra trace level concentrations 58
3.3. Conclusions 61
Acknowledgments 61
References 61
4. Pitfalls in quantitative LC MS/MS: metabolite contribution to measured
drug concentration
M. Jemal
4.1. Introduction 65
4.2. Analytical pitfalls due to metabolite in source conversion 65
4.3. Analytical pitfalls due to the simultaneous formation of
[M+H]+ and [M+NHJ+ ions from a drug as well as its
metabolite 74
4.4. Analytical pitfalls due to conversion of metabolite to the
parent drug during sample collection, handling, extraction,
and analysis 81
4.5. Bioanalytical method design for drug quantification in the presence
of a metabolite that may degrade to generate the drug 82
4.6. Strategy of using post dose samples to establish validity of
bioanalytical LC MS/MS methods 91
4.7. Summary and conclusions 99
References 100
5. In vitro DMPK screening in drug discovery, role of LC MS/MS
I. Chu and A.A. Nomeir
5.1. Introduction 105
5.2. CYP inhibition screening 105
5.2.1. Background 105
5.2.2. Types of inhibition 106
5.2.3. Experimental procedure 107
5.2.4. Sample plate set up 108
5.2.5. Quantification with LC MS/MS 109
5.2.6. IC50 determination 109
5.2.7. Throughput HO
5.3. Caco 2 permeability HI
5.3.1. Background HI
5.3.2. Mechanisms of absorption 112
ix
5.3.3. Caco 2 screening assay 112
5.3.4. Efflux evaluation 113
5.3.5. LC MS or LC MS/MS? 113
; 5.3.6. Multiplexed ion source (MUX®) 114
¦ 5.3.7. Determination of apparent permeability 115
; 5.3.8. Assay precision 116
5.3.9. Throughput 116
5.4. Blood Brain barrier 116
5.4.1. Background 116
5.4.2. Cell culture 117
5.4.3. Transport studies 117
5.4.4. Assay precision 118
5.4.5. In vivo in vitro correlation 118
5.5. Conclusion 120
Acknowledgment 120
References 120
6. Metabolite identification by LC MS: applications in drug discovery
and development
C.E.C.A. Hop and C. Prakash
6.1. Introduction 123
6.2. Metabolite identification 125
6.3. Mass spectrometers for metabolite identification 126
6.3.1. Single and triple quadrupole mass spectrometer 127
6.3.2. 3 Dimensional ion trap mass spectrometer 127
6.3.3. Q TOF mass spectrometer: 128
6.3.4. Common biotransformations 129
6.4. Additional tools for metabolite identification 130
6.4.1. Chemical derivatization 130
6.4.2. Radiolabeled compounds 131
6.4.3. Isotope patterns 131
6.4.4. LC NMR MS 132
6.4.5. H/D exchange 132
6.5. Applications 133
6.5.1. Metabolism of a potent neurokinin 1 receptor antagonist 133
6.5.2. Metabolism of a potent PPARy agonist 139
6.5.3. Metabolism of an antipsychotic drag ziprasidone 142
6.5.3.1. Use of two different radiolabels 143
6.5.3.2. Precursor ion spectrum 145
6.5.3.3. Differentiation of isobaric metabolites 145
6.5.4. Biotransformation of an anxiolytic drag candidate,
CP 93,393 146
6.6. Future trends 153
Acknowledgments 154
References 154
!
X !
