Oral Bioavailability and Drug Delivery

Ming Hu, PhD, is Professor of Pharmaceutics at the College of Pharmacy, University of Houston, Texas, USA.

Xiaoling Li, PhD, is Professor of Pharmaceutics at the TJL School of Pharmacy, University of the Pacific, California, USA.

List of Contributors xxix

Foreword xxxix

Preface xli

1 Barriers to Oral Bioavailability – An Overview 1
Ming Hu and Xiaoling li

1.1 Introduction 1

References 4

2 Solubility of Pharmaceutical Solids 5
Pramila Sharma, Yi Gao, Heran li, Bhaskara R. Jasti, Sanming li, and Xiaoling li

2.1 Introduction 5

2.2 Fundamentals of Solubility 6

2.3 Solubility and Oral Bioavailability 19

2.4 Strategies to Improve Solubility 21

2.5 Summary 24

Abbreviations 25

References 25

3 In Vitro Dissolution of Pharmaceutical Solids 31
Tze Ning Hiew and Paul W.S. Heng

3.1 Dissolution Theory and Fundamentals 31

3.2 Dissolution of Drug Products 34

3.3 In Vitro Dissolution Methods for Ensuring Quality of Commercial Drug Products 36

3.4 In Vitro Dissolution Methods in Product Development 38

3.5 Automation in Dissolution Testing and Prediction 40

3.6 Conclusions 42

References 42

4 Biological and Physiological Features of the Gastrointestinal Tract Relevant to Oral Drug Absorption 47
Paul C.L. Ho

4.1 Introduction 47

4.2 Biological Features of Gastrointestinal Tract 47

4.3 Physiological Features of Gastrointestinal Tract 51

4.4 Other Physiological Factors 54

4.5 Conclusion 56

References 56

5 Absorption of Drugs Via Passive Diffusion and Carrier-Mediated Pathways 61
Amit Kokate, Jae H. Chang, and Miki S. Park

Disclaimer 61

5.1 Introduction 61

5.2 Passive Diffusion 62

5.3 Carrier-Mediated Transport 67

5.4 Summary 75

References 75

6 Determinant Factors for Passive Absorption of Drugs 79
Wei Zhu and Mikolaj Milewski

6.1 Introduction 79

6.2 Fundamentals of Drug Absorption 79

6.3 Absorption Determining Factors 82

6.4 Rate Limiting Steps in Absorption and Prediction of Dosing Amount Absorbed 86

6.5 Overview of In Silico Prediction of Absorption and Pharmacokinetics for Oral Dosage Forms 88

6.6 Summary 89

References 90

7 Protein Binding and Drug Distribution 95
HaiAn Zheng and Marcel Musteata

7.1 Introduction 95

7.2 Protein–Drug Binding in Plasma 95

7.3 Modeling of Binding Equilibria 97

7.4 Bioanalytical Methods for Studying Drug–Protein Binding 98

7.5 Impact of Drug–Protein Binding on Pharmacokinetic Parameters 105

7.6 Physicochemical Factors that Affect Protein–Drug Binding and Drug Distribution 106

7.7 Physiological and Pathological Factors that Affect Protein–Drug Binding and Drug Distribution 107

References 107

8 Drug Transport Across the Placental Barrier 111
Valentina Bryant, Mansi Shah, Jennifer Waltz, and Erik Rytting

8.1 Introduction 111

8.2 Pharmacokinetics of Drugs Administered During Pregnancy 111

8.3 Placental Development and Structure 112

8.4 Functions of the Human Placenta 113

8.5 Mechanisms of Drug Transport Across the Placenta 114

8.6 Mechanisms of Drug Metabolism Within the Placenta 116

8.7 Strategies to Alter Drug Transport Across the Placenta 117

8.8 Experimental Models of the Human Placenta 118

References 122

9 Biopharmaceutics Classification System: Theory and Practice 131
Mehul Mehta, Jayabharathi Vaidyanathan, and Lawrence Yu

