Drug Metabolism Handbook E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 2100

Veröffentlichungsjahr: 2022

Beschreibung

A comprehensive explanation of drug metabolism concepts and applications in drug development and cancer treatment In the newly revised second edition of Drug Metabolism Handbook: Concepts and Applications in Cancer Research, a distinguished team of researchers delivers an incisive and robust exploration of the drug metabolism system and a well-illustrated and detailed explanation of the latest tools and techniques used in the research, pharmacology, and medicine. The book discusses the creation of new molecular entities, drug development, troubleshooting, and other highly relevant concepts, guiding readers through new applications in pharmaceutical research, development, and assessment. The latest edition offers updated content on metabolism basics and the application of a variety of new techniques to cancer treatment, including mass spectrometry, imaging, metabolomics, and immunotherapy. It also offers in-depth case studies highlighting the role of metabolism in drug development. Readers will also benefit from: * A thorough introduction to drug metabolism, including a historical perspective, factors affecting metabolism, and biotransformations in drug metabolism * Comprehensive discussions of technologies for in vitro and in vivo studies, including mass spectrometry and accelerating metabolite identification with mass spectrometry * In-depth explorations of drug interactions, including discussions of enzyme inhibition and the characterization of cytochrome P450 mechanism-based inhibition * Fulsome treatments of drug toxicity, including the role of drug metabolism in toxicity, and allergic reactions to drugs Perfect for medicinal chemists, pharmaceutical scientists, and toxicologists, Drug Metabolism Handbook: Concepts and Applications in Cancer Research, Second Edition will also earn a place in the libraries of analytical chemists and drug discovery professionals.

Leseprobe

Table of Contents

COVER

TITLE PAGE

COPYRIGHT

PREFACE

LIST OF CONTRIBUTORS

VOLUME 1

PART I: INTRODUCTION

CHAPTER 1: Historical Perspective

1.1 CONTROVERSIES SPANNING PAST, PRESENT, AND FUTURE

1.2 1800S: DISCOVERY OF MAJOR DRUG METABOLISM PATHWAYS (CONTI AND BICKEL, 1977)

1.3 1900–1950S: CONFIRMATION OF MAJOR PATHWAYS AND MECHANISTIC STUDIES

1.4 1950S–1980: MODERN DRUG METABOLISM EMERGES, WITH ENZYMATIC BASIS

1.5 1980–2005: FIELD DRIVEN BY IMPROVED TECHNOLOGIES

1.6 2005+: HIGH TECHNOLOGY

REFERENCES

CHAPTER 2: Factors Affecting Metabolism

REFERENCES

CHAPTER 3: Biotransformations in Drug Metabolism

3.1 DRUG METABOLISM IN DRUG DEVELOPMENT AND DRUG THERAPY

3.2 PREDICTION OF METABOLITE AND ENZYME RESPONSIBLE

3.3 FUNCTIONAL GROUP BIOTRANSFORMATIONS: PHASE I, PHASE II, AND CATALYSIS

3.4 OXIDATIONS AND CYTOCHROME P450

3.5 ENZYMOLOGY AND MODIFIERS OF CYTOCHROME P450S

REFERENCES

CHAPTER 4: A Comprehensive Picture of Biotransformation in Drug Discovery

4.1 INTRODUCTION

4.2 RATE OF METABOLISM

4.3 METABOLISM OF SMALL MOLECULES

4.4 ANALYTICAL TECHNOLOGIES IN DRUG METABOLISM

4.5 BIOTRANSFORMATION FOR NOVEL MODALITIES – PEPTIDES AND PROTEIN DEGRADERS

4.6 CONCLUSION

REFERENCES

CHAPTER 5:

In Vivo

Drug Metabolite Kinetics

5.1 INTRODUCTION

5.2

IN VIVO

DRUG METABOLITE KINETIC CONCEPTS AND PRINCIPLES

5.3 EFFECT OF INHIBITION AND INDUCTION ON METABOLITE KINETICS

5.4 DETERMINATION OF FORMATION AND ELIMINATION CLEARANCE OF METABOLITE

5.5 INCORPORATION OF PHARMACOLOGICALLY ACTIVE METABOLITE(S) IN PHARMACOKINETIC/PHARMACODYNAMIC MODELING

5.6 SUMMARY

ABBREVIATIONS

REFERENCES

CHAPTER 6: LC-MS/MS-Based Proteomics Methods for Quantifying Drug-Metabolizing Enzymes and Transporters

6.1 INTRODUCTION

6.2 MASS SPECTROMETRY VERSUS ALTERNATIVE PROTEIN QUANTIFICATION METHODS

6.3 MASS SPECTROMETRY DATA ACQUISITION METHODS FOR PROTEOMICS ANALYSIS

6.4 TARGETED APPROACHES

6.5 UNTARGETED PROTEOMICS APPROACHES

6.6 RELATIVE QUANTIFICATION VERSUS ABSOLUTE QUANTIFICATION

6.7 LABEL-BASED PROTEOMICS

6.8 LABEL-FREE PROTEOMICS

6.9 DMET PROTEIN QUANTIFICATION USING LC-MS/MS-BASED PROTEOMICS

6.10 POTENTIAL APPLICATION OF DMET EXPRESSION STUDIES

6.11 CONSIDERATIONS OF DMET PROTEIN QUANTIFICATION UTILIZING LC-MS/MS METHODS

6.12 CONCLUSION

REFERENCES

PART II: TECHNOLOGIES FOR

IN VITRO

AND

IN VIVO

STUDIES

CHAPTER 7: Mass Spectrometry

7.1 INTRODUCTION

7.2 A BRIEF HISTORY

7.3 THE MASS SPECTROMETRY LITERATURE

7.4 MASS SPECTROMETRY INSTRUMENTATION

7.5 INTERPRETATION: WHAT DOES IT MEAN

7.6 CONCLUSIONS

REFERENCES

NOTES

CHAPTER 8: Accelerating Metabolite Identification Mass Spectrometry Technology Drives Metabolite Identification Studies Forward

8.1 INTRODUCTION

8.2 CRITERIA FOR LC-MS METHODS

8.3 MATRICES EFFECT

8.4 TOOL OF CHOICE FOR METABOLITE CHARACTERIZATION

8.5 STRATEGIES FOR IDENTIFYING UNKNOWN METABOLITES

8.6 ONLINE HD-LC-MS

8.7 “ALL-IN-ONE” RADIOACTIVITY DETECTOR, STOP FLOW, AND DYNAMIC FLOW FOR METABOLITE IDENTIFICATION

8.8 METABOLIC ACTIVATION STUDIES BY MASS SPECTROMETRY

8.9 STRATEGIES TO SCREEN FOR REACTIVE METABOLITES

8.10 SUMMARY

ABBREVIATIONS AND GLOSSARY

REFERENCES

CHAPTER 9: Role of Structural Modifications of Drug Candidates to Enhance Metabolic Stability

9.1 BACKGROUND

9.2 INTRODUCTION

9.3 SIGNIFICANCE OF METABOLITE CHARACTERIZATION AND STRUCTURE MODIFICATION

9.4 ENHANCE METABOLIC STABILITY

9.5 METABOLIC STABILITY AND INTRINSIC METABOLIC CLEARANCE

9.6 ADVANTAGES OF ENHANCING METABOLIC STABILITY

9.7 STRATEGIES TO ENHANCE METABOLIC STABILITY

9.8 ANALYTICAL TOOLS

9.9 CASE STUDIES

9.10 CONCLUSIONS

REFERENCES

CHAPTER 10: Drug Design Strategies: Role of Structural Modifications of Drug Candidates to Improve PK Parameters of New Drugs