7. The utility of in vitro screening for the assessment of electrophilic
metabolite formation early in drug discovery using HPLC MS/MS
D.E. Grotz, N.A. Clarke, and K.A. Cox
7.1. Introduction 159
7.1.1. Metabolite characterization 160
7.1.2. In vitro metabolic screening methodology 161
7.1.3. The significance of electrophilic metabolites 163
7.1.3.1. Glutathiones 164
7.1.3.2. Acylglucuronides 165
7.1.3.3. Acylglucosides and ,/V acetylglucosaminides 167
7.2. Current approaches 167
7.2.1. Background 167
7.2.2. Strategy 169
7.2.2.1. Materials and methods 169
7.2.2.2. Glutathione conjugation incubations 169
7.2.2.3. Acylglucuronide conjugation incubations 170
7.2.2.4. Acylglucoside and iV acetylglucosaminide
conjugation incubations 170
7.2.2.5. Screening method details 171
7.2.2.6. High performance liquid chromatographic (HPLC)
conditions 171
7.2.2.7. Mass spectrometric analysis 171
7.3. Results/discussion 172
7.4. Conclusions 177
7.5. Future 179
Acknowledgements 179
References 179
8. Liquid chromatography tandem mass spectrometry based metabolite
identification strategies in pharmaceutical research
M.R. Anari, P.R. Tiller, and T.A. Baillie
8.1. Introduction 183
8.2. Metabolite identification in drug discovery 184
8.3. Classical mass spectrometry based metabolite identification approach
in drug discovery 185
8.4. Parallel mass spectrometry based metabolite identification approach
in drug discovery 186
8.5. Integrated list dependent fast LC/MS in identifying metabolic soft
spots 187
8.6. Metabolite identification in preclinical development 188
8.7. Identification of unanticipated metabolites using data dependent
precursor ion and constant neutral loss scans 188
8.8. Detailed characterization of metabolites using radiochromatographic
techniques coupled to LC/MS 189
xi
8.9. Metabolite identification in clinical drug development 190
8.10. Detailed characterization of metabolites in humans 190
8.11. Quantitative similarity of the circulating metabolites in human versus
preclinical species 190
References 191
9. Quantification and structural elucidation of low quantities of radiolabeled
metabolites using microplate scintillation counting (MSC) techniques in
conjunction with LC—MS
M. Zhu, D. Zhang, and G.L. Skiles
9.1. Introduction 195
9.2. The HPLC MSC technique 196
9.3. Analytical characteristics of HPLC MSC 199
9.3.1. Sensitivity 199
9.3.2. Precision and accuracy 201
9.3.3. Matrix effect of biological samples 201
9.3.4. Radioactivity recovery determination 204
9.4. Application of MSC to quantitative analysis of drugs and
metabolites 205
9.4.1. Detection and profiling of low level metabolites 205
9.4.2. Analysis of drug and metabolite concentrations 208
9.4.3. Enzymology studies 209
9.5. Application of a combined of MSC and LC MS to metabolite
identification 210
9.5.1. A general LC MSC MS approach 210
9.5.2. Use of high resolution LC MS to enhance analytical
selectivity 215
9.5.3. Use of micro flow LC MS to enhance analytical
sensitivity 217
9.6. Conclusions 220
References 220
10. Oxidative metabolites of drugs and xenobiotics: LC MS methods to identify
and characterize in biological matrices
R. Ramanathan, S.K. Chowdhury, and K.B. Alton
10.1. Introduction 225
10.2. Dealkylation 226
10.2.1. Mono demethylation 227
10.2.1.1. Verapamil (Calan/Verelan) 227
10.2.1.2. Diazepam (Valium) 229
10.2.1.3. Omeprazole (Prilosec®) 230
10.2.2. Didemethylation and deethylation 231
10.2.2.1. Dextromethorphan 231
10.2.2.2. Lidocaine 231
xii
10.2.2.3. Phenacetin 232
10.2.2.4. Reboxetine (Edronax®) 232
10.2.2.5. Sildenafil (Viagra®) 233
10.2.2.6. Linezolid (Zyvox®) 234
10.2.3. Depropyl or deisopropylation 236
10.2.3.1. Selegiline (Sd Deprenyl®/Eldepryl®) 237
10.2.3.2. Buprenorphine (Subutex®) 238
10.2.3.3. Fluvastatin (Lescol®) 239
10.2.4. Dealkylation of larger moieties 240
10.2.4.1. Ritonavir (Norvir®) 240
10.2.4.2. Donepezil (Aricept®) 241
10.2.4.3. Tamoxifen (Nolvadex®) 241
10.2.4.4. Terfenadine (Seldane®) 242