9.1 Introduction 131

9.2 Theory 131

9.3 BCS-based Biowaiver 134

9.4 BCS Waiver Case Studies 136

9.5 BCS: Additional Regulatory Applications 138

9.6 Summary 138

References 139

10 Effects of Food on Drug Absorption 141
Zhu Zhou, Venugopal P. Marasanapalle, Xiaoling Li, and Bhaskara R. Jasti

10.1 Introduction 141

10.2 Mechanisms of Food Effects 147

10.3 Prediction of Food Effects 149

10.4 Summary 149

Abbreviations 150

References 150

11 Drug Metabolism in Gastrointestinal Tract 155
Rashim Singh, Dinh Bui, and Ming Hu

11.1 Introduction 155

11.2 Role of Intestinal Efflux Transporters in the Drug Disposition 161

11.3 Drug Metabolism–Transporter Coupling in Drug Disposition in GIT 163

11.4 Factors Affecting Intestinal Drug Metabolism 168

11.5 Biopharmaceutics Drug Disposition Classification System 170

11.6 Metabolism-Based Drug–Drug and Drug–Natural Product Interactions 171

11.7 Metabolic Interactions Between Gut Microbiome and Drugs in GIT 173

11.8 Metabolism-Based Xenobiotic-Induced Toxicity 174

11.9 GIT Metabolism-Based Drug-Designing and Lead Optimization in Drug Development 174

11.10 Summary 175

Abbreviations 176

References 176

12 Liver Drug Metabolism 189
Ritika Kurian, Leslie T. Steen, and Hongbing Wang

12.1 Introduction 189

12.2 Hepatic Structure and Function 189

12.3 Phase I Drug Metabolism 191

12.4 Phase II Drug Metabolism 199

12.5 Novel Platforms for Drug Metabolism Studies 204

12.6 Drug Metabolism and Its Impact on Adverse Drug Reactions 205

12.7 Conclusion 207

References 207

13 Urinary Excretion of Drugs and Drug Reabsorption 213
Jessica T. Babic, Jack Cook, and Vincent H. Tam

13.1 Introduction 213

13.2 Kidney as an Eliminating Organ 213

13.3 Drug Transporters and Their Role in Renal Elimination 220

13.4 Renal Elimination and Bioavailability 222

13.5 Augmented Renal Clearance 227

References 228

14 Excretion of Drugs and Their Metabolites into the Bile 233
Song Gao, Imoh Etim, Robin Sunsong, Christabel Ebuzoeme, Ting Du, and Dinh Bui

14.1 Introduction 233

14.2 Anatomy and Physiology of the Liver and Biliary System 234

14.3 Biliary Excreted Drugs and Metabolites 235

14.4 Impact of Biliary Excretion on ADME and Pharmacokinetics 235

14.5 Hepatic Transporters Involved in Biliary Excretion 245

14.6 Factors Affecting Biliary Secretion 248

14.7 Biliary Excretion Research Models 250

14.8 Concluding Remarks 255

Abbreviations 255

References 255

15 Pharmacokinetic Behaviors of Orally Administered Drugs 267
Hamdah Al Nebaihi, Dion R. Brocks, Jaime A. Yáñez, Marcus Laird Forrest, and Neal M. Davies

Objectives 267

15.1 Introduction 267

15.2 Physicochemical Factors Affecting Oral Concentration Time Profiles 274

15.3 Physiological Factors Affecting Oral Concentration Time Profiles 281

15.4 Food-Effects and Oral Concentration Time Profiles 296

15.5 The Impact of the Lymphatic System on Oral Bioavailability 298

15.6 Summation 303

Abbreviations 304

References 304

16 In Vitro-In Vivo Correlations of Pharmaceutical Dosage Forms 315
Deliang Zhou and Yihong Qiu

16.1 Introduction 315

16.2 Categories of In Vitro-In Vivo Correlations 316

16.3 Convolution and Deconvolution 317

16.4 Development and Assessments of an IVIVC 321

16.5 Applications of an IVIVC 324

16.6 Challenges 325

16.7 Physiologically Based Biopharmaceutics Models (PBBM) 326

16.8 Summary 328

References 329

17 Advanced Concepts in Oral Bioavailability Research – An Overview 333
Baojian Wu, Min Chen, and Ming Hu

Abbreviations 336

References 336

18 Expression and Pharmaceutical Relevance of Intestinal Transporters 339
Melanie A. Felmlee, Michael Ng, and Annie Lee

18.1 Introduction 339

18.2 Intestinal Drug Transport 340

18.3 Uptake Transporters 341

18.4 Efflux Transporters 350

18.5 Summary 353

References 353

19 Amino Acid Transporters 361
Liping Wang, Xiaoyan Li, Mengdi Ying, Ming Hu, and Zhongqiu Liu

19.1 Introduction 361

19.2 Classification of Amino Acid Transporters and their Functions 364

19.3 Epithelial Amino Acid Transporters 372

19.4 Endothelial Amino Acid Transporters 378

19.5 Regulation of Amino Acid Transport 380

19.6 Conclusion 382

Abbreviations 382

References 383

20 Drug Transporters and Their Role in Absorption and Disposition of Peptides and Peptide-Based Pharmaceuticals 393
David J. Lindley, Stephen M. Carl, Dea Herrera-Ruiz, Li F. Pan, Lori B. Ward, Jonathan M.E. Goole, Olafur S. Gudmundsson, Matthew Behymer, and Gregory T. Knipp

