This volume of the Handbook of Experimental Pharmacology (Concepts in Biochemical Pharmacology) will show that pharma­ cology has finally arrived as a true discipline in its own right, and is no longer the handmaiden of organic chemistry and physiology. Instead it is an amalgam of all the biological sciences including biochemistry, biophysical chemistry, physiology, pathology and clinical medicine. In the volumes that make up Concepts in Bioche­ mical Pharmacology we hope to convince Medical Schools what should now be obvious, that pharmacology is no longer that dull topic bridging the basic sciences with medicine, but is probably the most important subject in the medical curriculum. We are grateful for the advice of Dr. BYRON CLARKE, Director of the Pharmacology-Toxicology Program at the National Insti­ tutes of Health, whose support made possible much of the work described in this volume. Contents Section One: Routes of Drug Administration Chapter 1: Biological Membranes and Their Passage by Drugs. C. A. M. HOGBEN 1 References. . . . . . . . . . . . . . . . . . . . . . . . . . 8 Chapter 2: Absorption of Drugs from the Gastrointestinal Tract. L. S. SCHANKER. With 5 Figures. 9 I. Introduction. . . . . . . . . . . . . . . . . . . . . . . 9 II. Methods of Study. . . . . . . . . . . . . . . . . . . . . 9 III. Absorption from the Stomach . . . . . . . . . . . . . . . 11 IV. Intestinal Absorption of Non-Electrolytes and Weak Electrolytes 15 V. Absorption of Weak Electrolytes from the Colon and Rectum 18 VI. Intestinal Absorption of Organic Ions. . . . . . . . . . 19 VII. Intestinal Absorption of Macromolecules . . . . . . . . . . 19 VIII. Active Transport across the Intestinal Epithelium . . . . . 20 IX. Effect of EDTA on Drug Absorption from the Intestine . . . . . . .

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Section One: Routes of Drug Administration.- 1: Biological Membranes and Their Passage by Drugs.- References.- 2: Absorption of Drugs from the Gastrointestinal Tract.- I. Introduction.- II. Methods of Study.- III. Absorption from the Stomach.- IV. Intestinal Absorption of Non-Electrolytes and Weak Electrolytes.- V. Absorption of Weak Electrolytes from the Colon and Rectum.- VI. Intestinal Absorption of Organic Ions.- VII. Intestinal Absorption of Macromolecules.- VIII. Active Transport across the Intestinal Epithelium.- IX. Effect of EDTA on Drug Absorption from the Intestine.- X. Physiological Factors and Dosage Forms of Drugs as Related to Absorption from the Gastrointestinal Tract.- References.- 3: Buccal Apsorption of Drugs.- A. H. Beckett.- R. D. Hossie.- A. General Considerations.- B. Administration of Drugs via the Buccal Route.- C. Buccal Absorption Characteristics of Drugs.- I. General Method for the Buccal Absorption Test.- II. Results of the Buccal Absorption Test.- III. Absorption of Basic Drugs.- IV. Absorption of Acidic Drugs.- V. Correlation with Partition Coefficients of Acidic and Basic Drugs.- VI. Kinetics of Buccal Absorption of some Acids and Bases.- D. Distribution and Excretion of some Basic Drugs after Buccal Absorption in Man.- References.- 4: Subcutaneous and Intramuscular Injection of Drugs.- A. Introduction.- B. Anatomy of Injections.- Local Events.- C. Mechanism of Absorption.- 1. Blood Flow Measurement.- 2. Absorption Kinetics.- 3. Pellet Absorption.- 4. Dynamic Events.- 5. Molecular Weight.- D. Biological Factors.