Oral Bioavailability and Drug Delivery E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Serie: Wiley series in drug discovery and development
• Sprache: Englisch

Seitenzahl: 2689

Veröffentlichungsjahr: 2024

Beschreibung

ORAL BIOAVAILABILITY AND DRUG DELIVERY Improve the performance and viability of newly-developed and approved drugs with this crucial guide Bioavailability is the parameter which measures the rate and extent to which a drug reaches a user's circulatory system depending on the method of administration. For example, intravenous administration produces a bioavailability of 100%, since the drugs are injected directly into the circulatory system; in the case of oral administration, however, bioavailability can vary widely based on factors which, if not properly understood, can result in a failure in drug development, adverse effects, and other complications. The mechanics of oral bioavailability are therefore critical aspects of drug development. Oral Bioavailability and Drug Delivery provides a comprehensive coverage of this subject as well as its drug development applications. Beginning with basic terminology and fundamental concepts, it provides a thorough understanding of the challenges and barriers to oral bioavailability as well as the possibilities for improving this parameter. The resulting book is an indispensable tool for drug development research. Oral Bioavailability and Drug Delivery readers will also find: * Discussion questions in many chapters to facilitate comprehension * Detailed discussion of topics including dissolution, absorption, metabolism, and more * Real-world examples of methods in actions throughout Oral Bioavailability and Drug Delivery is ideal for pharmaceutical and biotechnology scientists working in drug discovery and development; researchers in chemistry, biology, pharmacology, immunology, neuroscience, and other related fields; and graduate courses in drug development and delivery.

