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 xxixForeword xxxixPreface xli1 Barriers to Oral Bioavailability – An Overview 1Ming Hu and Xiaoling li1.1 Introduction 1References 42 Solubility of Pharmaceutical Solids 5Pramila Sharma, Yi Gao, Heran li, Bhaskara R. Jasti, Sanming li, and Xiaoling li2.1 Introduction 52.2 Fundamentals of Solubility 62.3 Solubility and Oral Bioavailability 192.4 Strategies to Improve Solubility 212.5 Summary 24Abbreviations 25References 253 In Vitro Dissolution of Pharmaceutical Solids 31Tze Ning Hiew and Paul W.S. Heng3.1 Dissolution Theory and Fundamentals 313.2 Dissolution of Drug Products 343.3 In Vitro Dissolution Methods for Ensuring Quality of Commercial Drug Products 363.4 In Vitro Dissolution Methods in Product Development 383.5 Automation in Dissolution Testing and Prediction 403.6 Conclusions 42References 424 Biological and Physiological Features of the Gastrointestinal Tract Relevant to Oral Drug Absorption 47Paul C.L. Ho4.1 Introduction 474.2 Biological Features of Gastrointestinal Tract 474.3 Physiological Features of Gastrointestinal Tract 514.4 Other Physiological Factors 544.5 Conclusion 56References 565 Absorption of Drugs Via Passive Diffusion and Carrier-Mediated Pathways 61Amit Kokate, Jae H. Chang, and Miki S. ParkDisclaimer 615.1 Introduction 615.2 Passive Diffusion 625.3 Carrier-Mediated Transport 675.4 Summary 75References 756 Determinant Factors for Passive Absorption of Drugs 79Wei Zhu and Mikolaj Milewski6.1 Introduction 796.2 Fundamentals of Drug Absorption 796.3 Absorption Determining Factors 826.4 Rate Limiting Steps in Absorption and Prediction of Dosing Amount Absorbed 866.5 Overview of In Silico Prediction of Absorption and Pharmacokinetics for Oral Dosage Forms 886.6 Summary 89References 907 Protein Binding and Drug Distribution 95HaiAn Zheng and Marcel Musteata7.1 Introduction 957.2 Protein–Drug Binding in Plasma 957.3 Modeling of Binding Equilibria 977.4 Bioanalytical Methods for Studying Drug–Protein Binding 987.5 Impact of Drug–Protein Binding on Pharmacokinetic Parameters 1057.6 Physicochemical Factors that Affect Protein–Drug Binding and Drug Distribution 1067.7 Physiological and Pathological Factors that Affect Protein–Drug Binding and Drug Distribution 107References 1078 Drug Transport Across the Placental Barrier 111Valentina Bryant, Mansi Shah, Jennifer Waltz, and Erik Rytting8.1 Introduction 1118.2 Pharmacokinetics of Drugs Administered During Pregnancy 1118.3 Placental Development and Structure 1128.4 Functions of the Human Placenta 1138.5 Mechanisms of Drug Transport Across the Placenta 1148.6 Mechanisms of Drug Metabolism Within the Placenta 1168.7 Strategies to Alter Drug Transport Across the Placenta 1178.8 Experimental Models of the Human Placenta 118References 1229 Biopharmaceutics Classification System: Theory and Practice 131Mehul Mehta, Jayabharathi Vaidyanathan, and Lawrence Yu9.1 Introduction 1319.2 Theory 1319.3 BCS-based Biowaiver 1349.4 BCS Waiver Case Studies 1369.5 BCS: Additional Regulatory Applications 1389.6 Summary 138References 13910 Effects of Food on Drug Absorption 141Zhu Zhou, Venugopal P. Marasanapalle, Xiaoling Li, and Bhaskara R. Jasti10.1 Introduction 14110.2 Mechanisms of Food Effects 14710.3 Prediction of Food Effects 14910.4 Summary 149Abbreviations 150References 15011 Drug Metabolism in Gastrointestinal Tract 155Rashim Singh, Dinh Bui, and Ming Hu11.1 Introduction 15511.2 Role of Intestinal Efflux Transporters