Kinetics of drug action.

Most drugs, toxins, hormones, and the like bring about their biologic actions by reacting with specific receptors somewhere in the body. Scientists working in all areas of biologic science have shown increasing interest in the analysis of drug-receptor interactions in the broadest sense. Studies of drugs (binding) to receptors in situ and to isolated and partly purified receptors are becoming common practice. The action of a drug in the body is, however, a kinetic event not only with respect to transport of drug molecules to the environment of the receptors, but also with respect to the drug-receptor interaction itself. Kinetics of Drug Action is an integrative approach to drug transport through the body, membrane transport toward the receptors, and the kinetics of drug- receptor interaction. This volume is aimed at providing a critical and penetrating study of the problems relevant to the kinetics or drug action from drug dosage to the final response. It is felt that the critical surveys presented in this volume will contribute significantly to receptor study research in various biologic fields and to a better understanding of drug action. I would like to express my gratitude to our secretary Miss MARGOT JANSSEN for the extensive typing of manuscripts and to our laboratory assistant Miss COBY HURKMANS for her dedicated assistance in the correcting some of the manuscripts and preparating the index.

General Introduction.- 1 Physicochemical Fundamentals and Thermodynamics of the Membrane Transport of Drugs..- I. Introduction.- II. Systems and Membrane Types.- A. Homogenous System.- B. Heterogeneous Continuous System.- C. Heterogeneous Discontinuous System.- D. Membrane Types.- 1. Liquid-Phase Membranes.- 2. Pore Membranes.- a) Narrow-Pore Membranes.- b) Coarse-Pore Membranes.- c) Charged Porous Membranes.- 3. Composed Membranes.- a) Composed Pore Membranes.- b) Composed Liquid Phase-Pore Membranes.- 4. Biological Membranes.- a) Membranes with Passive Carrier Transport.- b) Membranes with Active Transport.- III. Classification of Membrane Transport.- A. Diffusion Across Membranes.- 1. Driving Forces.- 2. Mechanism and Kinetics.- 3. Specificity.- 4. Inhibition Characteristics.- B. Facilitated Diffusion.- 1. Mechanism.- 2. Driving Force.- 3. Counter-Transport.- 4. Kinetics.- 5. Specificity.- 6. Competitive Inhibition.- C. Active Transport.- D. Pinocytosis.- 1. Mechanism.- 2. Specificity.- 3. Inhibition.- IV. Kinetics and Thermodynamics of Membrane Transport.- A. Conventional Equations.- B. Introductory Remarks on the Thermodynamics of Irreversible Processes.- C. Passive Transport of Nonelectrolytes.- 1. Flux Equations.- 2. Significance of the Phenomenologic Coefficients.- a) Ideal Semipermeable Membrane.- b) Coarse Porous Membrane.- c) Reflection Coefficient.- d) Permeability Coefficient.- 3. Coupling of Fluxes.- 4. Interpretation of Membrane Transport by Means of Frictional Coefficients.- a) General Equations.- b) Connections Between Frictional and Phenomenologic Coefficients.- c) Physical Significance of the Coefficients.- D. Passive Transport of Electrolytes Across Charged Membranes.- 1. General Relations.- 2. Introduction of Frictional Coefficients.- 3. Permeability and Reflection Coefficients of 1–1-Valent Salts.- 4. Permeability and Reflection Coefficients of 1–2- and 2–1-Valent Salts.- E. Passive Carrier Transport.- Kinetic Analysis and Flux Equations.- a) Basic Equations.- b) Limiting Cases.- c) Counter-Transport and Competitive Exchange Diffusion.- F. Active Transport.- 1. Kinetic Analysis and Conventional Flux Equations.- 2. Phenomenologie Treatment. Flux Equations.- G. Remarks on Nonlinear Thermodynamic Approach to Membrane Transport.- 1. Introduction.- 2. Examples and Models.- Appendix. Glossary of Symbols.- References.- 2 Pharmacokinetics. Kinetic Aspects of Absorption, Distribution, and Elimination of Drugs..- I. Introduction.- A. Basic Definitions.- B. Historical Outline.- II. Pharmacokinetic Models.- A. Choise of Models.- B. Critique of Models.- III. Models for Single-Dose Administration.- A. Intra- and Extravascular Administration.- B. Elimination.- 1. Biotransformation.- 2. Renal Excretion.- 3. Extrarenal Excretion.- C. Distribution.- Protein Binding Models.- D. Absorption.- 1. Absorption from Parenteral Sites.- 2. Absorption from Enteral Sites.- 3. Transport Through the Gastrointestinal Tract.- 4. Absorption from Gastrointestinal Tract.