Leseprobe

Table of Contents

Cover

Table of Contents

Title Page

Copyright

Dedication

List of Contributors

Foreword

Preface

1 Barriers to Oral Bioavailability – An Overview

1.1 Introduction

References

2 Solubility of Pharmaceutical Solids

2.1 Introduction

2.2 Fundamentals of Solubility

2.3 Solubility and Oral Bioavailability

2.4 Strategies to Improve Solubility

2.5 Summary

Abbreviations

References

3

In Vitro

Dissolution of Pharmaceutical Solids

3.1 Dissolution Theory and Fundamentals

3.2 Dissolution of Drug Products

3.3

In Vitro

Dissolution Methods for Ensuring Quality of Commercial Drug Products

3.4

In Vitro

Dissolution Methods in Product Development

3.5 Automation in Dissolution Testing and Prediction

3.6 Conclusions

References

4 Biological and Physiological Features of the Gastrointestinal Tract Relevant to Oral Drug Absorption

4.1 Introduction

4.2 Biological Features of Gastrointestinal Tract

4.3 Physiological Features of Gastrointestinal Tract

4.4 Other Physiological Factors

4.5 Conclusion

References

5 Absorption of Drugs Via Passive Diffusion and Carrier-Mediated Pathways

Disclaimer

5.1 Introduction

5.2 Passive Diffusion

5.3 Carrier-Mediated Transport

5.4 Summary

References

6 Determinant Factors for Passive Absorption of Drugs

6.1 Introduction

6.2 Fundamentals of Drug Absorption

6.3 Absorption Determining Factors

6.4 Rate Limiting Steps in Absorption and Prediction of Dosing Amount Absorbed

6.5 Overview of In Silico Prediction of Absorption and Pharmacokinetics for Oral Dosage Forms

6.6 Summary

References

7 Protein Binding and Drug Distribution

7.1 Introduction

7.2 Protein–Drug Binding in Plasma

7.3 Modeling of Binding Equilibria

7.4 Bioanalytical Methods for Studying Drug–Protein Binding

7.5 Impact of Drug–Protein Binding on Pharmacokinetic Parameters

7.6 Physicochemical Factors that Affect Protein–Drug Binding and Drug Distribution

7.7 Physiological and Pathological Factors that Affect Protein–Drug Binding and Drug Distribution

References

8 Drug Transport Across the Placental Barrier

8.1 Introduction

8.2 Pharmacokinetics of Drugs Administered During Pregnancy

8.3 Placental Development and Structure

8.4 Functions of the Human Placenta

8.5 Mechanisms of Drug Transport Across the Placenta

8.6 Mechanisms of Drug Metabolism Within the Placenta

8.7 Strategies to Alter Drug Transport Across the Placenta

8.8 Experimental Models of the Human Placenta

References

9 Biopharmaceutics Classification System: Theory and Practice

9.1 Introduction

9.2 Theory

9.3 BCS-based Biowaiver

9.4 BCS Waiver Case Studies

9.5 BCS: Additional Regulatory Applications

9.6 Summary

References

10 Effects of Food on Drug Absorption

10.1 Introduction

10.2 Mechanisms of Food Effects

10.3 Prediction of Food Effects

10.4 Summary

Abbreviations

References

11 Drug Metabolism in Gastrointestinal Tract

11.1 Introduction

11.2 Role of Intestinal Efflux Transporters in the Drug Disposition

11.3 Drug Metabolism–Transporter Coupling in Drug Disposition in GIT

11.4 Factors Affecting Intestinal Drug Metabolism

11.5 Biopharmaceutics Drug Disposition Classification System

11.6 Metabolism-Based Drug–Drug and Drug–Natural Product Interactions

11.7 Metabolic Interactions Between Gut Microbiome and Drugs in GIT

11.8 Metabolism-Based Xenobiotic-Induced Toxicity

11.9 GIT Metabolism-Based Drug-Designing and Lead Optimization in Drug Development

11.10 Summary

Abbreviations

References

12 Liver Drug Metabolism

12.1 Introduction

12.2 Hepatic Structure and Function

12.3 Phase I Drug Metabolism

12.4 Phase II Drug Metabolism

12.5 Novel Platforms for Drug Metabolism Studies

12.6 Drug Metabolism and Its Impact on Adverse Drug Reactions

12.7 Conclusion

References

13 Urinary Excretion of Drugs and Drug Reabsorption

13.1 Introduction

13.2 Kidney as an Eliminating Organ

13.3 Drug Transporters and Their Role in Renal Elimination

13.4 Renal Elimination and Bioavailability

13.5 Augmented Renal Clearance

References

14 Excretion of Drugs and Their Metabolites into the Bile

14.1 Introduction

14.2 Anatomy and Physiology of the Liver and Biliary System

14.3 Biliary Excreted Drugs and Metabolites

14.4 Impact of Biliary Excretion on ADME and Pharmacokinetics

14.5 Hepatic Transporters Involved in Biliary Excretion

14.6 Factors Affecting Biliary Secretion

14.7 Biliary Excretion Research Models

14.8 Concluding Remarks

Abbreviations

References

15 Pharmacokinetic Behaviors of Orally Administered Drugs

15.1 Introduction

15.2 Physicochemical Factors Affecting Oral Concentration Time Profiles

15.3 Physiological Factors Affecting Oral Concentration Time Profiles

15.4 Food-Effects and Oral Concentration Time Profiles

15.5 The Impact of the Lymphatic System on Oral Bioavailability

15.6 Summation

Abbreviations

References

16

In Vitro

-

In Vivo

Correlations of Pharmaceutical Dosage Forms

16.1 Introduction

16.2 Categories of

In Vitro-In Vivo

Correlations

16.3 Convolution and Deconvolution

16.4 Development and Assessments of an IVIVC

16.5 Applications of an IVIVC

16.6 Challenges

16.7 Physiologically Based Biopharmaceutics Models (PBBM)

16.8 Summary

References

17 Advanced Concepts in Oral Bioavailability Research – An Overview

Abbreviations

References

18 Expression and Pharmaceutical Relevance of Intestinal Transporters

18.1 Introduction

18.2 Intestinal Drug Transport

18.3 Uptake Transporters

18.4 Efflux Transporters

18.5 Summary

References

19 Amino Acid Transporters

19.1 Introduction

19.2 Classification of Amino Acid Transporters and their Functions

19.3 Epithelial Amino Acid Transporters

19.4 Endothelial Amino Acid Transporters

19.5 Regulation of Amino Acid Transport

19.6 Conclusion

Abbreviations

References

20 Drug Transporters and Their Role in Absorption and Disposition of Peptides and Peptide-Based Pharmaceuticals

20.1 Introduction

20.2 Transport Systems Mediating Peptide-based Pharmaceutical Absorption and Disposition: The Solute Carrier (SLC) Family

20.3 ATP Binding Cassette (ABC) Transporters

20.4 Gastrointestinal Tract-Specific Transporter Activity

20.5 Conclusions

Acknowledgments

References

21 OATP Transporters in Hepatic and Intestinal Uptake of Orally Administered Drugs

21.1 Introduction

21.2 Hepatic OATP1B1 and OATP1B3

21.3 OATP2B1 in the Intestine

21.4 OATP1A2 in the intestine

21.5 Summary

Acknowledgement

References

22 ABC Transporters in Intestinal and Liver Efflux

22.1 Introduction

22.2 Apical Membrane Efflux Proteins

22.3 Basolateral/Lateral Membrane Efflux Proteins

22.4 Clinical Relevance of ABC Transporters in Oral Bioavailability of Drugs

22.5 Pharmacogenomics of ABC Transporters

22.6 Regulation of Efflux Transporters

22.7 Summary

Abbreviations

Acknowledgments

References

23 Interplay Between Metabolic Enzymes and Transporters

23.1 Pathways and Functions of Drug Metabolic Enzymes and Transporters

23.2 Interplay Between Metabolic Enzymes and Transporters

23.3 Conclusion

References

24 Systemic Versus Local Bioavailability Enabled by Recycling

24.1 Introduction

24.2 Systemic Bioavailability

24.3 Local Bioavailability

24.4 Factors Affecting Bioavailability

24.5 Enterohepatic Recycling (EHR)

24.6 Hepatoenteric Recycling (HER)

24.7 Enteroenteric Recycling (EER)

24.8 Summary

References

25 Intestinal Microbiome and Its Impact on Metabolism and Safety of Drugs

25.1 Introduction

25.2 Direct Metabolism by Intestinal Microbiome

25.3 Indirect Mechanisms Affecting Drug Metabolism

25.4 Impact of Intestinal Microbiome on Drug Treatment in Clinical Practice

25.5 Conclusion and Future Perspectives

References

26 Drug–Drug Interactions and Drug–Dietary Chemical Interactions

26.1 Introduction

26.2 Drug–Drug Interactions (DDIs)

26.3 Drug–Dietary Chemical Interactions in Oral Bioavailability

26.4 Summary

Abbreviations

References

27 Regulatory Considerations in Metabolism- and Transport-Based Drug Interactions

Disclaimer

27.1 Overview of Drug–Drug Interactions

27.2 Regulatory Recommendations of DDI Studies

27.3 Highlights of the Final Guidances for Industry:

In Vitro

and Clinical Drug Interaction Studies – Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions

27.4 Role of Physiologically Based Pharmacokinetic (PBPK) Modeling in DDI Assessment

27.5 A Labeling Example to Illustrate the Translation of Complicated Drug Interaction Results to Labeling: Tipranavir

27.6 Examples to Illustrate the Use of PBPK in Supporting Labeling for Drugs that are Dual CYP3A/P-GP Substrates

27.7 Summary

Acknowledgement

References

28 Formulation Approaches to Improve Oral Bioavailability of Drugs

28.1 Introduction

28.2 Theoretical Considerations for Formulation Development of Poorly Water-Soluble Drugs

28.3 Formulation Considerations for the Development of Poorly Water-Soluble Drugs

28.4 Other Formulation Approaches

References

29 Lipid-Based and Self-Emulsifying Oral Drug Delivery Systems

29.1 Introduction

29.2 Lipid-based Drug Delivery Systems

29.3 Advantages and Limitations of Lipid-Based and Self-Emulsifying Drug Delivery Systems

29.4 Summary

References

30 Oral Delivery of Nanoparticles: Challenges and Opportunities

30.1 Introduction

30.2 Role of Nanoparticle Shape, Size, and Surface in Oral Delivery of Nanoparticles

30.3 Characterization Methods of Nanoparticles for Oral Delivery

30.4 State-of-the-Art Carriers Designed and Applied in Oral Delivery of Nanoparticles

30.5 Challenges and Coexisting Opportunities

References

31 Oral Delivery of Therapeutic Peptides: Strategies for Product Development

31.1 Introduction

31.2 Overview of Approaches to Enabling Oral Peptide Delivery

31.3 Observation and Data Analysis of Low BA with Large Variabilities

31.4 Recommended Strategies for Oral Peptide Product Development

Abbreviations

References

32 Prodrugs to Improve Oral Delivery

32.1 Introduction

32.2 Factors Associated With Oral Drug Absorption

32.3 Intestinal Physiology and Background

32.4 Strategies to Improve the Bioavailability of Orally Administered Drugs

32.5 Prodrug Overview and Classification

32.6 Prodrug Strategies to Improve Aqueous Solubility

32.7 Prodrug Approaches for Enhancing Absorption

32.8 Prodrug Approaches for Targeting Enzymes

32.9 Prodrug Approaches for Targeting Membrane Transporters

32.10 Conclusion

Abbreviations

References

33 Gastroretentive Drug Delivery Systems

33.1 Introduction

33.2 Oral Drug Delivery – Challenges and Opportunities

33.3 Human Gastric Physiology Relevant to GRDDS Design

33.4 Technologies

33.5 New Drug Development Considerations

33.6 Commercial GRDDS Products and Investigational New Products

33.7 Future Outlook

Acknowledgments

References

34 Enhancing Oral Bioavailability Using 3D Printing Technology

34.1 Introduction

34.2 3D Printing in Pharmaceutical Applications

34.3 Novel Tablet Structures Possible with 3D Printing

34.4 Application of 3D Printing in Oral Bioavailability Enhancement

34.5 Future Outlook for 3D Printing and Bioavailability Enhancement

34.6 Summary

References

35 Anatomical and Physiological Factors Affecting Oral Drug Bioavailability in Rats, Dogs, Monkeys, and Humans

35.1 Introduction

35.2 Determinants of Oral Bioavailability

35.3 Summary

References

36

In Vivo

Methods for Oral Bioavailability Studies

36.1 Introduction

36.2 Factors that Affect Oral Availability

36.3

In Vivo

Animal Techniques

36.4 Animals Used in Bioavailability Studies

36.5 General Considerations for Blood Sampling

36.6 Statistical Considerations for Data Handling. (AUC Calculations in Sparse Sampling Designs)

36.7 Practical Examples in Rat Model

36.8 Intestinal Perfusion (see also Chapter 42)

36.9 Mathematical Considerations

References

37 Caco-2 Cell Culture Model for Oral Drug Absorption

37.1 Introduction

37.2 Description

37.3 Utility

37.4 Recent Progress

37.5 Significance of Caco-2 Cell Culture Model in Drug Discovery and Development

37.6 Example

37.7 Concluding Remarks

References

38 OATP Overexpressed Cells and Their Use in Drug Uptake Studies

38.1 Introduction to OATP Cell Assay

38.2 Materials

38.3 Methods

38.4 Data Analysis

38.5 Notes

References

39 Use of Human Intestinal and Hepatic Tissue Fractions and Microbiome as Models in Assessment of Drug Metabolism and its Impact on Oral Bioavailability