10.3. Oxidative deamination 242
10.3.1. Amphetamine 242
10.3.2. Benzphetamine (Didrex) 243
10.3.3. Terbinafine (Lamisil®) 243
10.4. Oxidation of carbon 244
10.4.1. Hydroxylation 244
10.4.1.1. Loratadine (Claritin®) 245
10.4.1.2. Diclofenac (Cataflain/Voltaren) 247
10.4.1.3. Debrisoquine 249
10.4.1.4. Midazolam 250
10.4.1.5. Bupropion (Wellbutrin®/Zyban®) 252
10.4.1.6. Terfenadine (Seldane®) 252
10.4.2. Epoxidation 253
10.4.2.1. Protryptiline (Vivactil) 253
10.4.2.2. Carbamazepine (Atretol/Carbatrol/Epitol/
Tegretol) 254
10.5. Oxidation of nitrogen 256
10.5.1. iV Oxides 256
10.5.1.1. Loratadine 257
10.5.1.2. Clozapine (Clozaril®) 259
10.5.2. Hydroxylamines 260
10.5.2.1. Dapsone (Avlosulfon) 261
10.5.2.2. Debrisoquine 262
10.6. Oxidation of sulfur 263
10.6.1. S Oxidation/sulfoxides 263
10.6.1.1. Cimetidine (Tagamet®) 263
10.6.1.2. Clindamycin (Cleocin®) 263
10.6.1.3. Omapatrilat (Vanlev) 264
10.6.2. Sulfones 266
10.6.2.1. Chlorpromazine (Megaphen) 266
10.6.2.2. Ziprasidone (Geodon®) 267
xiii
10.7. ^ Oxidation 268
10.8. Dehalogenation 269
10.8.1. Halothane 270
10.8.2. Tolfenamic acid 270
10.9. Future directions of metabolite characterization/identification 271
References 272
11. Detection and characterization of highly polar metabolites by LC MS: proper
selection of LC column and use of stable isotope labeled drug to study meta¬
bolism of ribavirin in rats
S.K. Chowdhury, V.S. Gopaul, N. Blumenkrantz, R. Zhong,
K.M. Kulmatycki, and K.B. Alton
11.1. Introduction 277
11.2. Experimental 279
11.2.1. Materials 279
11.2.2. Preparation of stock and working solutions 279
11.2.3. Instrumentation 279
11.2.4. Chromatographic conditions 280
11.2.5. Mass spectrometry conditions 281
11.2.6. Drug administration and specimen collection 281
11.2.7. Sample preparation for LC MS analysis 282
11.2.7.1. Urine 282
11.2.7.2. Plasma 282
11.3. Results 283
11.3.1. Plasma metabolites 285
11.3.2 Urinary metabolites 288
11.4. Discussion 289
11.5. Conclusions 292
Acknowledgment 293
References 293
12. Cytochwme P450 (CYP) and UDP glucuronosyltransferase (UGT) enzymes:
role in drug metabolism, polymorphism, and identification of their involvement
in drug metabolism
A. Ghosal, R. Ramanathan, N.S. Kishnani, S.K. Chowdhury, and
K.B. Alton
12.1. Introduction 295
12.2. Cytochrome P450 (CYP) and subfamilies 296
12.2.1. CYP1 family 297
12.2.2. CYP2 family 300
12.2.3. CYP3 family 301
12.2.4. CYP4 family 303
xiv
12.3. Role of CYPs in drag metabolism 303
12.4. Polymorphism 304
12.5. Identification of P450 involvement in drag metabolism
(phenotyping) 306
12.5.1. Typical incubation with human liver microsomes 307
12.5.2. Screening enzymes responsible for the metabolism of
NCEs using recombinant human P450 enzymes 307
12.5.3. Correlation analysis 308
12.5.4. Inhibition by antibodies 309
12.5.5. Inhibition by chemicals 309
12.5.6. Sample analysis 310
12.5.7. Characterization of enzymology for the metabolism of
loratadine: a representative example 310
12.6. High throughput screening for inhibition of CYP enzymes 316
12.7. UDP glucuronosyltransferase (UGT) 317
12.8. Identification of UGT enzyme(s) involved in the metabolism 320
12.8.1. Incubation with pooled human liver microsomes 322
12.8.2. Screening of recombinant human UGT enzymes 322
12.8.3. Correlation study 323
12.8.4. Inhibition study with chemical inhibitors of UGTs 323
12.9. UGT and polymorphism 326
12.10. Future trends 326
Acknowledgment 327
References 327
Subject Index 337
|
| adam_txt |
Contents
Preface v
List of contributors xv
1. LC—MS and drug metabolism: a journey back in time, present trends
and future directions
K.B. Alton
1.1. Introduction 1
References 5
2. Strategies for increasing throughput for PK samples in a drug discovery
environment
W.A. Korfmacher
2.1. Introduction 7
2.2. Strategies for early PK assays 9
2.2.1. Enhanced mass resolution a new analytical tool for
PK assays 18
2.2.2. CARRS an example of an integrated PK assay
strategy 22
2.3. Conclusions 29
References 30