- 5. First-Order Absorption Kinetics with Zero-Time Shift.- 6. Nonfirst-Order Models of Absorption.- E. Multicompartment Kinetics.- 1. The Two Compartment Model.- 2. The Slope of the Log Concentration-Time Curve.- 3. A Three Compartment Model.- IV. Multiple Dose Administration.- A. The Therapeutic Purpose.- 1. Intravascular Administration of Multiple Doses.- 2. Continuous Intravenous Infusion.- 3. Extravascular Administration of Multiple Dose Therapy.- 4. Drug Accumulation and the Desired Plateau Effect.- B. Dosage Regimens.- 1. Empirical Rules for Dosage Regimens.- 2. Theory of Dosage Regimens.- 3. Theory of Dosage Regimens: The Average Concentration in the Dosage Interval.- 4. Dosage Regimens for Rapidly Absorbed Drugs.- 5. Dosage Regimens for Slowly Absorbed Drugs.- V. Conclusion.- References.- 3 Pharmacokinetics of Biotransformation..- I. Introduction.- A. Elimination of Drugs by a Clearance Process.- B. Flow-Limited Elimination of Drugs.- C. Supply-Limited Elimination of Drugs.- D. Capacity-Limited Elimination of Drugs.- E. The Relationship Between the Metabolic Enzyme Activity and the Metabolic Clearance.- F. The Plasma Decay Curve as a Result of Metabolic Clearance.- G. Calculation of Enzymatic Constants from the Plasma Decay Curve.- H. Simultaneous Supply-Limited and Capacity-Limited Elimination of Drugs.- I. Dissociation Constants Obtained from Microsomal Enzymes.- J. Inhibition of Drug Metabolism by Other Drugs.- K. Induction of Microsomal Enzymes and the Liver Clearance.- L. The Liver Clearance Under Pathologic Conditions.- M. Drug-Dependent Destruction of Metabolic Clearance Processes.- N. Elimination of Parent Drug and its Metabolite.- O. Saturation Kinetics of Metabolite Formation and Capacity-Limited Elimination.- P. Multicompartment Kinetics and Capacity-Limited Elimination.- Q. Oral Administration and Capacity-Limited Elimination.- R. Oral Administration and Capacity-Limited Elimination in the Liver.- S. The Accumulation Plateau Following Repetitive Dosing of a Drug.- T. The Accumulation Plateau and Capacity-Limited Elimination.- U. The Accumulation Plateau and Capacity-Limited Elimination in the Liver Compartment.- V. The Renal Excretion Rate in Case of Capacity-Limited Elimination.- W. Metabolite Concentrations Following Chronic Medication.- X. Bioavailability and Capacity-Limited Elimination.- II. Conclusion.- References.- 4 General Theory of Drug-Receptor Interactions. Drug-Receptor Interaction Models. Calculation of Drug Parameters..- I. Introduction.- A. The Utility of Theoretical Mathematical Models in Molecular Pharmacology.- B. The Affinity Between Drug Molecules and Receptors; the Concepts Drug Activity and Receptor.- C. Intrinsic Activity; the Concepts Agonism, Competitive Antagonism, and Dualism.- II. Drugs, Receptors and Effects.- A. Different Types of Antagonism.- 1. Chemical Antagonism.- 2. Competitive Antagonism.- 3. Noncompetitive Antagonism.- a) Metaffinoid Antagonism.- b) Metactoid Antagonism.- 4. Functional Antagonism.- 5. Physical Antagonism.- B. Classification of Drugs in Families.- C. From Drug Administration to Effect; Drug-Receptor Interaction Models; Experiments on Isolated Organs.- III. Agonistic Interaction.- A. The Model of Agonism.- B. Intrinsic Activity in the Agonistic Formula.- C. Theoretical Concentration-Effect Curves. Sets of Curves Characterized by Parallel Shifting or by a Change in Slope.- D. Discussion of the Presuppositions in the Agonistic Model.- IV. Competitive Interaction.- A. The Model of Competitive Interaction.- B. Implications of the Model of Competitive Interaction.- V. Metactoid Interaction.- A. The Model of Metactoid Interaction.- B. Implications of the Model of Metactoid Interaction; the Concept Receptor Reserve.- VI. Metaffinoid Interaction.- A. The Model of Metaffinoid Interaction.- B. Metaffinoid Interaction. Implications of Equation 55.- C. An Alternative Model for Metaffinoid Interaction.- D. A More Generalized Metaffinoid Model.- VII. Functional Interaction.- A. The Model of Functional Interaction.- 1. The Original Model of Functional Interaction.- 2. A New Model of Functional Interaction.- B. Implications of the New Model of Functional Interaction.- VIII. Plural Affinities.- IX. Numerical Expressions of Intrinsic Activity and Affinity.- A. Calculation of ?E and pD2.- B. Calculation of pKAS and ?S.- C. Calculation of pA2-values.- D. Calculation of ß?E and pD2?.- E. Affinity and Intrinsic Activity Values for Functional Antagonists.