39.1 Introduction

39.2 Gastrointestinal Tract and Absorption (see Also Chapter 5)

39.3 Mechanisms of Drug Absorption and Concept of Oral Bioavailability (see also Chapters 4–6)

39.4 Intestinal Metabolism and Oral Bioavailability (see Also Chapter 11)

39.5

In Vitro

Systems Applied to Assess Intestinal Metabolism

39.6

In Vitro

Systems Applied to Assess Human Hepatic First-Pass Metabolism (see Also Chapter 12)

39.7 Long-Term Hepatocyte Culture and Slow Metabolizing Drug Candidate

39.8 Microbiome and Absorption: A New Perspective

39.9 Summary

Acknowledgments

Abbreviations

References

40 Liver Perfusion and Primary Hepatocytes for Studying Drug Metabolism and Metabolite Excretion

40.1 Introduction

40.2 Liver Perfusion

40.3 Primary Hepatocytes

40.4 Organ Perfusion Versus Hepatocyte Studies

40.5 Perspectives

Acknowledgements

Abbreviations

References

41 Determination of Regulation of Drug Metabolizing Enzymes and Transporters

41.1 Introduction

41.2 In vivo Methods

41.3 In vitro Methods

41.4 Biochemical, Biophysical and Structural Analysis of NRs Using Purified Proteins

41.5 Conclusions

Acknowledgments

References

42 Intestinal Perfusion Methods for Oral Drug Absorptions

42.1 Introduction

42.2 Application and Recent Development of the Intestinal Perfusion Method

42.3 Data Interpretation and Method Comparison

42.4 Common

In Vitro

Methods Studying Intestinal Permeability and Metabolism

42.5 Summary

42.6 Methodologies and Experimental Data Analysis

Acknowledgment

References

43 In Silico Prediction of Oral Drug Absorption

43.1 Introduction

43.2 QSPR Modeling

43.3 PBPK Modeling

43.4 PBBM Modeling as a Subset of PBPK Modeling

43.5 Applications of PBPK/PBBM Modeling

43.6 PBPK Software

43.7 Summary

References

44 Computational Modeling of Drug Oral Bioavailability

44.1 Introduction

44.2 Computational Modeling of Bioavailability

44.3 Conclusions

Acknowledgment

References

45 Blood–Brain Barrier Permeability Assessment for Small-Molecule Drug Discovery Using Computational Techniques

45.1 Introduction

45.2 Basic Principle of the BBB Permeation

45.3 Role of the BBB in Drug Delivery

45.4 Experimental Methods for Assessing BBB Permeability

45.5 Computational Method to Predict BBB Permeability

Abbreviations

References

Index

End User License Agreement

List of Tables

Chapter 2

Table 2.1 Terms of Approximate Solubility.

Table 2.2 Effects of various factors on solubility.

Table 2.3 Effect of pH and ionic strength on the solubility of weak electrol...

Table 2.4 Absorption limiting steps and conditions.

Table 2.5 Marketed products utilizing solubility-enhancement technologies.

Table 2.6 Brief introduction to formulation through other approaches.

Chapter 4

Table 4.1 The relative anatomical lengths and surface areas of various regio...

Table 4.2 Some metabolic reactions of the intestinal microflora and examples...

Chapter 5

Table 5.1 Various forms and the characteristics of solute movement in biolog...

Table 5.2 SLC transporter family members with known expression in GI tract....

Chapter 7

Table 7.1 Complex components of the blood plasma

Chapter 8

Table 8.1 Examples of hormones produced by the placenta and their main funct...

Chapter 9

Table 9.1

In vitro

–

in vivo

(IVIV) correlation expectations for immediate rel...

Table 9.2 Solubility data for example 1.

Chapter 10

Table 10.1 U.S. FDA label recommendations for usage of drugs based on known ...

Table 10.2 Examples of drugs known to exhibit food effects.

Table 10.3 Physicochemical and physiological differences in fed and fasted s...

Chapter 11

Table 11.1 Quantitative protein expression of CYPs and UGTs in human jejunum...

Table 11.2 Summary of the effect of nuclear receptor activation on target ge...

Table 11.3 Summary of the effect of nuclear receptor activation on target ge...

Table 11.4 Transporters effects predicted by BDDCS following oral dosing.

Chapter 12

Table 12.1 Summary of phase II enzymes and their cofactors

Chapter 13

Table 13.1 Anionic drug interactions and non-interactions for tubular secret...

Table 13.2 Cationic drug interactions and non-interactions for tubular secre...

Table 13.3 Amount of furosemide excreted following single oral administratio...

Table 13.4 Renal clearance and bioavailability of cimetidine after intraveno...

Chapter 14

Table 14.1 Drugs secreted into bile as parent compounds.

Table 14.2 Drugs secreted into the bile as metabolites.

Chapter 15

Table 15.1 Influence of changes in absorption (

k

a

) or elimination rate const...

Table 15.2 Particle size, disintegration time and dissolution rate of three ...

Table 15.3 Pharmacokinetic parameters following oral administration of danaz...

Table 15.4 Pharmacokinetics parameters of oral solution and nanocrystalline ...

Table 15.5 Comparison of oral formulations with and without cyclodextrin....

Table 15.6 Acetylation phenotypes and ethnicity.

Chapter 16

Table 16.1 Typical system definitions in linear system analysis for oral del...

Chapter 18

Table 18.1 Uptake transporter substrates and inhibitors.

Table 18.2 Efflux transporter substrates and inhibitors.

Chapter 19

Table 19.1 The currently known families of amino acid transporters in epithe...

Table 19.2 Amino acid transport systems and identified transporters in mamma...

Chapter 20

Table 20.1 Some families of relevant transporters affecting peptide-based dr...

Table 20.2 A partial list of therapeutic compounds that have been demonstrat...

Table 20.3 Classification of P-gp Inhibitors.

Chapter 22

Table 22.1 Substrates and inhibitors of ABC transporters in liver and intest...

Chapter 23

Table 23.1 Distribution of UGT isoforms at mRNA expression level.

Chapter 24

Table 24.1 Calculation of absolute bioavailability and relative bioavailabil...

Table 24.2 Factors that influence drug bioavailability.

