Physicochemical and Biomimetic Properties in Drug Discovery

KLARA VALKO is an Investigator in the Analytical Chemistry Department of Molecular Discovery Research at GlaxoSmithKline. Dr. Valko has more than thirty years of experience in HPLC, GC, and LC/MS. She also has more than ten years of experience teaching physicochemical measurements and ADME optimization tools at the UCL School of Pharmacy. Currently, Dr. Valko is an Honorary Professor, leading the Physchem/ADME module for a drug discovery MSc course.

“This is one of those books that will not gather dust on the shelf (barring an epochal revolution in the field) because it will be a constant point of reference for established scientists participating in multidisciplinary pharmaceutical research teams or those who wish to establish themselves in this area.”  (Doody’s, 16 January 2015)

• Preface xi1 The Drug Discovery Process 1Summary 7Question for Review 7References 72 Drug-Likeness and Physicochemical Property Space of Known Drugs 9Summary 12Questions for Review 13References 133 Basic Pharmacokinetic Properties 15Absorption 17Plasma Protein Binding 20Distribution 22Volume of Distribution 23Unbound Volume of Distribution 29Half-Life 30Metabolism and Clearance 30Free Drug Hypothesis 31Summary 31Questions for Review 32References 334 Principles and Methods of Chromatography for the Application of Property Measurements 34Theoretical Background of Chromatography 35Retention Factor and Its Relation to the Distribution Constant Between the Mobile and the StationaryPhases 37Measure of Separation Efficiency 40Resolution and Separation Time 42Gradient Elution 44Applicability of Chromatography for Measurements of Molecular Properties 47Summary 49Questions for Review 50References 505 Molecular Physicochemical Properties that Influence Absorption and Distribution—Lipophilicity 52Partition Coefficient 52Lipophilicity Measurements by Reversed Phase Chromatography with Isocratic Elution 58Lipophilicity Measurements by Reversed Phase Chromatography with Gradient Elution 68Lipophilicity of Charged Molecules—pH Dependence of Lipophilicity 72Biomimetic Lipophilicity Measurements by Chromatography 78Comparing Various Lipophilicity Measures by the Solvation Equation Model 90Summary 102Questions for Review 105References 1056 Molecular Physicochemical Properties that Influence Absorption and Distribution—Solubility 112Definition of Solubility 112Molecular Interactions with Water 116Various Solubility Measurements that can be Applied During the Drug Discovery Process 119Conditions that Affect Solubility 121Solubility–pH Profile 132Solubility and Dissolution in Biorelevant Media 134Composition of Fasted State Simulated Intestinal Fluid (FaSSIF) 136Preparation of FaSSIF Solution 136Composition of Fed State Simulated Intestinal Fluid (FeSSIF) 136Preparation of FeSSIF solution 136Summary 143Questions for Review 146References 1467 Molecular Physicochemical Properties that Influence Absorption and Distribution—Permeability 150Biological Membranes 150Artificial Membranes 153Physicochemical Principles of Permeability 155Experimental Methods to Measure Artificial Membrane Permeability 159Relationships Between Permeability, Lipophilicity, and Solubility 166Chromatography as a Potential Tool for Measuring the Rate of Permeation 171Summary 175Questions for Review 178References 1788 Molecular Physicochemical Properties that Influence Absorption and Distribution—Acid Dissociation Constant—pKa 182Definition of pKa 182Methods for Determining pKa 188Spectrophotometric Determination of pKa 192Determination of pKa by Capillary Electrophoresis 195Chromatographic Approaches for the Determination of pKa 197Summary 207Questions for Review 209References 2099 Models with Measured Physicochemical and Biomimetic Chromatographic Descriptors—Absorption 213Lipinski Rule of Five 214Absorption Models with Lipophilicity and Size 217Biopharmaceutics Classification System (BCS) 221Absorption Potential—Maximum Absorbable Dose 227Abraham Solvation Equations for Modeling Absorption 232Effect of Active Transport and Metabolizing Enzymes on Oral Absorption and Bioavailability 235Summary 236Questions for Review 238References 23810 Models with Measured Physicochemical and Biomimetic Chromatographic Descriptors—Distribution 242Models for Volume of Distribution 249Plasma Protein Binding 276Blood/Brain Distributions 288Tissue Distribution 294Summary 296Questions for Review 298References 29811 Models with Measured Physicochemical and Biomimetic Chromatographic Descriptors—Drug Efficiency 303Drug Efficiency 303Summary 327Questions for Review 327References 32812 Applications and Examples in Drug Discovery 330Structure–Lipophilicity Relationships 330Structure–Solubility Relationships 346Structure–Permeability Relationships 354Structure–Charge State Relationships 362Structure–Protein Binding Relationships 366Structure–Phospholipid Binding Relationships 371Summary 376Questions for Review 379References 379Appendix A Answers to the Questions for Review 387Appendix B List of Abbreviations and Symbols 427Index 433