10.1 ACTIVE METABOLITES

10.2 ORAL ABSORPTION AND INTRAVENOUS DOSE

10.3 PK ANALYSIS

10.4 CASE STUDIES

10.5 PRODRUGS TO INCREASE WATER SOLUBILITY

10.6 CONCLUSION

REFERENCES

CHAPTER 11: Chemical Structural Alert and Reactive Metabolite Concept as Applied in Medicinal Chemistry to Minimize the Toxicity of Drug Candidates

11.1 IMPORTANCE OF REACTIVE INTERMEDIATES IN DRUG DISCOVERY AND DEVELOPMENT

11.2 IDIOSYNCRATIC DRUG TOXICITY AND MOLECULAR MECHANISMS

11.3 KEY TOOLS AND STRATEGIES TO IMPROVE DRUG SAFETY

11.4 PEROXIDASES

11.5 ACYL GLUCURONIDATION AND

S

-Acyl-CoA Thioesters

11.6 COVALENT BINDING

11.7 MECHANISTIC STUDIES

11.8 PRECLINICAL DEVELOPMENT

11.9 CLINICAL DEVELOPMENT: STRATEGY

11.10 CASE STUDIES

11.11 CONCLUSION AND FUTURE POSSIBILITIES

REFERENCES

CHAPTER 12: Studies of Reactive Metabolites using Genotoxicity Arrays and Enzyme/DNA Biocolloids – 2021

12.1 INTRODUCTION

12.2 ON DEMAND METABOLIC REACTIONS

12.3 ARRAYS WITH ELECTROCHEMICAL DETECTION

12.4 ELECTROCHEMILUMINESCENT ARRAYS

12.5 ECL ARRAYS CAN MEASURE BOTH DNA OXIDATION AND NUCLEOBASE ADDUCTION

12.6 DETECTING SITE-SPECIFIC DAMAGE TO

TUMOR SUPPRESSOR

GENES

12.7 EMERGING TECHNOLOGIES AND METHODS

12.8 CONCLUSIONS AND FUTURE OUTLOOK

ACKNOWLEDGMENTS

BIOGRAPHIES

REFERENCES

PART III: DRUG INTERACTIONS

CHAPTER 13: Enzyme Inhibition

13.1 INTRODUCTION

13.2 MECHANISMS OF ENZYME INHIBITION

13.3 COMPETITIVE INHIBITION

13.4 NONCOMPETITIVE INHIBITION

13.5 UNCOMPETITIVE INHIBITION

13.6 PRODUCT INHIBITION

13.7 TRANSITION-STATE ANALOGS

13.8 SLOW, TIGHT-BINDING INHIBITORS

13.9 MECHANISM-BASED INACTIVATORS

13.10 INHIBITORS THAT ARE METABOLIZED TO REACTIVE PRODUCTS THAT COVALENTLY ATTACH TO THE ENZYME

13.11 SUBSTRATE INHIBITION

13.12 PARTIAL INHIBITION

13.13 INHIBITION OF CYTOCHROME P450 ENZYMES

13.14 REVERSIBLE INHIBITORS

13.15 QUASI-IRREVERSIBLE INHIBITORS

13.16 MECHANISM-BASED INACTIVATORS

REFERENCES

CHAPTER 14: Xenobiotic Receptor-Mediated Gene Regulation in Drug Metabolism and Disposition

14.1 INTRODUCTION

14.2 PREGNANE X RECEPTOR

14.3 CONSTITUTIVE ANDROSTANE/ACTIVATED RECEPTOR (CAR)

14.4 CLOSING REMARKS AND PERSPECTIVES

ACKNOWLEDGMENTS

REFERENCES

CHAPTER 15: Characterization of Cytochrome P450 Mechanism Based Inhibition

15.1 INTRODUCTION

15.2 INHIBITORS THAT UPON ACTIVATION BIND COVALENTLY TO THE P450 APOPROTEIN

15.3 INHIBITORS THAT INTERACT IN A PSEUDOIRREVERSIBLE MANNER WITH HEME IRON

15.4 INACTIVATION THAT CAUSE DESTRUCTION OF THE PROSTHETIC HEME GROUP, OFTEN TIMES LEADING TO HEME-DERIVED PRODUCTS THAT COVALENTLY MODIFY THE APOPROTEIN

REFERENCES

CHAPTER 16: An Introduction to Metabolic Reaction-Phenotyping

16.1 INTRODUCTION

16.2 SIGNIFICANT DRUG-METABOLIZING ENZYMES

16.3 COMMON

IN VITRO

METHODS TO ASSESS DRUG METABOLISM

16.4

IN VITRO

TO

IN VIVO

EXTRAPOLATION OF METABOLIC CLEARANCE

16.5 SUMMARY

REFERENCES

CHAPTER 17: Epigenetic Regulation of Drug-Metabolizing Enzymes in Cancer

17.1 INTRODUCTION

17.2 DNA METHYLATION OF DME

17.3 HISTONE MODIFICATION

17.4 NONCODING RNA

17.5 RNA METHYLATION

17.6 CLOSING REMARKS AND PERSPECTIVES

ACKNOWLEDGMENTS

REFERENCES

CHAPTER 18: Epigenetic Regulation of Drug Transporters in Cancer

18.1 INTRODUCTION

18.2 DNA METHYLATION

18.3 HISTONE MODIFICATIONS

18.4 NONCODING RNA

18.5 Closing Remarks and Perspectives

ACKNOWLEDGMENTS

REFERENCES

VOLUME 2

PART IV: TOXICITY

CHAPTER 19: The Role of Drug Metabolism in Toxicity

19.1 INTRODUCTION

19.2 DRUG METABOLIZING ENZYMES

19.3 CLASSIFICATION OF TOXICITY

19.4 MOLECULAR MECHANISMS OF TOXICITY

19.5 ORGAN SYSTEMS TOXICOLOGY

19.6 CARCINOGENESIS

19.7 TERATOGENESIS

19.8 ABROGATION/MITIGATION OF BIOACTIVATION – CASE EXAMPLES

19.9 EXPERIMENTAL METHODS FOR SCREENING

19.10 SUMMARY

ACKNOWLEDGMENT

References

CHAPTER 20: Allergic Reactions to Drugs

20.1 INTRODUCTION

20.2 IMMUNE SYSTEM: A BRIEF OVERVIEW

20.3 DRUG METABOLISM AND THE HAPTEN HYPOTHESIS

20.4 ALLERGIC REACTIONS TO DRUGS (EXAMPLES)

20.5 CONCLUSION

ACKNOWLEDGMENTS

REFERENCES

NOTE

CHAPTER 21: Chemical Mechanisms in Toxicology

21.1 INTRODUCTION

21.2 GLUTATHIONE ADDUCTS

21.3 COVALENT BINDING

21.4 STRUCTURAL ALERTS

21.5 EXAMPLES OF METABOLIC ACTIVATION

21.6 CONCLUSION

ACKNOWLEDGMENTS

REFERENCES

NOTE

CHAPTER 22: Role of Bioactivation Reactions in Chemically Induced Nephrotoxicity

22.1 TOXICOLOGICAL IMPLICATIONS OF RENAL STRUCTURE AND FUNCTION

22.2 INTERORGAN AND INTRARENAL BIOACTIVATION PATHWAYS

22.3 CYTOCHROME P450 (CYP)-DEPENDENT BIOACTIVATION IN THE RENAL PROXIMAL TUBULE

22.4 FLAVIN-CONTAINING MONOOXYGENASE (FMO)-DEPENDENT BIOACTIVATION IN THE RENAL PROXIMAL TUBULE

22.5 GLUTATHIONE (GSH)-DEPENDENT BIOACTIVATION IN THE RENAL PROXIMAL TUBULE

22.6 RENAL METABOLISM OF ACETAMINOPHEN (PARACETAMOL) BY THE KIDNEYS

22.7 IMPACT OF CHRONIC KIDNEY DISEASE ON DRUG METABOLISM

22.8 SUMMARY AND CONCLUSION

REFERENCES

PART V: APPLICATIONS

CHAPTER 23: Mapping the Heterogeneous Distribution of Cancer Drugs by Imaging Mass Spectrometry