Table 24.3 Drugs that undergo enterohepatic recycling.

Chapter 25

Table 25.1 Summary of impact of intestinal microbiome on drug pharmacokineti...

Chapter 26

Table 26.1 Summary of major pharmacokinetics drug–drug interactions in human...

Table 26.2 Summary of major dietary product with Drug–dietary chemical inter...

Chapter 27

Table 27.1 Examples of

in vivo

substrate, inhibitor, and inducer for specifi...

Table 27.2 Phase 2 enzymes.

Table 27.3 Selected human drug transporters, their locations, function, and ...

Table 27.4 Classification of strong, moderate, and weak perpetrators for CYP...

Table 27.5 Classification of sensitive and moderate sensitive substrate for ...

Table 27.6 Decision criteria recommended in the FDA final

in vitro

DDI guida...

Table 27.7 Effect of atazanavir on raltegravir [144].

Table 27.8 Drug interaction information in the APTIVUS labeling.

Table 27.9 Example of PBPK application in DDI assessment for CYP3A/P-gp dual...

Chapter 28

Table 28.1 Dissolution time of particles with different particle size and so...

Table 28.2 Estimation of maximum absorbable dose based on API solubility.

Table 28.3 Formulation development strategy to reduce the absorption barrier...

Chapter 29

Table 29.1 Lipid formulation classification system.

Table 29.2 Examples of commercial liposomal, emulsion, oil based suspension ...

Table 29.3 Examples of commercial SEDDS and SMEDDS products.

Chapter 31

Table 31.1 Commercially Available Oral Products of Therapeutic Peptides (NDA...

Table 31.2 Data analysis of observed small variability on

T

max

and large var...

Table 31.3 20 Most Common Amino Acids Commonly Found in Peptides.

Chapter 32

Table 32.1 Chemical structures and properties of approved orally administere...

Chapter 33

Table 33.1 Type of GRDDS and its

in vitro

assessment technique for gastroret...

Table 33.2 Commercial GRDDS-based products and investigational new products....

Table 33.3 Clinical trials (as of December 2020) utilizing gastroretentive m...

Chapter 35

Table 35.1 Comparison of the anatomical lengths of the intestinal tract and ...

Table 35.2 Comparison of the absolute surface areas and surface area of the ...

Table 35.3 The absorption of a set of hydrophilic drugs in rat, dog, and hum...

Chapter 36

Table 36.1A Adapted from FORBES: The best selling drugs in America (02.27.06...

Table 36.1B Top selling drugs in 2018.

Table 36.2 Animal size, blood volumes, and recommended dosing volumes.

Table 36.3 Comparative lengths of small intestine.

Table 36.4 Limit volumes and recovery periods.

Table 36.5 Total blood volumes and recommended maximum blood sample volumes ...

Table 36.6 Table 36.5 Summary of advantages and disadvantages of the various...

Chapter 37

Table 37.1 Origin and characteristics of different Caco-2 cell clones.

Table 37.2 Difference Percent Recovery of Naringenin and Percent Excretion o...

Chapter 38

Table 38.1 Examples of

in vitro

substrates and inhibitors of OATPs.

Table 38.2 Data calculation for rate of E

2

G uptake. Intracellular concentrat...

Table 38.3 Data calculation for rifampicin inhibition on E

2

G.

Chapter 42

Table 42.1 A typical bile sample analyst spreadsheet in rat intestinal perfu...

Table 42.2 A typical blood sample analyst spreadsheet in rat intestinal perf...

Table 42.3 A typical permeability calculation spreadsheet in rat intestinal ...

Chapter 43

Table 43.1 A summary of available software programs to calculate molecular d...

Table 43.2 A summary of available QSPR software programs to calculate ADME p...

Table 43.3 A summary of software programs to perform PBPK modeling and simul...

Table 43.4 Key physicochemical and pharmacokinetic parameters for lesinurad....

Table 43.5 Clinical studies used for model development and validation for le...

Table 43.6 Physicochemical and pharmacokinetic parameters of bosutinib used ...

Chapter 44

Table 44.1 A list of PBPK models with available software implementations.

Table 44.2 A list of examples of the types of machine learning models covere...

Chapter 45

Table 45.1 Commercial software for predicting BBB permeability.

Table 45.2 Free online tools for predicting BBB permeability.

Table 45.3 Summary of rule-based methods for predicting BBB permeability.

Table 45.4 Summary of traditional QSAR/QSPR methods for predicting BBB perme...

Table 45.5 Summary of machine learning methods for predicting BBB permeabili...

Table 45.6 Summary of deep-learning methods for predicting BBB permeability....

List of Illustrations

Chapter 1

Figure 1.1 Organ Bioavailability Barriers to Drugs. We depicted a diagram th...

Chapter 2

Figure 2.1 The dissolution process of crystal drug.

Figure 2.2 Relationship between particle size and solubility.

Figure 2.3 Relationship between solubility and lipophilicity of 80 drug or d...

Figure 2.4 Solubility versus pH.

Figure 2.5 Correlation between solubility, permeability, and dose.

Figure 2.6 Biopharmaceutics classification system and various approaches for...

Figure 2.7 Simplified drug absorption schematic.

Figure 2.8 Strategies used to enhance solubility of poorly water-soluble dru...

Figure 2.9 pH-Solubility Profile of a Weakly Acidic Drug, Flurbiprofen, with...

Chapter 3

Figure 3.1 Schematic representation of the dissolution process of a solid do...

Figure 3.2 (a) The spectrum of acetylsalicylic acid obtained using a UV prob...

Figure 3.3 The second-derivative spectra of acetylsalicylic acid (dotted lin...

Chapter 4

Figure 4.1 The gastrointestinal tract of humans.

Figure 4.2 Cross-sections of the proximal small intestine of humans. The sur...

Figure 4.3 Diagram of a typical intestinal epithelial cell (enterocyte). The...

Figure 4.4 Diagrammatic representation of an intestinal villus. The large bl...

Chapter 5

Figure 5.1 Schematic illustrating the paracellular and transcellular pathway...

Figure 5.2 A simplified model of diffusion across gastrointestinal membranes...

Figure 5.3 Schematic diagram of drug transport across a membrane.

k

's are ki...

Figure 5.4 Kinetics of passive diffusion compared to carrier-protein mediate...

Figure 5.5 Schematic showing select drug transporters expressed in the human...

Figure 5.6 Schematic of inverse rate versus inverse substrate concentration ...

Chapter 6

Figure 6.1 A schematic representation of permeation pathways across the inte...

Figure 6.2 General permeability–lipophilicity relationship in intestinal dru...

Chapter 7

Figure 7.1 A crystal structure of human serum albumin complexed with dansyl-

Figure 7.2 Crystal structure of human alpha1-acid glycoprotein (PDB 3KQ0)....

Chapter 8

Figure 8.1 Cross-sectional illustration of the human placenta near term.

Figure 8.2 Transport processes within the human placental barrier. It should...

Figure 8.3 The placenta-on-a-chip consists of two layers of poly(dimethylsil...

Chapter 9

Figure 9.1 The fraction of dose absorbed as function of the human effective ...

Chapter 10

Figure 10.1 Pharmacokinetic classification of food–drug interactions (food e...