in the Drug Disposition 16111.3 Drug Metabolism–Transporter Coupling in Drug Disposition in GIT 16311.4 Factors Affecting Intestinal Drug Metabolism 16811.5 Biopharmaceutics Drug Disposition Classification System 17011.6 Metabolism-Based Drug–Drug and Drug–Natural Product Interactions 17111.7 Metabolic Interactions Between Gut Microbiome and Drugs in GIT 17311.8 Metabolism-Based Xenobiotic-Induced Toxicity 17411.9 GIT Metabolism-Based Drug-Designing and Lead Optimization in Drug Development 17411.10 Summary 175Abbreviations 176References 17612 Liver Drug Metabolism 189Ritika Kurian, Leslie T. Steen, and Hongbing Wang12.1 Introduction 18912.2 Hepatic Structure and Function 18912.3 Phase I Drug Metabolism 19112.4 Phase II Drug Metabolism 19912.5 Novel Platforms for Drug Metabolism Studies 20412.6 Drug Metabolism and Its Impact on Adverse Drug Reactions 20512.7 Conclusion 207References 20713 Urinary Excretion of Drugs and Drug Reabsorption 213Jessica T. Babic, Jack Cook, and Vincent H. Tam13.1 Introduction 21313.2 Kidney as an Eliminating Organ 21313.3 Drug Transporters and Their Role in Renal Elimination 22013.4 Renal Elimination and Bioavailability 22213.5 Augmented Renal Clearance 227References 22814 Excretion of Drugs and Their Metabolites into the Bile 233Song Gao, Imoh Etim, Robin Sunsong, Christabel Ebuzoeme, Ting Du, and Dinh Bui14.1 Introduction 23314.2 Anatomy and Physiology of the Liver and Biliary System 23414.3 Biliary Excreted Drugs and Metabolites 23514.4 Impact of Biliary Excretion on ADME and Pharmacokinetics 23514.5 Hepatic Transporters Involved in Biliary Excretion 24514.6 Factors Affecting Biliary Secretion 24814.7 Biliary Excretion Research Models 25014.8 Concluding Remarks 255Abbreviations 255References 25515 Pharmacokinetic Behaviors of Orally Administered Drugs 267Hamdah Al Nebaihi, Dion R. Brocks, Jaime A. Yáñez, Marcus Laird Forrest, and Neal M. DaviesObjectives 26715.1 Introduction 26715.2 Physicochemical Factors Affecting Oral Concentration Time Profiles 27415.3 Physiological Factors Affecting Oral Concentration Time Profiles 28115.4 Food-Effects and Oral Concentration Time Profiles 29615.5 The Impact of the Lymphatic System on Oral Bioavailability 29815.6 Summation 303Abbreviations 304References 30416 In Vitro-In Vivo Correlations of Pharmaceutical Dosage Forms 315Deliang Zhou and Yihong Qiu16.1 Introduction 31516.2 Categories of In Vitro-In Vivo Correlations 31616.3 Convolution and Deconvolution 31716.4 Development and Assessments of an IVIVC 32116.5 Applications of an IVIVC 32416.6 Challenges 32516.7 Physiologically Based Biopharmaceutics Models (PBBM) 32616.8 Summary 328References 32917 Advanced Concepts in Oral Bioavailability Research – An Overview 333Baojian Wu, Min Chen, and Ming HuAbbreviations 336References 33618 Expression and Pharmaceutical Relevance of Intestinal Transporters 339Melanie A. Felmlee, Michael Ng, and Annie Lee18.1 Introduction 33918.2 Intestinal Drug Transport 34018.3 Uptake Transporters 34118.4 Efflux Transporters 35018.5 Summary 353References 35319 Amino Acid Transporters 361Liping Wang, Xiaoyan Li, Mengdi Ying, Ming Hu, and Zhongqiu Liu19.1 Introduction 36119.2 Classification of Amino Acid Transporters and their Functions 36419.3 Epithelial Amino Acid Transporters 37219.4 Endothelial Amino Acid Transporters 37819.5 Regulation of Amino Acid Transport 38019.6 Conclusion 382Abbreviations 382References 38320 Drug Transporters and Their Role in Absorption and Disposition