23.1 INTRODUCTION

23.2 MSI INSTRUMENTATION

23.3 IMAGE ANALYSIS

23.4 SAMPLE PREPARATION

23.5 QUANTITATIVE MSI

23.6 MSI IN STUDYING THE DISTRIBUTION OF CANCER DRUGS

23.7 EMERGING IN VITRO APPLICATIONS

23.8 CLINICAL TRANSLATION

23.9 CONCLUSION AND PERSPECTIVES

REFERENCES

CHAPTER 24: Systemic Metabolomic Changes Associated with Chemotherapy: Role in Personalized Therapy

24.1 INTRODUCTION

24.2 METABOLOMICS: MAPPING METABOLOMIC ALTERATIONS IN CANCER

24.3 ANALYTICAL METHODS IN CANCER METABOLOMICS: GLOBAL AND TARGETED STRATEGIES

24.4 METABOLOMICS IN CANCER: EXPLORATION OF METABOLIC ALTERATIONS DURING DISEASE DEVELOPMENT, CHEMOTHERAPY AND DRUG RESISTANCE

24.5 CHALLENGES AND PROGRESS IN THE APPLICATION OF METABOLOMICS FOR THE DEVELOPMENT OF PERSONALIZED CANCER MEDICINE

24.6 FUTURE PERSPECTIVES AND FURTHER SCOPE OF IMPROVEMENT IN METABOLOMICS-ASSISTED CANCER THERAPY

24.7 CONCLUDING REMARKS

REFERENCES

CHAPTER 25: Metabolic Reprogramming in Cancer

25.1 INTRODUCTION

25.2 REPROGRAMMING OF CENTRAL CARBON METABOLISM (CCM)

25.3 GLUTAMINE ADDICTION OF CANCER CELLS

25.4 ARGININE AND POLYAMINE METABOLISM

25.5 SERINE, METHIONINE AND ONE CARBON METABOLISM

25.6 BRANCHED-CHAIN AMINO ACID (BCAA) METABOLISM

25.7 REPROGRAMMING OF OXIDATIVE STRESS RESPONSE MACHINERY

25.8 BIOSYNTHESIS OF PURINE AND PYRIMIDINE NUCLEOTIDES IN CANCER

25.9 REPROGRAMMING OF LIPID METABOLISM IN CANCER

25.10 METABOLIC REWIRING IN CANCER STEM CELLS (CSC)

25.11 FUTURE PERSPECTIVES

REFERENCES

CHAPTER 26: Case Study: Metabolism and Reactions of Alkylating Agents in Cancer Therapy

26.1 INTRODUCTION

26.2

IN VITRO

STUDIES

26.3 NOVEL REARRANGEMENT

26.4 IDENTIFICATION AND CHARACTERIZATION OF

IN VITRO

METABOLITE/DECOMPOSITION PRODUCTS OF LAROMUSTINE IN HLM

26.5 IDENTIFICATION AND CHARACTERIZATION OF

IN VITRO

CONJUGATION REACTIONS OF LAROMUSTINE

26.6 DISCUSSION

REFERENCES

CHAPTER 27: Rewiring of Drug Metabolism and Its Cross-talk with Metabolic Reprogramming in Cancer

27.1 INTRODUCTION

27.2 PATHWAYS INVOLVED IN ANTICANCER DRUG METABOLISM

27.3 ALTERATIONS IN DRUG METABOLISM IN CANCER

27.4 REWIRING OF DRUG METABOLISM IN RESPONSE TO ANTICANCER AGENTS

27.5 CROSS-TALK BETWEEN ENDOGENOUS AND DRUG METABOLISM IN CANCER

27.6 ROLE OF MICROENVIRONMENT IN DRUG METABOLISM

27.7 FUTURE PERSPECTIVES

ACKNOWLEDGMENT

REFERENCES

CHAPTER 28: Principles of Drug Metabolism and Interactions in Cardio-Oncology

28.1 INTRODUCTION

28.2 EXPRESSION OF CYP450 IN CANCER

28.3 EXPRESSION OF P-GLYCOPROTEIN IN CANCER

28.4 INTERACTIONS BETWEEN DRUG CLASSES IN CARDIO-ONCOLOGY BY CYP450 OR P-G

28.5 IMPACT OF GENOMIC VARIATION AND OTHER FORMS OF REGULATION

28.6 MULTIDISCIPLINARY TEAM APPROACH

28.7 CONCLUSION

REFERENCES

INDEX

END USER LICENSE AGREEMENT

List of Tables

Chapter 1

TABLE 1.1 Early development of the major drug metabolism pathways.

Chapter 3

TABLE 3.1 Effective uses of metabolism science in drug development and drug ...

TABLE 3.2 Major P450 reactions classified according to category and mechanis...

TABLE 3.3 Regioselectivity preferences of CYP3A4, CYP2D6, and CYP2C9.

Chapter 4

TABLE 4.1 Scaling factors using to extrapolate in vitro clearance to in vivo...

TABLE 4.2 Use of deuterium atoms to reduce the C—H bond cleavage via Kinetic...

TABLE 4.3 Comparison of P450 and aldehyde oxidase enzyme systems.

TABLE 4.4 List of important UGTs present in humans and their substrates.

TABLE 4.5 Comparison of mass analyzer with respect to key performance attrib...

TABLE 4.6 Common derivatization techniques for various functional groups.

TABLE 4.7 Mass shifts and mass defects of conjugated metabolites.

Chapter 5

TABLE 5.1 Characteristics and human half-life of some approved antibody-drug...

Chapter 7

TABLE 7.1 Example calculations of relative molecular mass.

TABLE 7.2 Accurate masses and natural abundances of selected stable isotopes...

TABLE 7.3 Elemental compositions consistent with an experimental accurate ma...

TABLE 7.4 Calculation of average molecular mass and polydispersity for Trito...

Chapter 8

TABLE 8.1 Common biotransformation reactions.

TABLE 8.2 Techniques that help in the search for, and identification of, met...

TABLE 8.3 Exchange of labile hydrogens in nimodipine and metabolites formed ...

Chapter 9

TABLE 9.1 Enhancement of metabolic stability through structural modification...

TABLE 9.2 Tools for the identification and characterization of metabolites....

Chapter 10

TABLE 10.1 Metabolism-driven optimization of PK properties by structure modi...

Chapter 11

TABLE 11.1 Examples of chemical structures activating to produce toxic metab...

TABLE 11.2 Selected tools to screen for reactive metabolites, covalent bindi...

Chapter 15

TABLE 15.1 GSH and other nucleophiles used in trapping electrophilic interme...

TABLE 15.2 Average enzyme abundances taken from SimP450 V7.1, illustrating t...

TABLE 15.3 A table of in vitro IC50 generated against three different P450 3...

Chapter 16

TABLE 16.1 Survey of drug-metabolizing enzymes mediating oxidation or reduct...

TABLE 16.2 Human cytochromes P450 and their substrate selectivity.

TABLE 16.3 Tissue distribution and substrates of major human uridine 5′-diph...

TABLE 16.4 Cytochrome P450 (CYP) substrates, inhibitors, and inducers (Unite...

TABLE 16.5 Common chemical inhibitors and recommended concentrations for in ...

TABLE 16.6 Examples of known substrates for the major human flavin-containin...

TABLE 16.7 Meta-analysis of hepatic cytochrome P450 (CYP) abundance.

TABLE 16.8 Examples of an integrated in vitro cytochrome P450 (CYP) reaction...

TABLE 16.9 Examples of in vitro cytochrome P450 (CYP) reaction phenotyping o...

