Handbook of. Metabolic Pathways. of Xenobiotics. Editor-in-Chief

Transcription

1 Handbook of Metabolic Pathways of Xenobiotics Editor-in-Chief Dr Philip W. Lee East China University of Science and Technology Shanghai, People's Republic of China WILEY

2 Contents of Volume 2 About the Editors Preface List of Contributors of Volumes 1 and 2 Abbreviations and Acronyms xxxiii xxxvii xxxix xli Theory and instrumentation of mass spectrometry and its application to drug metabolism 393 Stacy L. Gelhaus and Ian A. Blair Introduction 393 Liquid chromatography 394 Ultraperformance liquid chromatography 394 Microfluidic/chip technology 397 Ionization methods for LC-MS 398 Electrospray ionization 398 Atmospheric pressure chemical ionization 399 Atmospheric pressure photo-ionization 399 Atmospheric pressure laser ionization 399 Desorption electrospray ionization 400 Mass analyzers for LC-MS 402 Quadrupole mass analyzers 402 Ion-trap mass analyzers 402 LTQ-Orbitrap mass analyzer 403 Quadrupole time-of-flight mass analyzers 403 Fourier transform-ion cyclotron resonance mass analyzer 404 Ion mobility 404 Detectors 405 Stable isotope dilution methodology 406 Applications of LC-MS in drug metabolism studies 407 High-throughput analysis 407 In silico high-throughput analysis 409 Multivariate data analysis 409 Conclusions 412 Acknowledgments 413 References 414 Mass spectral interpretation 419 Li-Kang Zhang and Birendra N. Pramanik Introduction 419 Mass spectral interpretation 419

3 xii Contents of Volume 2 Molecular weight and empirical formula determination 420 Fragmentation reactions 427 Practical applications 429 Conclusion 450 References 450 Computational approaches in drug biotransformation studies: metabolite prediction 457 Nigel J. Waters and Michelle K. Dennehy Introduction 457 Approaches to metabolite prediction 460 Expert systems 460 Knowledge bases 465 Quantum mechanical-based models 468 Databases and derived rules 469 QSAR models 471 Qualitative versus quantitative drug metabolism modeling 473 Computational tools as an adjunct to experimental work 475 Challenges and limitations of SOM modeling 475 Conclusion and summary 477 References 477 High-throughput metabolite detection and quantitative-qualitative bioanalysis 481 Donghui Cui and Sean Yu Introduction 481 Metabolite detection using unit-resolution mass spectrometers 482 Metabolite detection using high-resolution mass spectrometers 484 Software advancement in data acquisition and processing 485 MSE scans 485 Auto-Dealkylation 486 Mass defect filter 486 MassFragment 488 Metabolynx data processing 488 Metabolic stability screen and quantitative-qualitative data acquisition 492 References 495 Metabolic stability screen in drug discovery 499 Chuang Lu Introduction 499 Metabolic stability screen and ADME models 500 In vitro experimental models 500 Design of in vitro models for screening for metabolic stability 511 Conclusion 518 Acknowledgment 518 References 518

4 Contents of Volume 2 xiii Application of triple-quadrupole and its hybrid mass spectrometers for the identification of drug metabolites 523 Zhi-Yi Zhang, Chandra Prakash, and Lin Xu Introduction 523 The instrument design and acquisition methods 524 Single-stage quadrupole 524 Triple-stage quadrupole 525 Hybrid quadrupole linear ion trap 527 Hybrid quadrupole time of flight 529 Spectral interpretation and structure determination in TSQ and its hybrid instruments 539 Molecular mass determination in TSQ and its hybrid instruments 531 Structural elucidation based on MS/MS (MS") product ion spectra 536 Summary and outlook 546 References 548 Role of ion trap LC-MS techniques for the identification of drug metabolites 553 Robert D. Pelletier and W. George Lai Introduction 553 Type of ion traps 553 Techniques of ion traps for identification of drug metabolites 554 Examples of using ion traps for identification of drug metabolites 556 Conclusions 563 Acknowledgment 564 References 564 Drug metabolite identification with high-resolution mass spectrometry 567 Haiying Zhang and Mingshe Zhu Introduction 567 High-resolution mass spectrometry brings in new and improved full-scan data-mining methods 568 Mass defect filter - a new capacity 568 Background subtraction with control samples - a new capacity 569 Isotope pattern filter - improved and more selective 569 Comparison with control sample using extracted ion chromatograms - improved performance 569 High-resolution mass spectrometry brings in new and improved data-dependent MS/MS acquisition methods 570 Mass-defect-dependent acquisition - a new capacity 570 List-dependent acquisition - improved and more selective 571 Isotope-pattern-triggered acquisition - improved performance 571 High-resolution mass spectrometry boosts the utility of nonspecific fragmentation data obtained in generic full-scan mode 571 Product ion filtering 572 Neutral loss filtering 572 Extracting product ion data for drug metabolites 572 Background subtraction to extract clean product ion data for drug metabolites 573