20.1 Introduction 393

20.2 Transport Systems Mediating Peptide-based Pharmaceutical Absorption and Disposition: The Solute Carrier (SLC) Family 397

20.3 ATP Binding Cassette (ABC) Transporters 399

20.4 Gastrointestinal Tract-Specific Transporter Activity 400

20.5 Conclusions 407

Acknowledgments 408

References 408

21 OATP Transporters in Hepatic and Intestinal Uptake of Orally Administered Drugs 417
Wei Yue, Taleah Farasyn, Alexandra Crowe, Khondoker Alam, Lucila Garcia-Contreras, Yifan Tu, and Lu Wang

21.1 Introduction 417

21.2 Hepatic OATP1B1 and OATP1B 3 417

21.3 OATP2B1 in the Intestine 420

21.4 OATP1A2 in the intestine 421

21.5 Summary 422

Acknowledgement 422

References 422

22 ABC Transporters in Intestinal and Liver Efflux 429
Marilyn E. Morris and Tianjing Ren

22.1 Introduction 429

22.2 Apical Membrane Efflux Proteins 430

22.3 Basolateral/Lateral Membrane Efflux Proteins 442

22.4 Clinical Relevance of ABC Transporters in Oral Bioavailability of Drugs 444

22.5 Pharmacogenomics of ABC Transporters 445

22.6 Regulation of Efflux Transporters 445

22.7 Summary 446

Abbreviations 446

Acknowledgments 447

References 447

23 Interplay Between Metabolic Enzymes and Transporters 455
Zuoxu Xie, Lu Wang, Zicong Zheng, Yifan Tu, Yi Rong, Ming Hu, and Stephen Wang

23.1 Pathways and Functions of Drug Metabolic Enzymes and Transporters 455

23.2 Interplay Between Metabolic Enzymes and Transporters 462

23.3 Conclusion 467

References 468

24 Systemic Versus Local Bioavailability Enabled by Recycling 473
Yifan Tu, Lu Wang, and Ming Hu

24.1 Introduction 473

24.2 Systemic Bioavailability 473

24.3 Local Bioavailability 474

24.4 Factors Affecting Bioavailability 474

24.5 Enterohepatic Recycling (EHR) 475

24.6 Hepatoenteric Recycling (HER) 479

24.7 Enteroenteric Recycling (EER) 480

24.8 Summary 480

References 480

25 Intestinal Microbiome and Its Impact on Metabolism and Safety of Drugs 483
Xin Y. Chu and Paul C.L. Ho

25.1 Introduction 483

25.2 Direct Metabolism by Intestinal Microbiome 483

25.3 Indirect Mechanisms Affecting Drug Metabolism 489

25.4 Impact of Intestinal Microbiome on Drug Treatment in Clinical Practice 492

25.5 Conclusion and Future Perspectives 492

References 493

26 Drug–Drug Interactions and Drug–Dietary Chemical Interactions 501
Mengbi Yang, Yuanfeng Lyu, and Zhong Zuo

26.1 Introduction 501

26.2 Drug–Drug Interactions (DDIs) 501

26.3 Drug–Dietary Chemical Interactions in Oral Bioavailability 510

26.4 Summary 517

Abbreviations 517

References 518

27 Regulatory Considerations in Metabolism- and Transport-Based Drug Interactions 523
Xinning Yang, Sue-Chih Lee, Xinyuan Zhang, and Lei Zhang

Disclaimer 523

27.1 Overview of Drug–Drug Interactions 523

27.2 Regulatory Recommendations of DDI Studies 527

27.3 Highlights of the Final Guidances for Industry: In Vitro and Clinical Drug Interaction Studies – Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions 528

27.4 Role of Physiologically Based Pharmacokinetic (PBPK) Modeling in DDI Assessment 544

27.5 A Labeling Example to Illustrate the Translation of Complicated Drug Interaction Results to Labeling: Tipranavir 547