Chapter 11

Figure 11.1

Relative expression levels of major CYPs (a), UGT (b), and SULT

...

Figure 11.2

Expression of efflux transporters on the apical and basolateral

...

Figure 11.3

Triple Recycling.

Parent drugs get absorbed and some percentage ...

Figure 11.4

“Double jeopardy” Theory.

The figure depicts the tra...

Figure 11.5

“Revolving door” Theory.

The figure depicts the tran...

Chapter 12

Figure 12.1 Diagram of liver microstructure. (a) The architecture of the liv...

Figure 12.2 Cytochrome P450s and the catalytic cycle. (a) The basic structur...

Figure 12.3 Reactive oxygen species. (a) The conversion of molecular oxygen ...

Figure 12.4 Acetaminophen metabolism. The metabolism of acetaminophen illust...

Figure 12.5 Human liver CYP isoforms. The major hepatic CYP isoforms involve...

Figure 12.6 Target genes of PXR, CAR, and AhR. On the left, PXR and CAR are ...

Figure 12.7 Micropatterned liver cell coculture model. Procedure for the dev...

Figure 12.8 Representation of a Liver Chip that recapitulates the cytoarchit...

Chapter 13

Figure 13.1 Structure of a nephron.

Figure 13.2 Estimation of renal clearance from plasma and urinary data. The ...

Figure 13.3 Semilogarithmic plot of the amount of the drug remaining to be e...

Figure 13.4 Relationship between the elimination rate constant (renal, nonre...

Figure 13.5 Relationship between excretion rate and plasma concentration for...

Figure 13.6 Relationship between the free fraction of a drug in plasma and t...

Figure 13.7 Relationship between the free fraction of a drug in plasma and t...

Figure 13.8 Relationship between excretion rate and plasma concentration for...

Figure 13.9 Major renal transporters involved in the renal secretion of drug...

Figure 13.10 Scatter plot of individual subjects' pregabalin renal clearance...

Chapter 14

Figure 14.1

Structures of hepatocytes and biliary system

. Two domains of hep...

Figure 14.2

PK profile of enterohepatic recycling compounds.

Multiple absorp...

Figure 14.3

Hepatic transporters.

Uptake and basolateral and apical efflux t...

Figure 14.4

SCH model

. Hepatocytes are clamped into two layers of collagen g...

Figure 14.5

SCH model with standard HBSS and Ca-free HBSS buffers

. Tight jun...

Figure 14.6

Intestinal perfusion model.

Drug solution is perfused through in...

Chapter 15

Figure 15.1 Schematic representation showing the interrelation between absor...

Figure 15.2 Concentration–time profile of zero-order and first-order reactio...

Figure 15.3 Concentration–time profile of zero-order and first-order reactio...

Figure 15.4 Mammillary pharmacokinetic compartment models;

where

, compartmen...

Figure 15.5 Physiologically based pharmacokinetic (PBPK) model incorporating...

Figure 15.6 Plasma concentration–time profile following oral administration....

Figure 15.7 Plasma concentration–time profile following an extravascular dos...

Figure 15.8 Mean plasma concentrations (± SD,

n

 = 6) of acamprosate after in...

Figure 15.9 Regression of relative absorbability of griseofulvin on log-spec...

Figure 15.10 Steady-state serum digoxin concentration after administration o...

Figure 15.11 Nonlinear least squares regression curve for plasma allopurinol...

Figure 15.12 Ketoconazole (a) and dipyridamole (b) plasma profile in dogs, p...

Figure 15.13 Theoretical plasma concentration–time curves of model formulati...

Figure 15.14 Comparison of mean plasma VPA concentration–time profiles durin...

Figure 15.15 Nonlinear least squares regression curve for mean pindolol conc...

Figure 15.16 Plasma concentration–time profile in two subjects following sin...

Figure 15.17 Compartmental model of drug metabolism.

Figure 15.18 Plasma concentration versus time curves of amiodarone (AM) and ...

Figure 15.19 Mean steady-state plasma-concentration–time curves of RIS (risp...

Figure 15.20 Serum concentrations of morphine after oral administration of 7...

Figure 15.21 Individual cimetidine plasma concentration (ng/ml) time profile...

Figure 15.22 Inhibitory effect of propantheline on paracetamol absorption in...

Figure 15.23 Mean serum alprazolam and its metabolite (4-OH and alpha OHALP)...

Figure 15.24 Plasma concentration–time profile of UK-81252 after oral admini...

Figure 15.25 Arithmetic mean ± SEM plasma concentration versus time profiles...

Figure 15.26 Mean (

n

 = 12) serum concentrations of sumatriptan after oral ad...

Figure 15.27 Plasma concentration–time curves of paclitaxel in female FVB wt...

Figure 15.28 Plasma concentration–time curves after oral administration of p...

Figure 15.29 Typical subject's plasma ranitidine concentration–time profiles...

Figure 15.30 (Mean ± SD) Ranitidine profiles in the absence (Control) and pr...

Figure 15.31 Mean plasma concentration time profile of veralipride (Closed c...

Figure 15.32 Serum concentration–time profiles of digoxin for three genotype...

Figure 15.33 Mean plasma concentration–time (± SEM) profile for isoniazid in...

Figure 15.34 Mean plasma concentration–time (± SEM) profile for acetyl isoni...

Figure 15.35 Whole blood cyclosporine concentration (mean values ± SE of the...

Figure 15.36 Mean plasma veparamil concentrations of control (

n

 = 6) and pre...

Figure 15.37 Serum veparamil enantiomers concentration–time profile in healt...

Figure 15.38 Mean (SEM) plasma concentrations of budesonide after Entocort c...

Figure 15.39 Geometric mean steady-state plasma concentration–time courses o...

Figure 15.40 Mean plasma concentration–time profile of solifenacin in health...

Figure 15.41 An individual patient's serum ibuprofen enantiomer concentratio...

Figure 15.42 Cefatrizine serum concentrations (mean ± SD, μg/ml) in 20 femal...

Figure 15.43 Mean ± SD plasma concentration versus time profiles of halofant...

Figure 15.44 The target sites in enterocytes of the small intestine for vari...

Figure 15.45 Mean serum concentrations versus time graph for amiodarone in 1...

Figure 15.46 Simulated effects of lymphatic absorption on the concentration ...

Chapter 16

Figure 16.1 Illustration of the Superposition Principle.

Figure 16.2 Illustration of some system definitions in linear system analysi...

Figure 16.3 Illustration of point-area convolution with unequal time steps....

Figure 16.4 Illustration of the two-stage approach for IVIVC.

Figure 16.5 Dissolution space for anticipated bioequivalence to lesinurad IR...

Chapter 17

Figure 17.1

Examples of advanced concepts in oral bioavailability research

. ...

Chapter 18

Figure 18.1 Intestinal localization of ABC and SLC transporters. Uptake tran...

Chapter 19

Figure 19.1 The illustration depicts renal reabsorption of cationic amino ac...

Figure 19.2 Intestinal absorption of amino acids. The inwardly directed Na

+

...

Figure 19.3 The amino acid transporters that are upregulated in cancer and t...

Figure 19.4 The possible relationship between

L

-arginine transporter via sys...

