Contents
Preface IX
Foreword XIII
Introduction
1 Function, Composition, and Organization of Membranes 2
1.1 The Physiology of Cells and the Importance of Membranes for
their Function 2
1.2 Composition and Organization of Membranes 3
1.2.1 Mammalian Membranes 3
1.2.2 Bacterial Membranes 14
1.2.3 Fungal Membranes 17
1.2.4 Artificial Membranes, Liposome Preparation, and Properties 18
1.3 Dynamic Molecular Organization of Membranes 21
1.3.1 Thermotropic and Lysotropic Mesomorphism of Phospholipids 21
1.3.2 Phase Separation and Domain Formation 24
1.4 Possible Effects of Drugs on Membranes and Effects of Membranes on
Drug Molecules 27
References 30
2 Octanol–Water Partitioning versus Partitioning into Membranes 35
References 49
3 Analytical Tools for the Analysis and Quantification of Drug–Membrane
Interactions 51
3.1 High-performance Liquid Chromatography (HPLC) 52
3.1.1 Determination of the Retention Time on “Artificial Membrane”
Columns 52
3.2 Displacement of 45Ca2+ from Phospholipid Head Groups 54
3.2.1 Studies of Drug–Membrane Interactions using Phospholipid
Monolayers 54
3.3 Differential Scanning Calorimetry (DSC) 58
3.3.1 Phase Transition and Domain Formation 58
3.4 Fluorescence Techniques 75
3.5 Fourier Transform Infrared Spectroscopy (FT-IR) 77
3.6 Electron Spin Resonance (ESR) 79
3.7 Small-angle Neutron and X-ray Diffraction 83
3.8 Nuclear Magnetic Resonance (NMR) 87
3.8.1 Study of Membrane Polymorphism by 31P-NMR 88
3.8.2 Effect of Cholesterol and Diacylglycerols 89
3.8.3 Effect of Drugs 92
3.8.3.1 31P-NMR for the Study of Changes in Orientation of Phospholipid
Head Group 92
3.8.4 Determination of Drug Transmembrane Transport 96
3.8.5 1H-NMR in Combination with Pr3+ for the Study of Drug Location 100
3.8.6 The Use of 2H-NMR and 13C-NMR to Determine the Degree of
Order and the Molecular Dynamics of Membranes 103
3.8.7 Change in relaxation rate, 1/T2: a Method of Quantifying
Drug–Membrane Interaction 105
3.8.8 NOE-NMR in the Study of Membrane-induced Changes in
Drug Conformation 112
3.9 Circular Dichroism (CD) 116
3.10 UV Spectroscopy 117
3.11 Combined Techniques for Studying Drug–Membrane Interaction 120
3.11.1 Combination of DSC and NMR 120
3.11.2 Combination of DSC and X-ray Diffraction 122
3.11.3 Combination of DSC and ESR 124
3.11.4 Combination of DSC and Fluorescence 126
3.11.5 Combination of FT-IR and NMR 129
3.11.6 Combination of UV and 2H-NMR 129
3.11.7 Combination of DSC, FT-IR, and NMR 130
3.12 Summary 132
References 135
4 Drug–Membrane Interaction and Pharmacokinetics of Drugs 141
4.1 Drug Transport 141
4.1.1 Absorption Models 148
4.1.1.1 Caco-2 Cells as an Absorption Model 148
4.1.1.2 Parallel Artificial Membrane Permeation Assay (PAMPA) 155
4.1.1.3 Surface Plasmon Resonance Biosensor Technique 155
4.1.1.4 The Use of IAM Columns 157
4.1.1.5 Partitioning into Immobilized Liposomes 159
4.1.2 Computational Methods, QSAR 161
4.2 Drug Distribution 168
4.2.1 Distribution into the Brain Compartment 168
4.2.2 Distribution, Localization, and Orientation of Drugs in Various
Tissues and Membranes 173
4.2.3 Distribution in vivo 180