3. Commonly encountered analytical problems and their solutions in liquid
chromatography/tandem mass spectrometry (LC/MS/MS) methods used in
drug development
T.K. Majumdar
3.1. Introduction 35
3.2. Commonly encountered analytical problems and solutions 36
3.2.1. Problems with sample collection and analyte stability 36
3.2.2. Problem with positive controls 37
3.2.3. Carryover problem 38
3.2.4. Problem with retention time shift in HPLC 41
3.2.5. Problems related to the mobile phase composition and
ionization of analytes 43
3.2.6. Problems with ion suppression and matrix effect in the API
interface 43
3.2.7. Problems with stable isotope labeled IS 47
3.2.8. Problem of matrix interference due to the presence of
metabolites or other endogenous compounds 49
viii
3.2.9. The use of gas phase cluster ions for method sensitivity
problem 54
3.2.10. Problem with post column ion source induced changes of
pro drugs and metabolites 56
3.2.11. Problems with both mass spectrometric and chromatographic
resolutions in accurate quantification of parent compound
and metabolites 57
3.2.12. Problem with quantifying an unstable and light sensitive j
compound at ultra trace level concentrations 58 \
3.3. Conclusions 61
Acknowledgments 61
References 61
4. Pitfalls in quantitative LC MS/MS: metabolite contribution to measured
drug concentration
M. Jemal
4.1. Introduction 65
4.2. Analytical pitfalls due to metabolite in source conversion 65
4.3. Analytical pitfalls due to the simultaneous formation of
[M+H]+ and [M+NHJ+ ions from a drug as well as its
metabolite 74
4.4. Analytical pitfalls due to conversion of metabolite to the
parent drug during sample collection, handling, extraction,
and analysis 81
4.5. Bioanalytical method design for drug quantification in the presence
of a metabolite that may degrade to generate the drug 82
4.6. Strategy of using post dose samples to establish validity of
bioanalytical LC MS/MS methods 91
4.7. Summary and conclusions 99
References 100
5. In vitro DMPK screening in drug discovery, role of LC MS/MS
I. Chu and A.A. Nomeir
5.1. Introduction 105
5.2. CYP inhibition screening 105
5.2.1. Background 105
5.2.2. Types of inhibition 106
5.2.3. Experimental procedure 107
5.2.4. Sample plate set up 108
5.2.5. Quantification with LC MS/MS 109
5.2.6. IC50 determination 109
5.2.7. Throughput HO
5.3. Caco 2 permeability HI
5.3.1. Background HI
5.3.2. Mechanisms of absorption 112
ix
5.3.3. Caco 2 screening assay 112
5.3.4. Efflux evaluation 113
5.3.5. LC MS or LC MS/MS? 113
; 5.3.6. Multiplexed ion source (MUX®) 114
¦ 5.3.7. Determination of apparent permeability 115
; 5.3.8. Assay precision 116
5.3.9. Throughput 116
5.4. Blood Brain barrier 116
5.4.1. Background 116
5.4.2. Cell culture 117
5.4.3. Transport studies 117
5.4.4. Assay precision 118
5.4.5. In vivo in vitro correlation 118
5.5. Conclusion 120
Acknowledgment 120
References 120
6. Metabolite identification by LC MS: applications in drug discovery
and development
C.E.C.A. Hop and C. Prakash
6.1. Introduction 123
6.2. Metabolite identification 125
6.3. Mass spectrometers for metabolite identification 126
6.3.1. Single and triple quadrupole mass spectrometer 127
6.3.2. 3 Dimensional ion trap mass spectrometer 127
6.3.3. Q TOF mass spectrometer: 128
6.3.4. Common biotransformations 129
6.4. Additional tools for metabolite identification 130
6.4.1. Chemical derivatization 130
6.4.2. Radiolabeled compounds 131
6.4.3. Isotope patterns 131
6.4.4. LC NMR MS 132
6.4.5. H/D exchange 132
6.5. Applications 133
6.5.1. Metabolism of a potent neurokinin 1 receptor antagonist 133
6.5.2. Metabolism of a potent PPARy agonist 139
6.5.3. Metabolism of an antipsychotic drag ziprasidone 142
6.5.3.1. Use of two different radiolabels 143
6.5.3.2. Precursor ion spectrum 145
6.5.3.3. Differentiation of isobaric metabolites 145
6.5.4. Biotransformation of an anxiolytic drag candidate,
CP 93,393 146
6.6. Future trends 153
Acknowledgments 154
References 154
!
X !