Chapter 20

Figure 20.1 A representative depiction of a number of transporters expressed...

Chapter 22

Figure 22.1 ABC transporters in the intestine. Drug in the gut lumen can ent...

Figure 22.2 ABC transporters in the hepatocyte. ABCB1, ABCB4, ABCB11, ABCC2,...

Chapter 23

Figure 23.1 Schematic representation of the double jeopardy theory. Substrat...

Figure 23.2 Schematic representation of the revolving door theory. Substrate...

Figure 23.3 The pictorial representation of recycling of raloxifene in which...

Figure 23.4 The pictorial representation of recycling of icaritin in which e...

Chapter 24

Figure 24.1 Enterohepatic recycling (EHR) starts from hepatic metabolism, wh...

Figure 24.2 Hepatoenteric recycling (HER) starts from intestinal metabolism,...

Figure 24.3 Uptake and efflux transporters expressed in hepatocytes. This fi...

Figure 24.4 Uptake and efflux transporters are expressed in enterocytes. Thi...

Chapter 25

Figure 25.1 Metabolism of the prodrugs sulfasalazine, olsalazine, and balsal...

Figure 25.2 Metabolism of active digoxin to inactive dihydrodigoxin by

cgr

i...

Figure 25.3 Schematic conversion pathway of levodopa by gut bacterial enzyme...

Figure 25.4 Decrease in intestinal toxic effects of diclofenac, indomethacin...

Figure 25.5 Microbial metabolite,

p

-cresol, competes with acetaminophen for ...

Chapter 26

Figure 26.1 Major pharmacokinetics based DDI and HDI pathways illustrated in...

Chapter 27

Figure 27.1 Hypothetical exposure–response relationship. determination of a ...

Figure 27.2 FDA DDI guidance history.

Figure 27.3 CYP-based drug–drug interaction studies decision framework.

Figure 27.4 Evaluation of an Investigational Drug as a Substrate of Transpor...

Figure 27.5 Evaluation of an investigational drug as an inhibitor of P-gp or...

Figure 27.6 Evaluation of an Investigational Drug as an Inhibitor of OATP1B1...

Figure 27.7 Evaluation of an Investigational Drug as an Inhibitor of OAT1, O...

Chapter 28

Figure 28.1 Illustration of concentration profiles of API during its dissolu...

Figure 28.2 Schematic diagram of a hammer mill.

Figure 28.3 Spring and Parachute effect showing the effect of polymer on dru...

Figure 28.4 Ishikawa diagram showing factors impacting the quality of spray-...

Figure 28.5 Ishikawa diagram showing factors impacting the hot-melt extruded...

Chapter 29

Figure 29.1 Illustration of emulsion formation in aqueous media.

Figure 29.2 Illustration of absorption of lipid-based drug formulations.

Chapter 30

Figure 30.1 Challenges and barriers affecting oral drug delivery.

Chapter 31

Figure 31.1 A diagram of human GIT (stomach, small intestine, and colon), la...

Figure 31.2 A representative PK profile of oral peptide products in human an...

Chapter 32

Figure 32.1 Factors associated with oral drug absorption.

Figure 32.2 Classification of prodrugs and concept for their

in vivo

bioacti...

Chapter 33

Figure 33.1 Anatomical compartments of the human stomach.

Figure 33.2 Four phases of MMC; phase III is considered to be the most inten...

Figure 33.3 Correlation between gastric retention time and calorie content o...

Figure 33.4 Different technologies available for development of GRDDS and th...

Figure 33.5 Location of the tablet in the stomach of a healthy volunteer. In...

Figure 33.6 GI tract transit in a subject as per magnetic moment monitoring....

Figure 33.7 Accordion Pill technology.

Figure 33.8 Lyndra's stellate dosage form offering gastroretention by floata...

Chapter 34

Figure 34.1 Illustration of various types of 3D printing technology, includi...

Figure 34.2 (a) Rendered images of caplet designs with decreasing channel si...

Figure 34.3 (a) Design A: Multilayered drug compartment in core–shell struct...

Figure 34.4

In vitro

and

in vivo

studies of MED™ 3D printed Design B tofacit...

Figure 34.5 (a) Schematic drawing and photographs of SEDDS-loaded pulsatile ...

Figure 34.6 Digital images of results from the tablet design attempt for 3DP...

Figure 34.7 Plasma level–time curves for glimepiride (a) and rosuvastatin (b...

Figure 34.8 In vitro release of glimepiride from (a) the prepared 3D-printed...

Figure 34.9 Mean plasma concentration versus time profiles for BBR after ora...

Figure 34.10 The schematic drawing of gastro-retentive tablet with an air ch...

Figure 34.11 (a) The structure of the gastro-retentive (GR) system. The nove...

Figure 34.12 Drug release profiles of the formulations used in the experimen...

Figure 34.13 Apparent permeability coefficients (Papp) of CPT-loaded micelle...

Figure 34.14 (a) Design of various tablets: (A) Caps, base, shell, and infil...

Chapter 35

Figure 35.1 Comparative bulk pH across the gastrointestinal tract of rat, do...

Chapter 36

Figure 36.1 Different carrier-mediated transporters are expressed in the lip...

Figure 36.2 Cartoon representing a ported animal dosed and undergoing sequen...

Figure 36.3 Example of average plasma time profiles in rat obtained after or...

Figure 36.4 Scheme of the intestinal perfusion technique.

Chapter 37

Figure 37.1 A schematic of the Caco-2 cell culture model.

Figure 37.2 Multiple pathways for intestinal absorption of a compound: (1) p...

Figure 37.3 Caco-2 cell transport: Experimental, cell, and analytical instru...

Figure 37.4 Summary of Naringenin (10 μM) transport Experiment in Caco-2 cel...

Figure 37.5 Apical and Basolateral Transport of Naringenin and Naringenin Gl...

Figure 37.6 Difference in Transport of Naringenin and Naringenin Glucuronide...

Chapter 38

Figure 38.1 Michaelis–Menten Fitting curve of E

2

G. Substrate (E

2

G) concentra...

Figure 38.2 Rifampicin inhibition curve on E

2

G. Substrate (E

2

G) concentratio...

Chapter 40

Figure 40.1

Localization of hepatobiliary transporters in hepatocytes. ABC t

...

Figure 40.2 Metabolism of diflunisal using rat liver perfusion

Figure 40.3 Morphologic changes in sandwich-cultured cryopreserved human hep...

Figure 40.4

Flowchart of the hepatocyte uptake study.

Prior to the uptake st...

Figure 40.5

Working model of sandwich-cultured hepatocytes.

Because depletio...

Figure 40.6

Fluorescence and phase-contrast micrographs of hepatocytes treat

...

Chapter 41

Figure 41.1 Domain structure of nuclear receptors. Nuclear receptors are com...

Figure 41.2 Strategies to create the loss-of-function knockout, gain-of-func...

Figure 41.3 Creation of PXR null mice. (a) Restriction map of the PXR gene a...

Figure 41.4 Creation of PXR transgenic mice. (a). Schematic representation o...

Figure 41.5 Creation of transgenic mice that harbor conditional expression o...

Figure 41.6 Drug response profile in the humanized mice. Mice with indicated...