of Peptides and Peptide-Based Pharmaceuticals 393David 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. Knipp20.1 Introduction 39320.2 Transport Systems Mediating Peptide-based Pharmaceutical Absorption and Disposition: The Solute Carrier (SLC) Family 39720.3 ATP Binding Cassette (ABC) Transporters 39920.4 Gastrointestinal Tract-Specific Transporter Activity 40020.5 Conclusions 407Acknowledgments 408References 40821 OATP Transporters in Hepatic and Intestinal Uptake of Orally Administered Drugs 417Wei Yue, Taleah Farasyn, Alexandra Crowe, Khondoker Alam, Lucila Garcia-Contreras, Yifan Tu, and Lu Wang21.1 Introduction 41721.2 Hepatic OATP1B1 and OATP1B 3 41721.3 OATP2B1 in the Intestine 42021.4 OATP1A2 in the intestine 42121.5 Summary 422Acknowledgement 422References 42222 ABC Transporters in Intestinal and Liver Efflux 429Marilyn E. Morris and Tianjing Ren22.1 Introduction 42922.2 Apical Membrane Efflux Proteins 43022.3 Basolateral/Lateral Membrane Efflux Proteins 44222.4 Clinical Relevance of ABC Transporters in Oral Bioavailability of Drugs 44422.5 Pharmacogenomics of ABC Transporters 44522.6 Regulation of Efflux Transporters 44522.7 Summary 446Abbreviations 446Acknowledgments 447References 44723 Interplay Between Metabolic Enzymes and Transporters 455Zuoxu Xie, Lu Wang, Zicong Zheng, Yifan Tu, Yi Rong, Ming Hu, and Stephen Wang23.1 Pathways and Functions of Drug Metabolic Enzymes and Transporters 45523.2 Interplay Between Metabolic Enzymes and Transporters 46223.3 Conclusion 467References 46824 Systemic Versus Local Bioavailability Enabled by Recycling 473Yifan Tu, Lu Wang, and Ming Hu24.1 Introduction 47324.2 Systemic Bioavailability 47324.3 Local Bioavailability 47424.4 Factors Affecting Bioavailability 47424.5 Enterohepatic Recycling (EHR) 47524.6 Hepatoenteric Recycling (HER) 47924.7 Enteroenteric Recycling (EER) 48024.8 Summary 480References 48025 Intestinal Microbiome and Its Impact on Metabolism and Safety of Drugs 483Xin Y. Chu and Paul C.L. Ho25.1 Introduction 48325.2 Direct Metabolism by Intestinal Microbiome 48325.3 Indirect Mechanisms Affecting Drug Metabolism 48925.4 Impact of Intestinal Microbiome on Drug Treatment in Clinical Practice 49225.5 Conclusion and Future Perspectives 492References 49326 Drug–Drug Interactions and Drug–Dietary Chemical Interactions 501Mengbi Yang, Yuanfeng Lyu, and Zhong Zuo26.1 Introduction 50126.2 Drug–Drug Interactions (DDIs) 50126.3 Drug–Dietary Chemical Interactions in Oral Bioavailability 51026.4 Summary 517Abbreviations 517References 51827 Regulatory Considerations in Metabolism- and Transport-Based Drug Interactions 523Xinning Yang, Sue-Chih Lee, Xinyuan Zhang, and Lei ZhangDisclaimer 52327.1 Overview of Drug–Drug Interactions 52327.2 Regulatory Recommendations of DDI Studies 52727.3 Highlights of the Final Guidances for Industry: In Vitro and Clinical Drug Interaction Studies – Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions 52827.4 Role of Physiologically Based Pharmacokinetic (PBPK) Modeling in DDI Assessment 54427.5 A Labeling Example to Illustrate the Translation of Complicated Drug Interaction Results to Labeling: Tipranavir 54727.6 Examples to Illustrate the Use of PBPK in Supporting Labeling for Drugs that are Dual CYP3A/P-GP Substrates 54927.7 Summary 549Acknowledgement 550References 55028 Formulation Approaches to Improve Oral Bioavailability of Drugs 559Zeren Wang, Chandan Bhugra, and Shun Chen28.1 Introduction 55928.2 Theoretical Considerations