7. The utility of in vitro screening for the assessment of electrophilic \
metabolite formation early in drug discovery using HPLC MS/MS
D.E. Grotz, N.A. Clarke, and K.A. Cox
7.1. Introduction 159
7.1.1. Metabolite characterization 160
7.1.2. In vitro metabolic screening methodology 161
7.1.3. The significance of electrophilic metabolites 163
7.1.3.1. Glutathiones 164
7.1.3.2. Acylglucuronides 165
7.1.3.3. Acylglucosides and ,/V acetylglucosaminides 167
7.2. Current approaches 167
7.2.1. Background 167
7.2.2. Strategy 169
7.2.2.1. Materials and methods 169
7.2.2.2. Glutathione conjugation incubations 169
7.2.2.3. Acylglucuronide conjugation incubations 170
7.2.2.4. Acylglucoside and iV acetylglucosaminide
conjugation incubations 170
7.2.2.5. Screening method details 171
7.2.2.6. High performance liquid chromatographic (HPLC)
conditions 171
7.2.2.7. Mass spectrometric analysis 171
7.3. Results/discussion 172
7.4. Conclusions 177
7.5. Future 179
Acknowledgements 179
References 179
8. Liquid chromatography tandem mass spectrometry based metabolite
identification strategies in pharmaceutical research
M.R. Anari, P.R. Tiller, and T.A. Baillie
8.1. Introduction 183
8.2. Metabolite identification in drug discovery 184
8.3. Classical mass spectrometry based metabolite identification approach
in drug discovery 185
8.4. Parallel mass spectrometry based metabolite identification approach
in drug discovery 186
8.5. Integrated list dependent fast LC/MS" in identifying metabolic soft
spots 187
8.6. Metabolite identification in preclinical development 188
8.7. Identification of unanticipated metabolites using data dependent
precursor ion and constant neutral loss scans 188
8.8. Detailed characterization of metabolites using radiochromatographic
techniques coupled to LC/MS 189
xi
8.9. Metabolite identification in clinical drug development 190
8.10. Detailed characterization of metabolites in humans 190
8.11. Quantitative similarity of the circulating metabolites in human versus
preclinical species 190
References 191
9. Quantification and structural elucidation of low quantities of radiolabeled
metabolites using microplate scintillation counting (MSC) techniques in
conjunction with LC—MS
M. Zhu, D. Zhang, and G.L. Skiles
9.1. Introduction 195
9.2. The HPLC MSC technique 196
9.3. Analytical characteristics of HPLC MSC 199
9.3.1. Sensitivity 199
9.3.2. Precision and accuracy 201
9.3.3. Matrix effect of biological samples 201
9.3.4. Radioactivity recovery determination 204
9.4. Application of MSC to quantitative analysis of drugs and
metabolites 205
9.4.1. Detection and profiling of low level metabolites 205
9.4.2. Analysis of drug and metabolite concentrations 208
9.4.3. Enzymology studies 209
9.5. Application of a combined of MSC and LC MS to metabolite
identification 210
9.5.1. A general LC MSC MS approach 210
9.5.2. Use of high resolution LC MS to enhance analytical
selectivity 215
9.5.3. Use of micro flow LC MS to enhance analytical
sensitivity 217
9.6. Conclusions 220
References 220
10. Oxidative metabolites of drugs and xenobiotics: LC MS methods to identify
and characterize in biological matrices
R. Ramanathan, S.K. Chowdhury, and K.B. Alton
10.1. Introduction 225
10.2. Dealkylation 226
10.2.1. Mono demethylation 227
10.2.1.1. Verapamil (Calan/Verelan) 227
10.2.1.2. Diazepam (Valium) 229
10.2.1.3. Omeprazole (Prilosec®) 230
10.2.2. Didemethylation and deethylation 231
10.2.2.1. Dextromethorphan 231
10.2.2.2. Lidocaine 231
xii
10.2.2.3. Phenacetin 232
10.2.2.4. Reboxetine (Edronax®) 232
10.2.2.5. Sildenafil (Viagra®) 233
10.2.2.6. Linezolid (Zyvox®) 234
10.2.3. Depropyl or deisopropylation 236
10.2.3.1. Selegiline (Sd Deprenyl®/Eldepryl®) 237
10.2.3.2. Buprenorphine (Subutex®) 238
10.2.3.3. Fluvastatin (Lescol®) 239