Chapter 19

TABLE 19.1 Families and major distribution of common human drug-metabolizing...

TABLE 19.2 Functional groups and drugs associated with reactive metabolite f...

TABLE 19.3 Drugs, putative reactive-intermediates, implicated enzymes, and a...

TABLE 19.4 Structural modification and mitigation of toxicity.

Chapter 20

TABLE 20.1 Partial list of carboxylic-acid containing drugs withdrawn from c...

Chapter 21

TABLE 21.1 Hard

versus

soft nucleophiles and electrophiles.

TABLE 21.2 Drugs or chemicals known to cause idiosyncratic hepatotoxicity....

TABLE 21.3 Examples of chemicals containing structural alerts and their corr...

Chapter 22

TABLE 22.1 Major cytochrome P450 (CYP) enzymes in rat and human kidney.

TABLE 22.2 Mammalian enzymes that catalyze cysteine conjugate β-lyase activi...

TABLE 22.3 Summary of some parameters altered in chronic kidney disease (CKD...

Chapter 23

TABLE 23.1 Use of MSI for studying the distribution of cancer drugs.

Chapter 24

TABLE 24.1 Metabolic alterations associated with chemotherapeutic drug resis...

Chapter 26

TABLE 26.1 Formation of C-7 and loss of substrate in incubations of [14C]lar...

TABLE 26.2 Results from Fourier transform ion cyclotron resonance-mass spect...

TABLE 26.3 Metabolite/decomposition products formed in HLM incubation.

TABLE 26.4

In vitro

conjugation reactions of laromustine and VNP4090CE.

Chapter 27

TABLE 27.1 Chemotherapy drugs and their modes of actions.

TABLE 27.2 Cytochrome P450s involved in cancer drug metabolism.

TABLE 27.3 Altered expression of Cytochrome P450s in cancer and its impact....

TABLE 27.4 UGTs and GSTs involved in cancer drug metabolism.

TABLE 27.5 Altered expression of UGTs in cancer and its impact on drug respo...

TABLE 27.6 Association between alteration in GST expression and therapeutic ...

Chapter 28

TABLE 28.1 Various cancer and anticoagulation drug classes associate with dru...

List of Illustrations

Chapter 1

Figure 1.1 Examples of first-observed metabolism reactions. (a) glycine conj...

Chapter 3

Figure 3.1 Role of drug metabolism in bioavailability and clearance.

Figure 3.2 Example of effective use of metabolism science: fexofenadine (All...

Figure 3.3 Examples of phase I reactions.

Figure 3.4 Examples of phase II reactions.

Figure 3.5 Relationships and nomenclature of cytochrome P450 members importa...

Figure 3.6 Average relative proportions of CYPs present in human liver.

Figure 3.7 Carbon hydroxylation under the unified mechanism. (i) H

⋅

ab...

Figure 3.8 Order of reactivity of sp

3

carbons toward cytochrome P450 oxidati...

Figure 3.9 Examples of carbon hydroxylation. (a) Benzylic carbon hydroxylati...

Figure 3.10 Mechanism for oxidation of ethanol and hydrated acetaldehyde by ...

Figure 3.11 Oxidation of sp

2

systems to form arene oxide or epoxide.

Figure 3.12 Examples of olefin (alkene) epoxidation and aromatic hydroxylati...

Figure 3.13 Unified P450 mechanism for N-dealkylation of amine nitrogen.

Figure 3.14 Unified P450 mechanism for O-dealkylation of ethers (a) and oxid...

Figure 3.15 Examples of N-dealkylation, O-dealkylation, and oxidative cleava...

Figure 3.16 Unified P450 mechanism for N-oxygenation.

Figure 3.17 Examples of nitrogen oxidation. (a) Primary amine oxidation, (b)...

Figure 3.18 Examples of sulfur oxidation.

Figure 3.19 Other oxidations relevant to drug metabolism.

Figure 3.20 Decision tree for prediction of dominant cytochrome P450 isoform...

Figure 3.21 Binding cavities of human cytochrome P450 members (show my own d...

Chapter 4

Figure 4.1 Representation of various liver systems that can be utilized to s...

Figure 4.2 List of typical reactions mediated by P450s.

Figure 4.3 Catalytic cycle for Cytochrome P450.

Figure 4.4 Relative amounts of P450s present in humans.

Figure 4.5 Effect of intrinsic clearance by reducing lipophilicity.

Figure 4.6 Example for blocking the site of metabolism by incorporation of f...

Figure 4.7 Example scaffold hopping to reduce metabolic liability.

Figure 4.8 Partial list of chemical scaffolds that can be metabolized by ald...

Figure 4.9 Catalytic cycle of aldehyde oxidase.

Figure 4.10 Catalytic cycle for flavin-dependent monooxygenase (FMOs).

Figure 4.11 The steps involved in the reduction of a nitro group to an amino...

Figure 4.12 (a) UPLC/TopCount radiochromatogram of the standard mixture (1, ...

Figure 4.13 Flowchart of optimized acquisition sequence method with backgrou...

Figure 4.14 In-depth structure elucidation of a low abundant ticlopidine GSH...

Figure 4.15 Proposed structures of pioglitazone metabolites in dog kidney an...

Figure 4.16 LC/MS analysis of pyridine and piperidine N-oxide in urine befor...

Figure 4.17 Aminolysis reaction showing nucleophilic displacement of glucuro...

Figure 4.18 Common mass defect filter templates and various classes of metab...

Figure 4.19 TIC and radiochromatogram of rat plasma following a single oral ...

Figure 4.20 (a) Unprocessed and (b) isotope filtering processed mass spectra...

Figure 4.21 Shown is the progression of GLP-1 receptor agonists and the chem...

Figure 4.22 Shown are all states of a solution NMR structure of Hepcidin (PD...

Figure 4.23 Synthetically and biosynthetically made crosslinks observed in (...

Figure 4.24 Both 2-pyridine carboxaldehyde derivatives (a) and 2-methylthioa...

Figure 4.25 Structures of commonly used IMIDs are shown (a) with a heat map ...

Chapter 5

Figure 5.1 A schematic representation of the fate of a metabolite (X) in the...

Figure 5.2 A metabolite kinetic model.

Figure 5.3 A hypothetical example that illustrates the conceptual difference...

Figure 5.4 Effects of the rate-limiting step in metabolite kinetics on the s...

Figure 5.5 Effects of the rate-limiting step in metabolite kinetics on the t...

Figure 5.6 The serum concentration–time profiles of trastuzumab deruxtecan (...

Figure 5.7 Effects of presystemically formed metabolites on the shape of met...

Figure 5.8 The plasma concentration–time profiles of midazolam and 1′-hydrox...

Figure 5.9 A representative hybrid physiologically based pharmacokinetic mod...

Figure 5.10 A kinetic model for sequential metabolism. CL

e

, CL

e

(m1), and CL

e

Figure 5.11 Inhibition of the formation clearance of a metabolite on metabol...

Figure 5.12 Sensitivity of various pharmacokinetic parameters to the inhibit...

Chapter 6

Figure 6.1 Schematic presentation of the data acquisition methods SRM/MRM, P...

Figure 6.2 Comparative bar graph contrasting the different data acquisition ...

Figure 6.3 Hepatic drug-metabolizing enzymes (a) and transporters (b) (DMET)...

Figure 6.4 Intestinal drug metabolizing enzymes (a) and transporters (b) (DM...

Figure 6.5 Renal drug metabolizing enzymes (a) and transporters (b) (DMET) e...

Chapter 7

Figure 7.1 Modular diagram of a mass spectrometer system. Upper panel is ill...

Figure 7.2 Applicability of various chromatography-mass spectrometry techniq...

Figure 7.3 Combining liquid chromatography with mass spectrometry involves a...