for Formulation Development of Poorly Water-Soluble Drugs 56028.3 Formulation Considerations for the Development of Poorly Water-Soluble Drugs 56328.4 Other Formulation Approaches 571References 57129 Lipid-Based and Self-Emulsifying Oral Drug Delivery Systems 575Pushkaraj Wagh, Jonathan Moreno, Christopher Nayar, and Jeffrey Wang29.1 Introduction 57529.2 Lipid-based Drug Delivery Systems 57529.3 Advantages and Limitations of Lipid-Based and Self-Emulsifying Drug Delivery Systems 58629.4 Summary 586References 58630 Oral Delivery of Nanoparticles: Challenges and Opportunities 591Qing Lin, Ling Zhang, and Zhirong Zhang30.1 Introduction 59130.2 Role of Nanoparticle Shape, Size, and Surface in Oral Delivery of Nanoparticles 59230.3 Characterization Methods of Nanoparticles for Oral Delivery 59330.4 State-of-the-Art Carriers Designed and Applied in Oral Delivery of Nanoparticles 59430.5 Challenges and Coexisting Opportunities 594References 59531 Oral Delivery of Therapeutic Peptides: Strategies for Product Development 599Puchun Liu31.1 Introduction 59931.2 Overview of Approaches to Enabling Oral Peptide Delivery 60431.3 Observation and Data Analysis of Low BA with Large Variabilities 60731.4 Recommended Strategies for Oral Peptide Product Development 609Abbreviations 613References 61332 Prodrugs to Improve Oral Delivery 619Arjun D. Patel, Shuchi Gupta, and Mamoun Alhamadsheh32.1 Introduction 61932.2 Factors Associated With Oral Drug Absorption 62032.3 Intestinal Physiology and Background 62032.4 Strategies to Improve the Bioavailability of Orally Administered Drugs 62132.5 Prodrug Overview and Classification 62232.6 Prodrug Strategies to Improve Aqueous Solubility 63032.7 Prodrug Approaches for Enhancing Absorption 63132.8 Prodrug Approaches for Targeting Enzymes 63132.9 Prodrug Approaches for Targeting Membrane Transporters 63232.10 Conclusion 633Abbreviations 634References 63433 Gastroretentive Drug Delivery Systems 637Vrushali Waknis and Ajit S. Narang33.1 Introduction 63733.2 Oral Drug Delivery – Challenges and Opportunities 63733.3 Human Gastric Physiology Relevant to GRDDS Design 63833.4 Technologies 63933.5 New Drug Development Considerations 64533.6 Commercial GRDDS Products and Investigational New Products 64933.7 Future Outlook 653Acknowledgments 654References 65434 Enhancing Oral Bioavailability Using 3D Printing Technology 657Timothy Tracy, Senping Cheng, Lei Wu, Xin liu, and Xiaoling li34.1 Introduction 65734.2 3D Printing in Pharmaceutical Applications 65734.3 Novel Tablet Structures Possible with 3D Printing 66034.4 Application of 3D Printing in Oral Bioavailability Enhancement 66334.5 Future Outlook for 3D Printing and Bioavailability Enhancement 67234.6 Summary 673References 67335 Anatomical and Physiological Factors Affecting Oral Drug Bioavailability in Rats, Dogs, Monkeys, and Humans 677Ayman El-Kattan35.1 Introduction 67735.2 Determinants of Oral Bioavailability 67735.3 Summary 691References 69136 In Vivo Methods for Oral Bioavailability Studies 701Ana Ruiz-Garcia and Marival Bermejo36.1 Introduction 70136.2 Factors that Affect Oral Availability 70136.3 In Vivo Animal Techniques 70636.4 Animals Used in Bioavailability Studies 70636.5 General Considerations for Blood Sampling 70836.6 Statistical Considerations for Data Handling. (AUC Calculations in Sparse Sampling Designs) 70836.7 Practical Examples in Rat Model 70936.8 Intestinal Perfusion (see also Chapter 42) 71036.9 Mathematical Considerations 711References 