10.2.4. Dealkylation of larger moieties 240
10.2.4.1. Ritonavir (Norvir®) 240
10.2.4.2. Donepezil (Aricept®) 241
10.2.4.3. Tamoxifen (Nolvadex®) 241
10.2.4.4. Terfenadine (Seldane®) 242
10.3. Oxidative deamination 242
10.3.1. Amphetamine 242
10.3.2. Benzphetamine (Didrex) 243
10.3.3. Terbinafine (Lamisil®) 243
10.4. Oxidation of carbon 244
10.4.1. Hydroxylation 244
10.4.1.1. Loratadine (Claritin®) 245
10.4.1.2. Diclofenac (Cataflain/Voltaren) 247
10.4.1.3. Debrisoquine 249
10.4.1.4. Midazolam 250
10.4.1.5. Bupropion (Wellbutrin®/Zyban®) 252
10.4.1.6. Terfenadine (Seldane®) 252
10.4.2. Epoxidation 253
10.4.2.1. Protryptiline (Vivactil) 253
10.4.2.2. Carbamazepine (Atretol/Carbatrol/Epitol/
Tegretol) 254
10.5. Oxidation of nitrogen 256
10.5.1. iV Oxides 256
10.5.1.1. Loratadine 257
10.5.1.2. Clozapine (Clozaril®) 259
10.5.2. Hydroxylamines 260
10.5.2.1. Dapsone (Avlosulfon) 261
10.5.2.2. Debrisoquine 262
10.6. Oxidation of sulfur 263
10.6.1. S Oxidation/sulfoxides 263
10.6.1.1. Cimetidine (Tagamet®) 263
10.6.1.2. Clindamycin (Cleocin®) 263
10.6.1.3. Omapatrilat (Vanlev) 264
10.6.2. Sulfones 266
10.6.2.1. Chlorpromazine (Megaphen) 266
10.6.2.2. Ziprasidone (Geodon®) 267
xiii
10.7. ^ Oxidation 268
10.8. Dehalogenation 269
10.8.1. Halothane 270
10.8.2. Tolfenamic acid 270
10.9. Future directions of metabolite characterization/identification 271
References 272
11. Detection and characterization of highly polar metabolites by LC MS: proper
selection of LC column and use of stable isotope labeled drug to study meta¬
bolism of ribavirin in rats
S.K. Chowdhury, V.S. Gopaul, N. Blumenkrantz, R. Zhong,
K.M. Kulmatycki, and K.B. Alton
11.1. Introduction 277
11.2. Experimental 279
11.2.1. Materials 279
11.2.2. Preparation of stock and working solutions 279
11.2.3. Instrumentation 279
11.2.4. Chromatographic conditions 280
11.2.5. Mass spectrometry conditions 281
11.2.6. Drug administration and specimen collection 281
11.2.7. Sample preparation for LC MS analysis 282
11.2.7.1. Urine 282
11.2.7.2. Plasma 282
11.3. Results 283
11.3.1. Plasma metabolites 285
11.3.2 Urinary metabolites 288
11.4. Discussion 289
11.5. Conclusions 292
Acknowledgment 293
References 293
12. Cytochwme P450 (CYP) and UDP glucuronosyltransferase (UGT) enzymes:
role in drug metabolism, polymorphism, and identification of their involvement
in drug metabolism
A. Ghosal, R. Ramanathan, N.S. Kishnani, S.K. Chowdhury, and
K.B. Alton
12.1. Introduction 295
12.2. Cytochrome P450 (CYP) and subfamilies 296
12.2.1. CYP1 family 297
12.2.2. CYP2 family 300
12.2.3. CYP3 family 301
12.2.4. CYP4 family 303
xiv
12.3. Role of CYPs in drag metabolism 303
12.4. Polymorphism 304
12.5. Identification of P450 involvement in drag metabolism
(phenotyping) 306
12.5.1. Typical incubation with human liver microsomes 307
12.5.2. Screening enzymes responsible for the metabolism of
NCEs using recombinant human P450 enzymes 307
12.5.3. Correlation analysis 308
12.5.4. Inhibition by antibodies 309
12.5.5. Inhibition by chemicals 309
12.5.6. Sample analysis 310
12.5.7. Characterization of enzymology for the metabolism of
loratadine: a representative example 310
12.6. High throughput screening for inhibition of CYP enzymes 316
12.7. UDP glucuronosyltransferase (UGT) 317
12.8. Identification of UGT enzyme(s) involved in the metabolism 320
12.8.1. Incubation with pooled human liver microsomes 322
12.8.2. Screening of recombinant human UGT enzymes 322
12.8.3. Correlation study 323
12.8.4. Inhibition study with chemical inhibitors of UGTs 323
12.9. UGT and polymorphism 326
12.10. Future trends 326
Acknowledgment 327
References 327
Subject Index 337 |
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| illustrated | Illustrated |
| index_date | 2024-07-02T14:32:36Z |
| indexdate | 2024-07-09T20:38:30Z |
