Oral Bioavailability and Drug Delivery (eBook, PDF)
From Basics to Advanced Concepts and Applications
Redaktion: Hu, Ming; Li, Xiaoling
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Oral Bioavailability and Drug Delivery (eBook, PDF)
From Basics to Advanced Concepts and Applications
Redaktion: Hu, Ming; Li, Xiaoling
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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…mehr
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- Produktdetails
- Verlag: John Wiley & Sons
- Seitenzahl: 928
- Erscheinungstermin: 29. Dezember 2023
- Englisch
- ISBN-13: 9781119660668
- Artikelnr.: 69861394
- Verlag: John Wiley & Sons
- Seitenzahl: 928
- Erscheinungstermin: 29. Dezember 2023
- Englisch
- ISBN-13: 9781119660668
- Artikelnr.: 69861394
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
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