4.3 Uptake into and Distribution within Bacterial Cells 187
4.3.1 Diffusion Through the Outer Asymmetric Core of E. coli 189
4.3.2 Self-promoted Uptake of Antibacterial Peptides 196
4.4 Drug Accumulation, Toxicity, and Selectivity 199
4.4.1 Selectivity 211
References 212
5 Drug–Membrane Interactions and Pharmacodynamics 217
5.1 Drug Efficacy 217
5.1.1 Effect on Membrane-integrated Enzymes 218
5.1.1.1 Activation and Inhibition of Protein Kinase C (PKC) 218
5.1.1.2 Inhibition of Phospholipase A2 (PLA2) 219
5.1.1.3 Drug–Membrane Interactions and Inhibition of Na+,K+-ATPase 220
5.1.2 Release of Pharmacological Response 223
5.1.2.1 Effect of Anesthetics 223
5.1.2.2 Negative Chronotropic (Cardiodepressant) Effect 228
5.1.2.3 Anti-inflammatory Effect 229
5.1.2.4 Effect of Antiarrhythmics 231
5.1.2.5 Calcium-Channel Blocking Activity 232
5.1.2.6 α-Adrenoceptor Agonist Activity 233
5.1.2.7 Anticonvulsive Effect 234
5.1.2.8 Antioxidant Effect 236
5.1.2.9 Antineoplastic Activity of Ether Phospholipids 236
5.1.2.10 Antimalarial Activity of Chloroquine 237
5.1.2.11 Conformation of Acetogenin Derivatives in Membranes and the
Relation to Cytotoxicity 238
5.1.2.12 A Membrane-forming and Inflammation-inducing Bacterial
Macromolecule 238
5.1.2.13 Drug–Membrane Interactions involved in Alzheimer’s Disease 239
5.2 Drug Resistance 241
5.2.1 Bacterial Cells 241
5.2.2 Reversal of Multidrug Resistance in Tumor Cells 245
5.2.3 Proposed Mechanisms of Action 247
5.2.4 Change in Composition of Membranes and Influence on P-gp,
Cytotoxic Agents, and MDR-reversing Drugs 250
5.2.4.1 Comparison of Lipid Composition of Sensitive and Resistant Cells 250
5.2.4.2 Membrane Composition and Functioning of Membrane-embedded
Proteins 254
5.2.5 Membrane Composition, Drug Binding, and Transport Kinetics 259
5.2.6 SARs and QSARs for Cytotoxic Agents and MDR Modifiers 276
References 285
6 Computer Simulation of Phospholipids and Drug–Phospholipid
Interactions 291
6.1 Modeling Strategies for Studying Phospholipids and Drug–Phospholipid
Interactions 291
6.1.1 Types of Representation of the Simulated System 292
6.1.1.1 Mean Field Simulations 292
6.1.1.2 All-atom Simulations 293
6.1.2 Monte Carlo Simulations 295
6.1.3 Molecular Dynamics Simulations 296
6.1.3.1 Starting Structure, and Equilibrium Time 298
6.1.3.2 Boundary Conditions 300
6.1.3.3 Long-range Electrostatics and Non-bonded Cut-off 300
6.1.3.4 Kind of Simulation System 302
6.2 Computer Simulations with Phospholipids 305
6.2.1 Distribution of Solutes 305
6.2.2 Mechanism of Diffusion through Phospholipid Membranes 309
6.2.3 Small Molecules and their Interaction with Phospholipids 314
6.2.3.1 Anesthetics 314
6.2.3.2 Dihydropyridines 315
6.2.4 Effect of Cholesterol on Membrane Structure 316
6.2.5 Interactions of peptides with phospholipids 322
6.2.5.1 Mean Field Simulations 322
6.2.5.2 All-atom Simulations 325
6.2.6 Simulations of Pore-forming Peptides and of the Diffusion of Ions
through Ion Channels 327
6.2.7 Non-equilibrium Molecular Dynamics Simulations 331
6.3 Concluding Remarks 332
References 334
Index 337