Figure 7.4 Schematic diagram of a moving belt LC-MS interface.

Figure 7.5 Electrospray ion source.

Figure 7.6 Comparison of EI mass spectra of hexadecane. The 1951 mass spectr...

Figure 7.7 Electrospray ionization mechanism.

Figure 7.8 Applicable range of molecules ionizable by APPI.

Figure 7.9 Desorption electrospray ionization source.

Figure 7.10 MS-MS operation modes.

Figure 7.11 Chromatography-mass spectroscopy data space.

Figure 7.12 Selected reaction monitoring MS-MS operation mode.

Figure 7.13 LC-MS separation of PFAAs, PFASs, fluorotelomers and others. Dia...

Figure 7.14 Fragmentations of classes of perfluoroalkanes. Top: perfluoroalk...

Figure 7.15 ESI mass spectrum of a molecule containing two chlorine atoms.

Figure 7.16 Comparison of the isotope pattern for the observed electrospray ...

Figure 7.17 Boron isotope patterns.

Figure 7.18 Observed isotope pattern (upper panel) and predicted model (lowe...

Structure 1

Figure 7.19 MS-MS product ion spectra of the

m/z

300 (top panel),

m/z

302 (m...

Figure 7.20 Partial accurate mass spectrum, comparing mass resolution calcul...

Figure 7.21 Example of high-resolution experiment on complex mixtures, showi...

Figure 7.22 Example of a high resolution experiment on complex mixtures, sho...

Figure 7.23 MS-MS product ion spectra of the

m/z

300 [M+H] at 10V (top ...

Figure 7.24 Top panel: ESI mass spectrum of sertraline. Bottom panel: ESI MS...

Scheme 7.1 ESI fragmentation of sertraline.

Structure 2

Figure 7.25 Positive ion ESI mass spectrum of a phosphatidylcholine, taken f...

Figure 7.26 Differentiation of keto (left structure and mass spectrum) and e...

Structure 3

Figure 7.27 Hydrogen–deuterium exchange of melamine in a DART ion source....

Structure 4

Figure 7.28 Positive ion electrospray mass spectrum of the molecular ion reg...

Figure 7.29 Deuterium exchanged molecular ion region of anidulafungin. (From...

Figure 7.30 Electrospray spectrum of sodium iodide clusters. The spectrum is...

Figure 7.31 Formation of different adduct ions under different solvent condi...

Structure 5

Figure 7.32 Positive ion ESI mass spectrum of a poly(ethylene glycol) mixtur...

Figure 7.33 Fast atom bombardment spectrum of a cetirizine poly(ethylene gly...

Structure 6

Structure 7

Figure 7.34 Electrospray mass spectrum of octoxynol (triton X).

Figure 7.35 Comparison of the isotope pattern of the doubly charged molecula...

Figure 7.36 Comparison of the isotope pattern of the singly charged molecula...

Figure 7.37 Positive ion ESI mass spectrum of bovine serum albumin. The aver...

Figure 7.38 Amino acid sequence of insulin.

Figure 7.39 Electrospray mass spectrum of insulin. Top panel: the multiply c...

Scheme 7.2 Reversible Schiff base formation between

o

-vanillin and the ε-ami...

Figure 7.40 Multiply charged ESI mass spectrum of porcine somatotropin (PST)...

Figure 7.41 Multiply charged electrospray mass spectrum of OV-PST.

Figure 7.42 MaxEnt®-transformed singly charged mass spectrum of OV-PST. This...

Chapter 8

Figure 8.1 The chemical structure of nimodipine with the labile H exchange a...

Figure 8.2 QTOF MS/MS spectra of metabolite M-3 in (a) D

2

O and (b) H

2

O.

Figure 8.3 Proposed metabolic pathways of nimodipine in hepatic microsomal i...

Figure 8.4 Proposed metabolic pathways of nimodipine in hepatic microsomal i...

Figure 8.5 Hardware schematic diagram of the LC-ARC system. Source: AIM Rese...

Figure 8.6 Chemical structure of [14C]dextromethorphan, the test compound us...

Figure 8.7 HPLC-MS chromatograms of [14C]dextromethorphan following incubati...

Figure 8.8 Representative LC-MS spectra of [M+H]+

m

/

z

274, M-1, (a) MS

2

, (b)...

Figure 8.9 Proposed metabolic pathways of dextromethorphan in human hepatic ...

Chapter 11

Figure 11.1 Reactive intermediate theory and idiosyncratic reactions/toxic e...

Chapter 12

Figure 12.1 Conceptual representation of films of DNA, polyions, and metabol...

Scheme 12.1 Polyions used to make films by layer-by-layer (LbL) alternate el...

Scheme 12.2 Microfluidic array system used for electrochemical detection of ...

Figure 12.2 Representative SWVs for oxidation of damaged DNA at different en...

Scheme 12.3 DNA adduct formation from metabolic cyt P450 bioactivation of (a...

Figure 12.3 Influence of substrate incubation time on SWV peak current ratio...

Scheme 12.4 Microfluidic ECL chip for multiple-enzyme screening of metabolit...

Scheme 12.5 Experimental design of 64 nanowell ECL array with films of enzym...

Scheme 12.6 Proposed metabolic pathways of NNK in humans.

Figure 12.4 ECL data from array wells containing Ru

II

PVP/enzyme/DNA films re...

Figure 12.5 Single reaction monitoring (SRM) LC-MS chromatograms for

m

/

z

299...

Figure 12.6 Automated genotoxicity screening array: (a) The 3D-printed devic...

Figure 12.7 ECL array results comparing extracted vapor from e-cigarettes wi...

Scheme 12.7 Strategy for detecting DNA damage using (a) DNA/enzyme films, (b...

Scheme 12.8 Major metabolic pathway of arylamines causing DNA adduct formati...

Scheme 12.9 Proposed pathway involving Cu

2+

and NADPH for ROS formation ...

Figure 12.8 Recolorized and reconstructed images of ECL for DNA oxidation (a...

Figure 12.9 Bar graphs showing (a) relative DNA oxidation rate and (b) relat...

Figure 12.10 An overview of the sequence-specific DNA hybridization damage e...

Chapter 14

Figure 14.1 Structure and functional domains of nuclear receptors. (a) Basal...

Figure 14.2 Schematic representation of the creation of hPXR “humanized” mic...

Figure 14.3 Newly proposed model of cross-talk between PXR and CAR in the re...

Chapter 15

Figure 15.1 A graphical breakdown of the various pathways that contribute to...

Figure 15.2 A simple graph depicting an imaginary time concentration profile...

Figure 15.3 A simple schematic describing the possible mechanisms of inhibit...

Figure 15.4 A schematic diagram showing the free-energy profile of the cours...

Figure 15.5 The catalytic cycle for cytochrome P450 enzyme oxidation reactio...

Figure 15.6 A brief listing of common P450 oxidation reactions.

Figure 15.7 Reaction scheme of a mechanism-based enzyme inactivator.

Figure 15.8 Multiple P450 3A4 oxidation reactions toward a single substrate,...

Figure 15.9 Mechanistic scheme for P450 enzyme-mediated bioactivation and su...

Figure 15.10 Mechanistic scheme for P450 enzyme-mediated bioactivation and s...

Figure 15.11 Mechanistic scheme for P450 enzyme-mediated bioactivation and s...

Figure 15.12 Mechanistic scheme for P450 enzyme-mediated bioactivation and s...

Figure 15.13 Mechanistic scheme for P450 enzyme-mediated bioactivation and s...

Figure 15.14 Mechanistic scheme for P450 enzyme-mediated bioactivation and s...

Figure 15.15 SimP450-generated single oral dose pharmacokinetic model of mid...

Figure 15.16 Represents a schematic of the MBI testing funnel describing the...