27.6 Examples to Illustrate the Use of PBPK in Supporting Labeling for Drugs that are Dual CYP3A/P-GP Substrates 549

27.7 Summary 549

Acknowledgement 550

References 550

28 Formulation Approaches to Improve Oral Bioavailability of Drugs 559
Zeren Wang, Chandan Bhugra, and Shun Chen

28.1 Introduction 559

28.2 Theoretical Considerations for Formulation Development of Poorly Water-Soluble Drugs 560

28.3 Formulation Considerations for the Development of Poorly Water-Soluble Drugs 563

28.4 Other Formulation Approaches 571

References 571

29 Lipid-Based and Self-Emulsifying Oral Drug Delivery Systems 575
Pushkaraj Wagh, Jonathan Moreno, Christopher Nayar, and Jeffrey Wang

29.1 Introduction 575

29.2 Lipid-based Drug Delivery Systems 575

29.3 Advantages and Limitations of Lipid-Based and Self-Emulsifying Drug Delivery Systems 586

29.4 Summary 586

References 586

30 Oral Delivery of Nanoparticles: Challenges and Opportunities 591
Qing Lin, Ling Zhang, and Zhirong Zhang

30.1 Introduction 591

30.2 Role of Nanoparticle Shape, Size, and Surface in Oral Delivery of Nanoparticles 592

30.3 Characterization Methods of Nanoparticles for Oral Delivery 593

30.4 State-of-the-Art Carriers Designed and Applied in Oral Delivery of Nanoparticles 594

30.5 Challenges and Coexisting Opportunities 594

References 595

31 Oral Delivery of Therapeutic Peptides: Strategies for Product Development 599
Puchun Liu

31.1 Introduction 599

31.2 Overview of Approaches to Enabling Oral Peptide Delivery 604

31.3 Observation and Data Analysis of Low BA with Large Variabilities 607

31.4 Recommended Strategies for Oral Peptide Product Development 609

Abbreviations 613

References 613

32 Prodrugs to Improve Oral Delivery 619
Arjun D. Patel, Shuchi Gupta, and Mamoun Alhamadsheh

32.1 Introduction 619

32.2 Factors Associated With Oral Drug Absorption 620

32.3 Intestinal Physiology and Background 620

32.4 Strategies to Improve the Bioavailability of Orally Administered Drugs 621

32.5 Prodrug Overview and Classification 622

32.6 Prodrug Strategies to Improve Aqueous Solubility 630

32.7 Prodrug Approaches for Enhancing Absorption 631

32.8 Prodrug Approaches for Targeting Enzymes 631

32.9 Prodrug Approaches for Targeting Membrane Transporters 632

32.10 Conclusion 633

Abbreviations 634

References 634

33 Gastroretentive Drug Delivery Systems 637
Vrushali Waknis and Ajit S. Narang

33.1 Introduction 637

33.2 Oral Drug Delivery – Challenges and Opportunities 637

33.3 Human Gastric Physiology Relevant to GRDDS Design 638

33.4 Technologies 639

33.5 New Drug Development Considerations 645

33.6 Commercial GRDDS Products and Investigational New Products 649

33.7 Future Outlook 653

Acknowledgments 654

References 654

34 Enhancing Oral Bioavailability Using 3D Printing Technology 657
Timothy Tracy, Senping Cheng, Lei Wu, Xin liu, and Xiaoling li

34.1 Introduction 657

34.2 3D Printing in Pharmaceutical Applications 657

34.3 Novel Tablet Structures Possible with 3D Printing 660

34.4 Application of 3D Printing in Oral Bioavailability Enhancement 663

34.5 Future Outlook for 3D Printing and Bioavailability Enhancement 672

34.6 Summary 673

References 673

35 Anatomical and Physiological Factors Affecting Oral Drug Bioavailability in Rats, Dogs, Monkeys, and Humans 677
Ayman El-Kattan