| institution | BVB |
| isbn | 0444517103 |
| language | English |
| oai_aleph_id | oai:aleph.bib-bvb.de:BVB01-014770463 |
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| physical | XVI, 338 S. Ill., graph. Darst. |
| publishDate | 2005 |
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| series | Progress in pharmaceutical and biomedical analysis |
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| spelling | Identification and quantification of drugs, metabolites and metabolizing enzymes by LC-MS ed. by Swapan K. Chowdhury 1. ed. Amsterdam [u.a.] Elsevier 2005 XVI, 338 S. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier Progress in pharmaceutical and biomedical analysis 6 Chromatography, Liquid methods Drug Design Drugs Metabolism Enzymes Physiology Pharmaceutical Preparations analysis Pharmaceutical Preparations metabolism Spectrum Analysis, Mass methods Enzym (DE-588)4014988-2 gnd rswk-swf Arzneimittel (DE-588)4003115-9 gnd rswk-swf LC-MS (DE-588)4539813-6 gnd rswk-swf Metabolit (DE-588)4138579-2 gnd rswk-swf LC-MS (DE-588)4539813-6 s Arzneimittel (DE-588)4003115-9 s DE-604 Metabolit (DE-588)4138579-2 s Enzym (DE-588)4014988-2 s Chowdhury, Swapan K. Sonstige (DE-588)185070825 oth Progress in pharmaceutical and biomedical analysis 6 (DE-604)BV010273310 6 HBZ Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=014770463&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Identification and quantification of drugs, metabolites and metabolizing enzymes by LC-MS Progress in pharmaceutical and biomedical analysis Chromatography, Liquid methods Drug Design Drugs Metabolism Enzymes Physiology Pharmaceutical Preparations analysis Pharmaceutical Preparations metabolism Spectrum Analysis, Mass methods Enzym (DE-588)4014988-2 gnd Arzneimittel (DE-588)4003115-9 gnd LC-MS (DE-588)4539813-6 gnd Metabolit (DE-588)4138579-2 gnd |
| subject_GND | (DE-588)4014988-2 (DE-588)4003115-9 (DE-588)4539813-6 (DE-588)4138579-2 |
| title | Identification and quantification of drugs, metabolites and metabolizing enzymes by LC-MS |
| title_auth | Identification and quantification of drugs, metabolites and metabolizing enzymes by LC-MS |
| title_exact_search | Identification and quantification of drugs, metabolites and metabolizing enzymes by LC-MS |
| title_exact_search_txtP | Identification and quantification of drugs, metabolites and metabolizing enzymes by LC-MS |
| title_full | Identification and quantification of drugs, metabolites and metabolizing enzymes by LC-MS ed. by Swapan K. Chowdhury |
| title_fullStr | Identification and quantification of drugs, metabolites and metabolizing enzymes by LC-MS ed. by Swapan K. Chowdhury |
| title_full_unstemmed | Identification and quantification of drugs, metabolites and metabolizing enzymes by LC-MS ed. by Swapan K. Chowdhury |
| title_short | Identification and quantification of drugs, metabolites and metabolizing enzymes by LC-MS |
| title_sort | identification and quantification of drugs metabolites and metabolizing enzymes by lc ms |
| topic | Chromatography, Liquid methods Drug Design Drugs Metabolism Enzymes Physiology Pharmaceutical Preparations analysis Pharmaceutical Preparations metabolism Spectrum Analysis, Mass methods Enzym (DE-588)4014988-2 gnd Arzneimittel (DE-588)4003115-9 gnd LC-MS (DE-588)4539813-6 gnd Metabolit (DE-588)4138579-2 gnd |
| topic_facet | Chromatography, Liquid methods Drug Design Drugs Metabolism Enzymes Physiology Pharmaceutical Preparations analysis Pharmaceutical Preparations metabolism Spectrum Analysis, Mass methods Enzym Arzneimittel LC-MS Metabolit |
| url | http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=014770463&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
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