71237 Caco-2 Cell Culture Model for Oral Drug Absorption 715Kaustubh Kulkarni, Lu Wang, and Ming Hu37.1 Introduction 71537.2 Description 71737.3 Utility 71937.4 Recent Progress 72037.5 Significance of Caco-2 Cell Culture Model in Drug Discovery and Development 72237.6 Example 72237.7 Concluding Remarks 727References 72738 OATP Overexpressed Cells and Their Use in Drug Uptake Studies 729Lu Wang, Zuoxu Xie, Yifan Tu, and Ming Hu38.1 Introduction to OATP Cell Assay 72938.2 Materials 73138.3 Methods 73138.4 Data Analysis 73238.5 Notes 733References 73539 Use of Human Intestinal and Hepatic Tissue Fractions and Microbiome as Models in Assessment of Drug Metabolism and its Impact on Oral Bioavailability 737Hani Zaher and George Zhang39.1 Introduction 73739.2 Gastrointestinal Tract and Absorption (see Also Chapter 5) 73739.3 Mechanisms of Drug Absorption and Concept of Oral Bioavailability (see also Chapters 4–6) 73839.4 Intestinal Metabolism and Oral Bioavailability (see Also Chapter 11) 73939.5 In Vitro Systems Applied to Assess Intestinal Metabolism 74039.6 In Vitro Systems Applied to Assess Human Hepatic First-Pass Metabolism (see Also Chapter 12) 74339.7 Long-Term Hepatocyte Culture and Slow Metabolizing Drug Candidate 74539.8 Microbiome and Absorption: A New Perspective 74739.9 Summary 748Acknowledgments 748Abbreviations 749References 74940 Liver Perfusion and Primary Hepatocytes for Studying Drug Metabolism and Metabolite Excretion 757Paresh P. Chothe, Sean Xiaochun Zhu, Sandeepraj Pusalkar, Chuang Lu, and Cindy Xia40.1 Introduction 75740.2 Liver Perfusion 75840.3 Primary Hepatocytes 76240.4 Organ Perfusion Versus Hepatocyte Studies 77140.5 Perspectives 772Acknowledgements 772Abbreviations 772References 77241 Determination of Regulation of Drug Metabolizing Enzymes and Transporters 779Sergio C. Chai, Taosheng Chen, and Wen Xie41.1 Introduction 77941.2 In vivo Methods 77941.3 In vitro Methods 78441.4 Biochemical, Biophysical and Structural Analysis of NRs Using Purified Proteins 78941.5 Conclusions 796Acknowledgments 796References 79642 Intestinal Perfusion Methods for Oral Drug Absorptions 801li li, Dinh Bui, Wei Zhu, and Eun-Jung (Zenobia) Jeong42.1 Introduction 80142.2 Application and Recent Development of the Intestinal Perfusion Method 80142.3 Data Interpretation and Method Comparison 80342.4 Common In Vitro Methods Studying Intestinal Permeability and Metabolism 80342.5 Summary 80742.6 Methodologies and Experimental Data Analysis 807Acknowledgment 813References 81543 In Silico Prediction of Oral Drug Absorption 819Jin Dong, Zhu Zhou, Yujuan Zheng, and Miki Susanto Park43.1 Introduction 81943.2 QSPR Modeling 81943.3 PBPK Modeling 82143.4 PBBM Modeling as a Subset of PBPK Modeling 82343.5 Applications of PBPK/PBBM Modeling 82443.6 PBPK Software 82743.7 Summary 839References 83944 Computational Modeling of Drug Oral Bioavailability 843Lon W.R. Fong, Beibei Huang, Rajan Chaudhari, and Shuxing Zhang44.1 Introduction 84344.2 Computational Modeling of Bioavailability 84444.3 Conclusions 851Acknowledgment 852References 85245 Blood–Brain Barrier Permeability Assessment for Small-Molecule Drug Discovery Using Computational Techniques 857Yankang Jing and Xiang-Qun Xie45.1 Introduction 85745.2 Basic Principle of the BBB Permeation 85745.3 Role of the BBB in Drug Delivery 85845.4 Experimental Methods for Assessing BBB Permeability 85845.5 Computational Method to Predict BBB Permeability 859Abbreviations 867References 867Index 871