35.1 Introduction 677

35.2 Determinants of Oral Bioavailability 677

35.3 Summary 691

References 691

36 In Vivo Methods for Oral Bioavailability Studies 701
Ana Ruiz-Garcia and Marival Bermejo

36.1 Introduction 701

36.2 Factors that Affect Oral Availability 701

36.3 In Vivo Animal Techniques 706

36.4 Animals Used in Bioavailability Studies 706

36.5 General Considerations for Blood Sampling 708

36.6 Statistical Considerations for Data Handling. (AUC Calculations in Sparse Sampling Designs) 708

36.7 Practical Examples in Rat Model 709

36.8 Intestinal Perfusion (see also Chapter 42) 710

36.9 Mathematical Considerations 711

References 712

37 Caco-2 Cell Culture Model for Oral Drug Absorption 715
Kaustubh Kulkarni, Lu Wang, and Ming Hu

37.1 Introduction 715

37.2 Description 717

37.3 Utility 719

37.4 Recent Progress 720

37.5 Significance of Caco-2 Cell Culture Model in Drug Discovery and Development 722

37.6 Example 722

37.7 Concluding Remarks 727

References 727

38 OATP Overexpressed Cells and Their Use in Drug Uptake Studies 729
Lu Wang, Zuoxu Xie, Yifan Tu, and Ming Hu

38.1 Introduction to OATP Cell Assay 729

38.2 Materials 731

38.3 Methods 731

38.4 Data Analysis 732

38.5 Notes 733

References 735

39 Use of Human Intestinal and Hepatic Tissue Fractions and Microbiome as Models in Assessment of Drug Metabolism and its Impact on Oral Bioavailability 737
Hani Zaher and George Zhang

39.1 Introduction 737

39.2 Gastrointestinal Tract and Absorption (see Also Chapter 5) 737

39.3 Mechanisms of Drug Absorption and Concept of Oral Bioavailability (see also Chapters 4–6) 738

39.4 Intestinal Metabolism and Oral Bioavailability (see Also Chapter 11) 739

39.5 In Vitro Systems Applied to Assess Intestinal Metabolism 740

39.6 In Vitro Systems Applied to Assess Human Hepatic First-Pass Metabolism (see Also Chapter 12) 743

39.7 Long-Term Hepatocyte Culture and Slow Metabolizing Drug Candidate 745

39.8 Microbiome and Absorption: A New Perspective 747

39.9 Summary 748

Acknowledgments 748

Abbreviations 749

References 749

40 Liver Perfusion and Primary Hepatocytes for Studying Drug Metabolism and Metabolite Excretion 757
Paresh P. Chothe, Sean Xiaochun Zhu, Sandeepraj Pusalkar, Chuang Lu, and Cindy Xia

40.1 Introduction 757

40.2 Liver Perfusion 758

40.3 Primary Hepatocytes 762

40.4 Organ Perfusion Versus Hepatocyte Studies 771

40.5 Perspectives 772

Acknowledgements 772

Abbreviations 772

References 772

41 Determination of Regulation of Drug Metabolizing Enzymes and Transporters 779
Sergio C. Chai, Taosheng Chen, and Wen Xie

41.1 Introduction 779

41.2 In vivo Methods 779

41.3 In vitro Methods 784

41.4 Biochemical, Biophysical and Structural Analysis of NRs Using Purified Proteins 789

41.5 Conclusions 796

Acknowledgments 796

References 796

42 Intestinal Perfusion Methods for Oral Drug Absorptions 801
li li, Dinh Bui, Wei Zhu, and Eun-Jung (Zenobia) Jeong

42.1 Introduction 801

42.2 Application and Recent Development of the Intestinal Perfusion Method 801

42.3 Data Interpretation and Method Comparison 803

42.4 Common In Vitro Methods Studying Intestinal Permeability and Metabolism 803

42.5 Summary 807

42.6 Methodologies and Experimental Data Analysis 807

Acknowledgment 813

References 815

43 In Silico Prediction of Oral Drug Absorption 819
Jin Dong, Zhu Zhou, Yujuan Zheng, and Miki Susanto Park

43.1 Introduction 819

43.2 QSPR Modeling 819

43.3 PBPK Modeling 821

43.4 PBBM Modeling as a Subset of PBPK Modeling 823

43.5 Applications of PBPK/PBBM Modeling 824

43.6 PBPK Software 827

43.7 Summary 839

References 839

44 Computational Modeling of Drug Oral Bioavailability 843
Lon W.R. Fong, Beibei Huang, Rajan Chaudhari, and Shuxing Zhang

44.1 Introduction 843

44.2 Computational Modeling of Bioavailability 844

44.3 Conclusions 851

Acknowledgment 852

References 852

45 Blood–Brain Barrier Permeability Assessment for Small-Molecule Drug Discovery Using Computational Techniques 857
Yankang Jing and Xiang-Qun Xie

45.1 Introduction 857

45.2 Basic Principle of the BBB Permeation 857

45.3 Role of the BBB in Drug Delivery 858

45.4 Experimental Methods for Assessing BBB Permeability 858

45.5 Computational Method to Predict BBB Permeability 859

Abbreviations 867

References 867

Index 871