Figure 15.17 The absolute energetic differences between different P450-catal...

Figure 15.18 Crystal structure of P450 2C9 with flurbiprofen bound (1R90.pdb...

Figure 15.19 Hypothetical drug molecule metabolized by two different P450 en...

Figure 15.20 P450 active sites have unique active site which may contribute ...

Figure 15.21 The structure of psoralen, 8-methoxypsoralen, and 5-methoxypsor...

Figure 15.22 Mechanistic scheme for P450 enzyme-mediated bioactivation of tr...

Figure 15.23 Mechanistic scheme for P450 enzyme-mediated bioactivation of ar...

Figure 15.24 Data transformed from the experimental design in Figure 15.25 c...

Figure 15.25 The 96-well plate preincubation format for determination of IC

5

...

Figure 15.26 Different plots for time-dependent inhibition data.

Figure 15.27 A 96-well plate preincubation format for determination of time-...

Figure 15.28 Kinetic formation of MIC by monitoring absorbance at 455 nm....

Figure 15.29 Measurement of carbon monoxide binding pre- and postincubation ...

Figure 15.30 Mechanistic scheme for P450 enzyme-mediated bioactivation and s...

Figure 15.31 LC-MS spectra and deconvoluted spectra for P450 3A4 apoprotein....

Figure 15.32 (a) Chromatogram illustrating separation of reductase and apopr...

Figure 15.33 Different mechanistic approaches to locating P450 nucleophiles ...

Figure 15.34 Chromatographic separation of peptides following proteinase K d...

Figure 15.35 (a) Covalent binding of EE to P450 3A5. SDS-PAGE separation of ...

Figure 15.36 A structural comparison of two compounds aimed as selective est...

Figure 15.37 Kinetic equations used to extrapolate

in vitro

MBI into clinica...

Chapter 19

Figure 19.1

Reactivity scheme for acyl glucuronides

. Acyl glucuronide can re...

Figure 19.2 Reactivity scheme for

N

-acetyl transferases.

Figure 19.3 Glutathione redox cycle.

Figure 19.4

General scheme of toxicity

. Toxicity of a drug and its metabolit...

Chapter 20

Figure 20.1 Scheme for the metabolism of drugs to chemically-reactive interm...

Figure 20.2 Chemical mechanisms for the covalent binding of penicillin to pr...

Figure 20.3 Proposed chemical mechanism for the metabolic activation of felb...

Figure 20.4 Chemical mechanism for the P450-mediated bioactivation of haloth...

Figure 20.5 Proposed chemical mechanism for the metabolic activation of tien...

Figure 20.6 Chemical mechanism for the P450-mediated bioactivation of sulfam...

Figure 20.7 Proposed scheme for the metabolic activation of carboxylic acid-...

Figure 20.8 Mechanism for transacylation of protein nucleophiles by 1-β-

O

-ac...

Figure 20.9 Mechanism for stable adduct formation with lysine-residues on pr...

Figure 20.10 Proposed chemical mechanism for the metabolic activation of ben...

Figure 20.11 Risk of allergic reactions to drugs (circles) and corresponding...

Chapter 21

Figure 21.1 Metabolic activation of benzo[

a

]pyrene leading to covalent bindi...

Figure 21.2 Metabolic activation of xenobiotics to chemically-reactive and p...

Figure 21.3 Chemically-reactive compounds react with GSH by one of two gener...

Figure 21.4 Tandem mass spectrometric LC-MS/MS screening for glutathione add...

Figure 21.5 Enzyme-mediated degradation of glutathione conjugates in the kid...

Figure 21.6 Tandem mass spectrometric LC-MS/MS screening for mercapturic aci...

Figure 21.7 Scheme for the metabolic activation of naphthalene and formation...

Figure 21.8 Scheme for the metabolic activation of suprofen to electrophilic...

Figure 21.9 Scheme for the metabolic activation of furosemide to reactive fu...

Figure 21.10 Scheme for the metabolic activation of the thiazolidinedione mo...

Figure 21.11 Scheme for the metabolic activation of bromobenzene and formati...

Figure 21.12 Proposed scheme for the metabolic activation of the raloxifene ...

Figure 21.13 Scheme for the metabolic activation of zafirlukast to an electr...

Figure 21.14 Proposed scheme for the concerted metabolic activation of valpr...

Figure 21.15 Proposed scheme for the metabolic activation of the zomepirac b...

Figure 21.16 Proposed scheme for the metabolic activation of the zomepirac a...

Figure 21.17 Proposed scheme for the metabolic activation of procarbazine le...

Figure 21.18 Proposed mechanism in the metabolic activation of isoniazid....

Figure 21.19 Proposed mechanism in the metabolic activation of acetaminophen...

Figure 21.20 Proposed mechanism of Nrf2 activation by reactive oxygen specie...

Figure 21.21 Proposed mechanisms in the metabolic activation of diclofenac....

Figure 21.22 Proposed mechanisms in the metabolic activation of the ovotoxin...

Figure 21.23 Proposed mechanisms in the metabolic activation of the estrogen...

Figure 21.24 Proposed mechanism in the metabolic activation of dapsone to a ...

Figure 21.25 Proposed mechanism in the metabolic activation of nitrobenzene ...

Chapter 22

Figure 22.1 Scheme of interorgan pathways involving cytochrome P450 (CYP) en...

Figure 22.2 Scheme of interorgan pathways involving GSH conjugation. Xenobio...

Figure 22.3 Bioactivation of GSH conjugates. Drug or xenobiotic (R-X) forms ...

Figure 22.4 Structures of representative cysteine conjugates that undergo re...

Figure 22.5 Validation of role of enzymatic and transport processes in the r...

Figure 22.6 Renal metabolism of acetaminophen (APAP). APAP may undergo eithe...

Chapter 23

Figure 23.1 Schematic presentation of (a) matrix-assisted laser desorption/i...

Figure 23.2 Workflow in recording the ion images of a tissue section. The io...

Figure 23.3 A typical MSI workflow in pharmaceutical research shows the step...

Figure 23.4 The top panel shows the MALDI-MSI data revealing the distributio...

Figure 23.5 Histological localization of the drug (epacadostat) and metaboli...

Figure 23.6 Temporal profile of enzalutamide (ENZ) penetration in an

ex vivo

Figure 23.7 MALDI-MSI showing the temporal profile of irinotecan (

m/z

587) p...

Figure 23.8 Detection of cetuximab, a monoclonal antibody, using MALDI-MSI i...

Figure 23.9 (a) Ion images of cetuximab distribution in treated and control ...

Chapter 24

Figure 24.1 A schematic diagram of the personalized metabolomics workflow f...

Chapter 25

Figure 25.1 Schematic representation of glucose metabolism in (a) normal ver...

Figure 25.2 Tumor suppressor and oncogene-mediated regulation of (a) glycoly...

Figure 25.3 Schematic representation of biosynthetic pathways diverging from...

Figure 25.4 Alterations in gluconeogenesis and

de novo

serine synthesis in c...

Figure 25.5 Schematic representation of altered glutamine metabolism in canc...

Figure 25.6 Schematic representation of changes in polyamine metabolism in c...

Figure 25.7 Alterations in serine, methionine, and one-carbon metabolism in ...

Figure 25.8 Alterations in branched-chain amino acid metabolism in cancer. M...

Figure 25.9 Metabolic reprogramming supporting antioxidant response machiner...

Figure 25.10 Alterations in (a) purine and (b) pyrimidine nucleotide biosynt...

Figure 25.11 Alterations in lipid metabolism in cancer. Metabolites are show...

Figure 25.12 Niche metabolic alterations in hypoxic tumor core associated wi...

Chapter 26

Scheme 26.1 The pathway of activation of cyclophosphamide and ifosfamide.