Figure 41.7 Semiquantitative RT-PCR analysis on the expression of steroidoge...

Figure 41.8 Real-time PCR analysis on liver RNA derived from the vehicle- an...

Figure 41.9 Induction of UGT1A expression by PXR activation. Liver microsome...

Figure 41.10 S20 induces the expression of drug-metabolizing enzymes and tra...

Figure 41.11 Cd36 is a direct transcriptional target of PXR. (a), the partia...

Figure 41.12 Overview of a typical pipeline needed to characterize purified ...

Figure 41.13 Illustration of time-resolved fluorescence energy transfer (TR-...

Figure 41.14 Illustration of the principles of protein thermal shift assay a...

Figure 41.15 Schematic representation of a typical HTS process. Following as...

Chapter 42

Figure 42.1 Typical flow chart of intestinal perfusion steps.

Figure 42.2 Four-site rat intestinal perfusion.

Chapter 43

Figure 43.1 A general schematic of a whole body PBPK model.

Figure 43.2 Various oral absorption models.

Figure 43.3 Approaches for building “safe space.”

Figure 43.4 A schematic graph of the advanced compartmental absorption and t...

Figure 43.5 The schematic graph shows the mechanism of lysosomal trapping of...

Figure 43.6 Structure of lesinurad.

Figure 43.7 (a) Modeling strategy. (b) verification of fitted particle size ...

Figure 43.8 Reported (squares) and simulated (lines) mean plasma concentrati...

Figure 43.9 Schematic representation of the ADAM model.

Figure 43.10 Observed and PBPK model-predicted bosutinib's plasma concentrat...

Figure 43.11 Observed and PBPK model-predicted bosutinib's plasma concentrat...

Chapter 44

Figure 44.1 A scheme of Dressman and Fleisher's mixing-tank model, which mod...

Figure 44.2 A simplified CAT model. Compared to the mixing-tank model, which...

Chapter 45

Figure 45.1 General pathway across the BBB. The transport of small molecules...

Figure 45.2 Survey on BBB permeability modeling-related publications by SciF...

Figure 45.3 Overview of rule-based methods for predicting BBB permeability....

Figure 45.4 Overview of traditional QSAR/QSPR methods for predicting BBB per...

Figure 45.5 Overview of machine-learning-based methods for predicting BBB pe...

Figure 45.6 Overview of deep-learning methods for predicting BBB permeabilit...

Guide

Cover

Title Page

Copyright

Dedication

List of Contributors

Foreword

Preface

Table of Contents

Begin Reading

Index

End User License Agreement

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Wiley Series in Drug Discovery and Development

Binghe Wang, Series Editor

Drug Delivery: Principles and ApplicationsEdited by Binghe Wang, Teruna Siahaan, and Richard A. Soltero

Computer Applications in Pharmaceutical Research and DevelopmentEdited by Sean Ekins

Glycogen Synthase Kinase-3 (GSK-3) and Its Inhibitors: Drug Discovery and DevelopmentEdited by Ana Martinez, Ana Castro, and Miguel Medina

Aminoglycoside Antibiotics: From Chemical Biology to Drug DiscoveryEdited by Dev P. Arya

Drug Transporters: Molecular Characterization and Role in Drug DispositionEdited by Guofeng You and Marilyn E. Morris

Drug-Drug Interactions in Pharmaceutical DevelopmentEdited by Albert P. Li

Dopamine Transporters: Chemistry, Biology, and PharmacologyEdited by Mark L. Trudell and Sari Izenwasser

Carbohydrate-Based Vaccines and ImmunotherapiesEdited by Zhongwu Guo and Geert-Jan Boons

ABC Transporters and Multidrug ResistanceEdited by Ahcène Boumendjel, Jean Boutonnat, and Jacques Robert

Drug Design of Zinc-Enzyme Inhibitors: Functional, Structural, and Disease ApplicationsEdited by Claudiu T. Supuran and Jean-Yves Winum

Kinase Inhibitor DrugsEdited by Rongshi Li and Jeffrey A. Stafford

Evaluation of Drug Candidates for Preclinical Development: Pharmacokinetics, Metabolism, Pharmaceutics, and ToxicologyEdited by Chao Han, Charles B. Davis and Binghe Wang

HIV-1 Integrase: Mechanism and Inhibitor DesignEdited by Nouri Neamati

Carbohydrate Recognition: Biological Problems, Methods, and ApplicationsEdited by Binghe Wang and Geert-Jan Boons

Chemosensors: Principles, Strategies, and ApplicationsEdited by Binghe Wang and Eric V. Anslyn

Medicinal Chemistry of Nucleic AcidsEdited by Li He Zhang, Zhen Xi, and Jyoti Chattopadhyaya

Plant Bioactives and Drug Discovery: Principles, Practice, and PerspectivesEdited by Valdir Cechinel Filho

Dendrimer-Based Drug Delivery Systems: From Theory to PracticeEdited by Yiyun Cheng

Cyclic-Nucleotide Phosphodiesterases in the Central Nervous System: From Biology to Drug DiscoveryEdited by Nicholas J. Brandon and Anthony R. West

Drug Transporters: Molecular Characterization and Role in Drug Disposition, 2ndEditionEdited by Guofeng You and Marilyn E. Morris

Drug Delivery: Principles and Applications, 2ndEditionEdited by Binghe Wang, Longqin Hu, and Teruna J. Siahaan

Carbon Monoxide in Drug Discovery: Basics, Pharmacology, and Therapeutic PotentialEdited by Binghe Wang and Leo E. Otterbein

Drug Transporters: Molecular Characterization and Role in Drug Disposition, Third EditionEdited by Guofeng You and Marilyn E. Morris

Hydrogen Sulfide: Chemical Biology Basics, Detection Methods, Therapeutic Applications, and Case Studies, First EditionEdited by Michael D. Pluth

Nucleic Acids in Medicinal Chemistry and Chemical Biology: Drug Development and Clinical Applications, First EditionEdited by Lihe Zhang, Xinjing Tang, Zhen Xi, and Jyoti Chattopadhyaya

Oral Bioavailability and Drug Delivery: From Basics to Advanced Concepts and Applications, First EditionEdited by Ming Hu and Xiaoling Li

Oral Bioavailability and Drug Delivery

From Basics to Advanced Concepts and Applications

Edited by

Ming Hu

University of Houston, Houston, TX, USA

Xiaoling Li

University of the Pacific, TJ Long School of Pharmacy, Stockton, CA, USA

Copyright © 2024 by John Wiley & Sons, Inc. All rights reserved.

Published by John Wiley & Sons, Inc., Hoboken, New Jersey.Published simultaneously in Canada.

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Library of Congress Cataloging-in-Publication Data:

Names: Hu, Ming, Ph. D., editor. | Li, Xiaoling, Ph. D., editor.

Title: Oral Bioavailability and Drug Delivery : from basics to advanced concepts and applications / edited by Ming Hu and Xiaoling Li.

Other titles: Wiley series in drug discovery and development.

Description: Hoboken, New Jersey : John Wiley & Sons, Inc., [2024] | Series: Wiley series in drug discovery and development | Includes bibliographical references and index.