- F. pA2 and pD2? of a Dual (Competitive and Metactoid) Antagonist.- G. Conclusion.- References.- 5 A Critical Survey of Receptor Theories of Drug Action..- I. Introduction.- II. The Mathematics of Drug-Receptor Interactions.- A. Interaction of One Drug with One Type of Receptor.- 1. The Drug-Receptor Reaction.- 2. Onset of Receptor Occupation.- 3. Offset of Receptor Occupation.- B. Interaction of Two Drugs with the Same Receptors.- 1. Competitive Interactions.- 2. Pseudo-Irreversible Interactions.- 3. Facilitated Displacement.- 4. Specific Noncompetitive Interaction.- C. Application of Equations for Receptor Occupation to Macroscopic Tissues.- D. Drug-Receptor Interactions and the Response.- III. Occupation Theories of Drug Action.- A. The Direct Occupation Theory.- 1. Clark’s Original Theory.- 2. Application of the Null Method to Studies of Drug Antagonism.- 3. Intrinsic Activity, Efficacy, and the Pharmacologic Stimulus.- a) Intrinsic Activity.- b) Efficacy and the Pharmacologic Stimulus.- 4. Intrinsic Efficacy.- 5. General Application of the Null Method to the Analysis of Dose-Response Curves.- 6. Estimation of Affinity Constants and Intrinsic Efficacies of Agonists.- 7. A Discussion of the Direct Occupation Theory of Drug Action.- 8. The Equilibrium Assumption.- 9. Variation of the Response with Time.- 10. A Negative Feedback Model.- 11. The Null Method and the Negative Feedback Model.- B. Agonists as Activators of Enzyme Systems.- 1. The Conformational Perturbation Theory of Drug Action.- 2. The Dynamic-Receptor Hypothesis.- 3. Application of the Null Method of the Dynamic-Receptor Hypothesis.- 4. Nondynamic Receptors.- 5. Comparison of Direct Occupation Theory and Latent-Enzyme Activation Hypotheses.- C. The Flux-Carrier Hypothesis and Intracellular Uptake of Drugs.- 1. The Flux-Carrier Hypothesis.- 2. Discussion of the Flux-Carrier Model.- 3. The Actions of Drugs on Depolarised Tissues, and Possible Intracellular Effects of Agonists.- D. The Allosteric Two-State Model.- 1. Basis of the Model.- 2. Application of the Null Method to the Allosteric Two-State Model, and Comparison of the Results with those Obtained on the Basis of the Direct Occupation Theory.- IV. The Rate Theory of Drug Action.- A. Agonist Action and the Rate Theory.- 1. The Kinetics of the Response.- 2. Specific Desensitisation.- B. Antagonists and the Rate Theory.- C. Discussion.- V. A General Discussion of the Various Receptor Models.- VI. A General Discussion of the Possible Uses of Receptor Models.- Appendix. Glossary of Symbols.- References.- 6 Drug-Receptor Inactivation: A New Kinetic Model..- I. Introduction.- II. Energetics of Receptor Activity.- III. Models in Which Trigger Energy is Generated.- IV. Models Involving Irreversible Alterations of Agonist or Receptor.- V. A Receptor Inactivation Theory.- VI. Stationary State Behavior with Single Agonists.- VII. Transient State Behavior with Single Agonists.- VIII. Stationary State Behavior with Agonist-Antagonist Mixtures.- IX. Transient State Behavior with Agonist-Antagonist Mixtures.- X. General Discussion.- XI. Summary.- Addendum A.- Addendum B.- Appendices: Glossary—Generalized Rate Equations for the Receptor Inactivation Model—“On” Effect—“Off” Effect—Analysis of Oscillations—Receptor Interactions with Agonist-Antagonist Mixtures.- References.- 7 Kinetics of Drug-Receptor Interaction..- I. Introduction.- A. Drug-Receptor Interactions and Pharmacologic Effect.- B. The Receptor.- II. Diffusion of Drug to Receptor.- A. Free Diffusion of Drug.- B. Effect of Intermolecular Forces on Diffusion.- III. Intermolecular Forces in Drug-Receptor Reactions.- IV. Kinetics of Drug-Receptor Association and Dissociation.- V. Possibilities for Measuring Rate Constants in Drug-Receptor Interaction.- VI. Conformational Changes in the Drug-Receptor Complex.- VII. Kinetics of Drug-Receptor Interaction, Including Conformational Changes.- A. Conformational Changes that are Fast in Comparison with Association and Dissociation.- B. Conformational Changes that are Slow in Comparison with Association and Dissociation.- C. Conformational Changes and Irreversible Antagonists.- VIII. Some Other Notions in Molecular Pharmacology.- A. Desensitization and Fade.- B. Receptor Reserve.- C. Homogeneity of Receptor Preparations.- D. Allosteric Models.- IX. Activation Parameters.- A. Arrhenius’ Equation and Transition-State Theory.- B. Energetics of Drug-Receptor Interaction.- References.- Conclusion.- Author Index.