Scheme 26.2 Chemical structures of carmustine and lomustine and their degrad...

Figure 26.1 (a) Chemical structures of laromustine and VNP4090CE and (b) Che...

Figure 26.2 Chromatograms from incubation of [14C]laromustine (100 μM) with ...

Figure 26.3 Correlation between the rate of formation of C-7 from [14C]larom...

Figure 26.4 FTMS results for MS/MS of m/z 325 peak using 9.4 T Bruker Qe FTI...

Figure 26.5 Proposed mechanism of formation fragmentation ions of

m/z

251, 1...

Figure 26.6 Proposed fragmentation ions of laromustine of

m/z

325, 327 and 3...

Figure 26.7 Proposed structure and fragmentation ions for C-7.

Figure 26.8 Proposed formation mechanism of MW 214 (C-4 and C-5).

Chapter 27

Figure 27.1 Schematic representation of different types of reactions catalyz...

Figure 27.2 Cross-talk between drug metabolism and endogenous metabolic mach...

Figure 27.3 Role of epigenetics in mediating cross-talk between cancer metab...

Figure 27.4 Role of microenvironment on cross talk between metabolic reprogr...

Chapter 28

Figure 28.1 Delicate balance between optimizing cardiovascular and cancer ou...

Figure 28.2 Cytochrome protein 450 (CYP450) and P-glycoprotein (P-g) in card...

Figure 28.3 Genetic variation and impact on drug response. Variations in pha...

Figure 28.4 Spectrum of phenotypes manifesting from Cytochrome protein 450 (...

Figure 28.5 Genomic, physiologic, and demographic regulators of Cytochrome p...

Figure 28.6 Variations in the genome to the microRNAome can influence the ph...

Figure 28.7 Factors that impact drug response. Overall drug response, and th...

Guide

Cover

Title Page

Copyright

Preface

List of Contributors

Table of Contents

Begin Reading

Index

End User License Agreement

Pages

iii

iv

xiii

xiv

xv

xvi

xvii

xviii

1

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384

385

386

387

388

389

390

391

392

393

394

395

396

397

398

399

400

401

402

403

404

405

407

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

427

428

429

430

431

432

433

434

435

436

437

438

439

440

441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

466

467

468

469

470

471

472

473

474

475

476

477

478

479

480

481

482

483

484

485

486

487

488

489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

505

506

507

508

509

510

511

512

513

514

515

516

517

518

519

520

521

522

523

524

525

526

527

528

529

530

531

532

533

534

535

536

537

538

539

540

541

542

543

544

545

546

547

548

549

550

551

552

553

554

555

556

557

558

559

560

561

562

563

564

565

566

567

568

569

570

571

573

574

575

576

577

578

579

580

581

582

583

584

585

586

587

588

589

590

591

592

593

594

595

596

597

598

599

600

601

602

603

605

607

608

609

610

611

612

613

614

615

616

617

618

619

620

621

622

623

624

625

626

627

628

629

630

631

632

633

634

635

636

637

638

639

640

641

642

643

644

645

646

647

648

649

650

651

652

653

654

655

656

657

658

659

660

661

662

663

664

665

666

667

668

669

670

671

672

673

674

675

676

677

678

679

680

681

682

683

684

685

686

687

688

689

690

691

692

693

694

695

696

697

698

699

700

701

702

703

704

705

706

707

708

709

710

711

712

713

714

715

716

717

718

719

720

721

722

723

724

725

726

727

728

729

730

731

732

733

734

735

736

737

738

739

740

741

742

743

745

746

747

748

749

750

751

752

753

754

755

756

757

758

759

760

761

762

763

764

765

766

767

768

769

770

771

773

775

776

777

778

779

780

781

782

783

784

785

786

787

788

789

790

791

792

793

794

795

796

797

798

799

800

801

802

803

804

805

806

807

808

809

811

812

813

814

815

816

817

818

819

820

821

822

823

824

825

826

827

828

829

830

831

832

833

834

835

836

837

838

839

841

842

843

844

845

846

847

848

849

850

851

852

853

854

855

856

857

858

859

860

861

862

863

864

865

866

867

868

869

870

871

872

873

874

875

876

877

878

879

880

881

882

883

884

885

886

887

888

889

890

891

892

893

894

895

896

897

898

899

900

901

902

903

904

905

906

907

908

909

910

911

912

913

914

915

916

917

918

919

920

921

922

923

924

925

926

927

928

929

930

931

932

933

934

935

936

937

938

939

940

941

942

943

944

945

946

947

948

949

950

951

952

953

954

955

956

957

958

959

960

961

962

963

964

965

966

967

968

969

970

971

972

973

974

975

976

977

978

979

980

981

982

983

984

985

986

987

988

989

990

991

992

993

994

995

996

997

998

999

1000

1001

1002

1003

1004

1005

1006

1007

1008

1009

1010

1011

1012

1013

1014

DRUG METABOLISM HANDBOOK

CONCEPTS AND APPLICATIONS IN CANCER RESEARCH

Volume 1

Second Edition

Edited by

Ala F. NassarYale University, USA

Associate Editors

Paul F. HollenbergThe University of Michigan Medical, USA

JoAnn ScatinaHealthcare investors, USA

Soumen Kanti MannaSaha Institute of Nuclear Physics, IN

Su ZengZhejiang University, CH

DRUG METABOLISM HANDBOOK

CONCEPTS AND APPLICATIONS IN CANCER RESEARCH

Volume 2

Second Edition

Edited by

Ala F. NassarYale University, USA

Associate Editors

Paul F. HollenbergThe University of Michigan Medical, USA

JoAnn ScatinaHealthcare investors, USA

Soumen Kanti MannaSaha Institute of Nuclear Physics, IN

Su ZengZhejiang University, CH

This second edition first published 2023© 2023 John Wiley & Sons, Inc.

Edition HistoryJohn Wiley & Sons (1e, 2009)

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions.

The right of Ala F. Nassar, Paul F. Hollenberg, JoAnn Scatina, Soumen Kanti Manna, and Su Zeng to be identified as the authors of the editorial material in this work has been asserted in accordance with law.

Registered OfficeJohn Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA

For details of our global editorial offices, customer services, and more information about Wiley products visit us at www.wiley.com.

Wiley also publishes its books in a variety of electronic formats and by print-on-demand. Some content that appears in standard print versions of this book may not be available in other formats.

Trademarks: Wiley and the Wiley logo are trademarks or registered trademarks of John Wiley & Sons, Inc. and/or its affiliates in the United States and other countries and may not be used without written permission. All other trademarks are the property of their respective owners. John Wiley & Sons, Inc. is not associated with any product or vendor mentioned in this book.

Limit of Liability/Disclaimer of WarrantyIn view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. While the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.

Library of Congress Cataloging-in-Publication Data applied for:

ISBN: 9781119851011[set]

Cover Design: WileyCover Image: © UGREEN 3S/Shutterstock.com

PREFACE

Studies on absorption, distribution, metabolism, and elimination–toxicology (ADME–Tox) have progressed over the years to the point where they now play a major role in drug discovery and development. Until the late 1980s, the primary role of drug metabolism groups in the pharmaceutical industry was to provide ADME–Tox information to support the regulatory package. During the last decade, with the rapid rise in new molecular entities (NMEs) from combinatorial chemistry and high-throughput biological screening, there is an urgent need for the determination of the ADME properties of these NMEs at very early stages in the drug discovery pipeline in order to facilitate the selection of “ideal” drug candidates for further development. Back integration of key studies into the discovery phase has resulted in earlier identification of potential DM/PK and safety liabilities. This information aids in decision making and, in many instances, has been incorporated into criteria for compound advancement into the development phase. Given the need for earlier and more rapid evaluation of a larger number of compounds, drug metabolism scientists have developed and incorporated numerous novel approaches into early drug discovery. These include “humanized” in vitro-based cell systems, sophisticated automation, higher-throughput ADME assays and screens, ultrasensitive analytical technologies, and computational models in order to accelerate the examination of the drug metabolism pathways of their NMEs. The success of this approach is evident, as the number of failures due to DM/PK liabilities has dramatically decreased. Clearly, there is a growing need for improving and expanding education of students as well as current practitioners involved in investigations in these areas. The needs for continuing education in the rapidly expanding and dynamic area of ADME-Tox studies are not being met at the university level, and oftentimes this is being taught in a piece-meal fashion on the job in pharmaceutical industries.