Identifiers: LCCN 2023018561 (print) | LCCN 2023018562 (ebook) | ISBN 9781119660651 (cloth) | ISBN 9781119660668 (adobe pdf) | ISBN 9781119660682 (epub)

Subjects: MESH: Biological Availability | Administration, Oral | Drug Development | Pharmacokinetics

Classification: LCC RS420 (print) | LCC RS420 (ebook) | NLM QV 38 | DDC 615.1/9–dc23/eng/20230829

LC record available at https://lccn.loc.gov/2023018561

LC ebook record available at https://lccn.loc.gov/2023018562

Cover design: WileyCover Images: © La Gorda/Shutterstock (Human digestive system); © Tridsanu Thopet/Shutterstock (falling capsules medication); © Dan Thornberg/Shutterstock (Basketball sitting on a rim with net); © Jenner Images/Getty Images (Falling white pills with one pink pill in mid air)

Dedicated to

My parents, Bailing Li and Jie Hu, for giving me life

My grandmother, Yunzhi Su, for raising me

My wife, Xinghang Ma, and sons, Richard and Louis, for their unconditional love, encouragement, and understanding.

Xiaoling Li

Dedicated to

My parents, Zhengye Hu and Qihua Chang, for Their Encouragement and Praise

My wife, Yanping Wang, for Her Love and Companionship

My daughter and son, Vivian and William, for Becoming Great Adults

My grandchildren, Stella and Arthur, for Bringing Joy and Continuing the Legacy

Ming Hu

List of Contributors

Khondoker AlamDepartment of Pharmaceutical SciencesUniversity of Oklahoma Health Sciences Center College of PharmacyOklahoma, OKUSA

Mamoun AlhamadshehDepartment of Pharmaceutics & Medicinal ChemistryThomas J. Long School of PharmacyUniversity of the PacificStockton, CAUSA

Jessica T. BabicDepartment of PharmacyMemorial Hermann-Texas Medical CenterHouston, TXUSA

Matthew BehymerDepartment of Industrial and Physical PharmacyCollege of PharmacyPurdue UniversityWest Lafayette, INUSA

Marival BermejoDepartment of Engineering: Pharmacy and Pharmaceutical Technology SectionSchool of PharmacyUniversidad Miguel Hernández de ElcheElcheAlicanteSpain

Chandan BhugraGlaxoSmithKlineCollegeville, PAUSA

Dion R. BrocksFaculty of Pharmacy and Pharmaceutical SciencesUniversity of AlbertaAlbertaCanada

Valentina BryantDepartment of Obstetrics and GynecologyUniversity of Texas Medical BranchGalveston, TXUSA

Dinh BuiDepartment of Pharmacological and Pharmaceutical SciencesCollege of PharmacyUniversity of HoustonHouston, TXUSA

Stephen M. CarlDepartment of Industrial and Physical PharmacyCollege of PharmacyPurdue UniversityWest Lafayette, INUSA

and

Bristol-Myers Squibb Research InstituteDiscovery PharmaceuticsPrinceton, NJUSA

Sergio C. ChaiDepartment of Chemical Biology and TherapeuticsSt. Jude Children's Research HospitalMemphis, TNUSA

Jae H. ChangExelixisAlameda, CAUSA

Rajan ChaudhariIntelligent Molecular Discovery LaboratoryDepartment of Experimental TherapeuticsThe University of Texas MD Anderson Cancer CenterHouston, TXUSA

Min ChenResearch Center for Biopharmaceutics and PharmacokineticsCollege of PharmacyJinan UniversityGuangzhouChina

Shun ChenShenzhen Pharmacin Co., LtdShenzhenChina

Taosheng ChenDepartment of Chemical Biology and TherapeuticsSt. Jude Children's Research HospitalMemphis, TNUSA

Senping ChengTriastek, Inc.NanjingJiangsuChina

Paresh P. ChotheGlobal Drug Metabolism and PharmacokineticsTakeda Development Center Americas, Inc. (TDCA)Lexington, MAUSA

Xin Y. ChuDepartment of PharmacyFaculty of ScienceNational University of SingaporeSingaporeSingapore

Jack CookClinical PharmacologyPfizer Inc.East Lyme, CTUSA

Alexandra CroweDepartment of Pharmaceutical SciencesUniversity of Oklahoma Health Sciences Center College of PharmacyOklahoma, OKUSA

Neal M. DaviesFaculty of Pharmacy and Pharmaceutical SciencesUniversity of AlbertaAlbertaCanada

Jin DongClinical Pharmacology and Quantitative PharmacologyClinical Pharmacology and Safety Sciences, R&DAstraZenecaGaithersburg, MDUSA

Ting DuDepartment of Pharmaceutical SciencesCollege of Pharmacy and Health SciencesTexas Southern UniversityHouston, TXUSA

Christabel EbuzoemeDepartment of Pharmaceutical SciencesCollege of Pharmacy and Health SciencesTexas Southern UniversityHouston, TXUSA

Ayman El-KattanIFM TherapeuticsBoston, MAUSA

Imoh EtimDepartment of Pharmaceutical SciencesCollege of Pharmacy and Health SciencesTexas Southern UniversityHouston, TXUSA

Taleah FarasynDepartment of Pharmaceutical SciencesUniversity of Oklahoma Health Sciences Center College of PharmacyOklahoma, OKUSA

Melanie A. FelmleeDepartment of Pharmaceutics and Medicinal ChemistryUniversity of the PacificThomas J. Long School of PharmacyStockton, CAUSA

Lon W.R. FongIntelligent Molecular Discovery LaboratoryDepartment of Experimental TherapeuticsThe University of Texas MD Anderson Cancer CenterHouston, TXUSA

Marcus Laird ForrestDepartment of Pharmaceutical ChemistrySchool of PharmacyUniversity of KansasLawrence, KSUSA

Song GaoDepartment of Pharmaceutical SciencesCollege of Pharmacy and Health SciencesTexas Southern UniversityHouston, TXUSA

Yi GaoAbbVie Inc.Formulation Sciences, Development Sciences, Research and DevelopmentNorth Chicago, ILUSA

Lucila Garcia-ContrerasDepartment of Pharmaceutical SciencesUniversity of Oklahoma Health Sciences Center College of PharmacyOklahoma, OKUSA

Jonathan M.E. GoolePharmacotherapy and Galenic Pharmacy Research DepartmentInstitute of PharmacyUniversite Libre de BruxellesBrusselsBelgium

Olafur S. GudmundssonBristol-Myers Squibb Research InstituteDiscovery PharmaceuticsPrinceton, NJUSA

Shuchi GuptaDepartment of Pharmaceutics & Medicinal ChemistryThomas J. Long School of PharmacyUniversity of the PacificStockton, CAUSA

Paul W.S. HengDepartment of PharmacyFaculty of ScienceNational University of SingaporeSingapore

Dea Herrera-RuizUniversidad Autónoma del Estado de MorelosFacultad de FarmaciaCuernavacaMexico

Tze Ning HiewDepartment of Pharmaceutical Sciences and Experimental TherapeuticsCollege of PharmacyUniversity of IowaIowa City, IAUSA

Paul C.L. HoDepartment of PharmacyFaculty of ScienceNational University of SingaporeSingaporeSingapore