5 xiv Contents of Volume 2 Neutral-loss-dependent MS/MS acquisition 573 A word on the impact of high-resolution mass spectrometry to metabolite detection 574 A word on the impact of high-resolution mass spectrometry to metabolite structural elucidation 574 Examples of applications 575 Application to high-throughput analysis of metabolic soft-spots in drug discovery 575 Application to screening of reactive metabolites in drug discovery 576 Applications to in vivo metabolite profiling 578 Application to characterization of unusual/novel metabolites 582 Conclusion and future opportunities 583 References 585 Strategies for the identification of unusual and novel metabolites using derivatization, hydrogen-deuterium exchange (HDX), and liquid chromatography-nuclear magnetic resonance (LC-NMR) spectroscopy techniques 591 Amin Kamel, Shawn Harriman, and Chandra Prakash Introduction 591 Biotransformation reactions 592 Analytical techniques for structural determination of metabolites 593 Nuclear magnetic resonance spectroscopy 593 Wet chemistry techniques combined with mass spectrometry 594 Applications 599 Metabolism of ziprasidone 599 Metabolism of elzasonan 604 Metabolism of CP-122, Hydrogen-deuterium exchange and accurate mass measurements to distinguish between isobaric metabolites and address time-dependent CYP inhibition 606 Metabolism of CP-533, Metabolism of torcetrapib 611 Metabolism of sunepitron 613 Conclusion 613 Acknowledgments 613 References 613 The use of nanoelectrospray mass spectrometry for the quantitation of metabolites in the absence of synthetic standards 619 Jing-Tao Wu Introduction 619 Nanoelectrospray and equimolar response 621 Nanoelectrospray 621 Instrumentation 621 Equimolar response with nanoelectrospray 622 Nanoelectrospray for metabolite quantitation 624 Conclusions and future directions 629 References 630

6 Contents of Volume 2 xv Quantitation of drug metabolites by radioactivity detection including accelerator mass spectrometry (AMS) 633 Angus N.R. Nedderman and Mark E. Savage Introduction 633 Key principles of radiochemical detection by scintillation counting 634 Use of radioactivity for drug metabolism and pharmacokinetic studies 635 Metabolite quantitation by fraction collection and off-line counting techniques 638 Overview of off-line approaches: scintillation vials and microtiter plates 638 Key considerations for off-line approaches 639 Summary of off-line approaches to metabolite quantitation 641 Metabolite quantitation by online radioflow counting techniques 643 Overview of online approaches: homogeneous and heterogeneous detection and stop-flow techniques 643 Key considerations for homogeneous and heterogeneous detection 644 Stop-flow approaches 647 Dynamic-flow approaches 649 Accelerator mass spectrometry 649 Background 649 Applications of AMS 651 Metabolite quantitation using AMS 651 Limitations and future developments of AMS 653 Comparative summary of online and off-line radiochemical quantitation methodologies 655 References 656 Application of quantitative NMR in drug metabolism studies 661 Abdul E. Mutlib Introduction 661 NMR as a quantitative tool (qnmr) 663 Background 663 Validation of qnmr to determine concentrations of isolated metabolites 664 Application of qnmr in drug discovery metabolism studies 670 Pharmacological evaluation of drug metabolites 670 qnmr to obtain mass balance of fluorinated discovery compounds 673 Application of qnmr in drug development metabolism studies 677 Addressing metabolites in safety testing using qnmr 677 qnmr to obtain mass balance of fluorinated development compounds 684 Conclusions 688 References 689 Early assessment of exposure of drug metabolites in humans using mass spectrometry 693 Natalia A. Penner, Joanna Zgoda-Pols, and Chandra Prakash Introduction 693 MIST guidance: scientific recommendation with flexible interpretation 694 ICH M3 Guidance 695 Approaches to address MIST guidance 696

7 xvi Contents of Volume 2 Use of in vitro and in vivo methods for prediction of human metabolites 696 Use of samples from FIH studies 698 Sample collection 698 Approaches for metabolite detection 700 Determination of response factors 706 Radiolabeled human study for assessment of metabolite exposure 713 Sample collection 713 Use of single-dose data to estimate SS exposure 714 Summary 715 Acknowledgment 717 References 717 Profiling and characterization of bioactive substances of herbal medicine and their metabolites using mass spectrometry 723 Xiaoyan Chen Introduction 723 LC-MS methodology 724 Interfacing systems 724 Mass analyzers 728 Importance of chromatographic separation 729 Identification of bioactive substances in herbal medicines 731 Ginseng extracts and ginsenosides 732 Danshen (Salvia miltiorrhiza) 734 Traditional Chinese medicine prescription 736 Profiling and characterization of metabolites of bioactive substances in herbal medicine 738 Saponins 739 Alkaloid 746 Flavonoids 757 Bioactivation of herbal medicines 764 Herbal medicine extracts or formula 773 Conclusion and future directions 778 References 779 Application of in silico metabolism and environmental degradation data to support chemical PBT assessment 787 Sabcho Dimitrov, Gilman Veith, and Ovanes Mekenyan Introduction 787 Persistency assessment 788 Retrospection 789 Specificities of microbial metabolism 790 CATALOGIC approach 793 Applicability domain 805 Model predictions and risk assessment 806 References 806 Index I