Therefore, the goal of this book is to provide a systematic approach for the education of students at the university level, as well as younger researchers and scientists changing fields in the pharmaceutical industry to improve their knowledge of drug metabolism by presenting in-depth coverage of the drug disposition process, pharmacokinetic drug–drug interactions, theory, and evaluation approaches and improving the decision-making process used for the structural modification of drug candidates to reduce toxicity. ADME-Tox experts in the field from both industry and academia have joined forces and offered their time to write this book, introducing students to modern concepts and practices of ADME-Tox. This book provides basic training in the areas of drug metabolism and disposition, including training programs for students as well as new employees in the pharmaceutical industry. Mastery of the material in this text will allow them to apply state-of-the-art research tools to in vitro and in vivo metabolism studies and contribute greatly to their abilities to perform pharmaceutical research in support of industrial, academic, and regulatory agency needs. One emphasis of the current edition – as evident from the title – is to improve our understanding of drug metabolism and discovery in the context of cancer. Metabolic reprogramming, which is a hallmark of cancer, is a target of several existing and experimental drugs. This book will discuss the nature of metabolic reprogramming in cancer and its cross-talk with drug metabolism. It will also present strategies and tools for elucidation of heterogeneity in drug disposition and metabolism in tumors as well as for therapeutic personalization.

This textbook consists of five parts. Part I provides an introduction to drug metabolism. Part II presents the in vitro and in vivo technologies used to investigate the metabolism of drugs and drug candidates. Part III presents an important area of drug–drug interaction. Part IV discusses the toxicity of drugs and their metabolites. Part V of this volume provides an up-to-date series of chapters on the applications of drug metabolism in cancer. This book provides a unique and useful approach for all those involved in drug discovery and development, and for clinicians and researchers in drug metabolism, pharmacology, and clinical pharmacology.

The editors and contributing authors greatly appreciate the commitment of the publishers to make this book available to our scientific colleagues in developing countries to enhance their knowledge in the area of ADME-Tox and to help them in furthering their careers in this very important area of research. Finally, we thank our many colleagues worldwide who have contributed to the development of the knowledge and techniques described in this book. We feel very fortunate to be able to participate in an area of scientific pursuit in which cooperation and collaboration between investigators in industry, academic institutions, and regulatory agencies is so strongly encouraged and highly valued. Drug Metabolism Handbook is a comprehensive reference devoted to the current state of research on the impact of various disease states on drug metabolism. The book contains valuable insights into mechanistic effects and examples of how to accurately predict drug metabolism during these different pathophysiological states. Each chapter clearly presents the effects of changes in drug metabolism enzymes and drug transporters on the pharmacokinetics, disposition, and potential toxicity of NMEs.

ALA F. NASSAR

School of Medicine, Yale University, CT, USA

August 2022

LIST OF CONTRIBUTORS

Shibdas Banerjee, Department of Chemistry, Indian Institute of Science Education and Research Tirupati, Tirupati, India

Ganesh K. Barik, Molecular Oncology Laboratory, National Centre for Cell Science, Pune, Maharashtra, India

and

Department of Biotechnology, Savitribai Phule Pune University, Pune, Maharashtra, India

Craig Beavers, Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, Lexington, KY, USA

Praneeta P. Bhavsar, Proteomics Lab, National Centre for Cell Science, Pune, Maharashtra, India

and

Department of Biotechnology, Savitribai Phule Pune University, Pune, Maharashtra, India

Sherry-Ann Brown, Cardio-Oncology Program, Division of Cardiovascular Medicine, Medical College of Wisconsin, Milwaukee, WI, USA

Joe R. Cannon, Bristol Myers Squibb, Lawrenceville, NJ, USA

Purva S. Damale, Department of Chemistry, Indian Institute of Science Education and Research Tirupati, Tirupati, India

Carl Davis, Pharmacokinetics, Dynamics & Metabolism, Pfizer Inc., La Jolla, CA, USA

Gift Echefu, Department of Medicine, Baton Rouge General Medical Center, Baton Rouge, LA, USA

Olubadewa Fatunde, Division of Cardiology, Department of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, USA

Mark P. Grillo, Cytokinetics, South San Francisco, CA, USA

Umesh M. Hanumegowda, ViiV Healthcare, Branford, CT, USA

Paul F. Hollenberg, Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, MI, USA

Eli G. Hvastkovs, Department of Chemistry, East Carolina University, Greenville, NC, USA

Sun Min Jung, Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, USA

Bhargab Kalita, Proteomics Lab, National Centre for Cell Science, Pune, Maharashtra, India

and

Amrita School of Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Kochi, Kerala, India

Sailaja Kamaraju, Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA

Roberta S. King, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI, USA

Ivan King, Department of Clinical Operations, Hinova Pharmaceuticals Inc., San Diego, CA, USA

Lawrence H. Lash, Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, USA

Jiapeng Li, Department of Clinical Pharmacy, University of Michigan, Ann Arbor, MI, USA

Subhabrata Majumder, Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India

and

Homi Bhabha National Institute, Mumbai, India

Soumen Kanti Manna, Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India

and

Homi Bhabha National Institute, Mumbai, India

Meera Mohan, Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA

Ala F. Nassar, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, USA

Carolyn Oxencis, Department of Pharmacy, Froedtert and the Medical College of Wisconsin, Milwaukee, WI, USA

Debasish Prusty, Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India

and

Homi Bhabha National Institute, Mumbai, India

Srikanth Rapole, Proteomics Lab, National Centre for Cell Science, Pune, Maharashtra, India

Dan A. Rock, Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck, San Francisco, CA, USA

James F. Rusling, Department of Chemistry and Institute of Materials Science, University of Connecticut, Storrs, CT, USA

and

Department of Surgery, Uconn Health Center, Farmington, CT, USA

and

School of Chemistry, National University of Ireland, Arts and Science Building, University Rd, Galway, Ireland

Manas K. Santra, Molecular Oncology Laboratory, National Centre for Cell Science, Pune, Maharashtra, India

Tanisha Sharma, Molecular Oncology Laboratory, National Centre for Cell Science, Pune, Maharashtra, India

and

Department of Biotechnology, Savitribai Phule Pune University, Pune, Maharashtra, India

Thomas R. Sharp, Department of Chemistry and Chemical Engineering, Tagliatela College of Engineering, University of New Haven, West Haven, CT, USA

Logan S. Smith, Department of Clinical Pharmacy, University of Michigan, Ann Arbor, MI, USA

Khushman Taunk, Proteomics Lab, National Centre for Cell Science, Pune, Maharashtra, India

and

Department of Biotechnology, Maulana Abul Kalam Azad University of Technology, Haringhata, Nadia, West Bengal, India

Prakash Vachaspati, The Biocon Bristol Myers Squibb Research & Development Center, Bangalore, India

Brianna Wallace, School of Pharmacy, Medical College of Wisconsin, Milwaukee, WI, USA

Hongbing Wang, Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, USA

Jiaqi Wang, Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Cancer Center, Zhejiang University, Hangzhou, China

and

Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Hangzhou, China

Yingying Wang, Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Cancer Center, Zhejiang University, Hangzhou, China

and

Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Hangzhou, China

Yu Wang, Institute of Drug Metabolism