- 1. Blood Flow.- 2. Connective Tissue.- 3. Glucocorticoids.- 4. Release of Biogenic Substances.- E. Injection Solutions.- 1. Injection Volume and Concentration.- 2. Tonicity.- 3. Hydrogen Ion Concentration.- F. Delayed Uptake.- 1. Prolonged Local Effect.- 2. Prolonged Systemic Effect.- G. Complications with Injections.- 1. Microbiological Contamination.- 2. Nerve Damage.- 3. Carcinogenesis.- H. Conclusion.- References.- 5: Absorption, Distribution and Excretion of Gaseous Anesthetics.- References.- 6: Aerosols.- I. Properties of Aerosols.- II. Measurement of Aerosols.- III. Generation of Aerosols.- IV. Deposition of Aerosols in the Respiratory Tract.- V. Absorption of Aerosols - Absorptive Surfaces.- VI. Absorption Studies.- VII. Summary.- References.- 7: Absorption of Drugs through the Skin.- A. Anatomy and Physiology.- I. Evolution.- II. Some Facts and Figures.- III. Anatomy.- 1. Epidermis.- 2. The Dermis (Corium).- 3. Subcutaneous Tissue.- 4. Appendages.- 5. pH.- IV. Dermatitis.- 1. Pathology.- 2. Structure Changes.- 3. Inflammation.- 4. Patterns.- B. Pathways of Percutaneous Absorption.- I. Introduction.- II. Alternate Pathways.- III. General Conclusions.- C. Factors Affecting Percutaneous Absorption.- I. Introduction.- II. Drug-skin Interactions.- 1. Skin Hydration.- 2. Circulatory Effects.- 3. Skin Metabolism.- 4. Binding of Drugs by Skin.- III. Vehicle-Skin Interactions.- 1. Effect on Skin Hydration.- 2. Temperature Effects.- 3. Solvent Effects.- IV. Drug-Vehicle Interactions.- 1. Release from Solutions.- 2. Release from Suspensions.- 3. Other Factors Influencing Release.- V. Drug-Vehicle-Skin Interactions.- 1. Diffusion Constant.- 2. Partition Coefficient.- 3. Drug Concentration.- VI. Summary.- D. Methods for Studying Percutaneous Absorption.- I. In Vitro.- 1. Diffusion Methods without a Membrane.- 2. Diffusion Methods with Membranes.- II. In Vivo.- 1. Animal Models.- 2. Remainder Analysis.- 3. Human Skin Window.- 4. Histology.- 5. Direct Observation.- 6. Systematic Observation.- 7. Dermal Perfusion.- E. Drugs and Methods for Percutaneous Absorption Studies.- F. Treatment.- I. Dermatologic Medications.- II. Anti-Inflammatory Agents - Topical Corticoids.- III. Vehicles.- References.- Section Two: Sites of Drug Transport and Disposition.- 8: The Nature of Drug-Protein Interaction.- A. Protein Structures.- B. Maintenance Forces of Protein Structure.- C. Protein Structure and Binding of Small Molecules.- I. Alterations of Structure at the Site of Binding of Small Molecules.- II. Alterations of Protein Structure at Sites Remote from the Binding Site of Small Molecules.- D. Forces in Protein-Small Molecule Interactions.- I. Bond Types.- II. "Hydrophobic Bonds".- III. Free Energy Considerations.- IV. Environmental Effects.- E. Albumins.- I. Structure of Albumin.- II. Albumin-Drug Interactions.- Conclusion.- References.- 9: Physical Methods for Studying Drug-Protein Binding.- A. Nonspectroscopic Techniques.- I. Rapid (or Kinetic) Dialysis.- II. Gel Filtration.- III. Heatburst Microcalorimetry.- B. Spectroscopic Techniques.- I. Ultraviolet and Visible Absorption Spectroscopy.- II. Fluorescence Spectroscopy.- III. Optical Rotatory Dispersion and Circular Dichroism.- IV. Nuclear Magnetic Resonance.- V. Other Spectroscopic Techniques.- VI. Stopped Flow and Relaxation Spectrometry.- References.- 10: Effect of Binding to Plasma Proteins on the Distribution, Activity and Elimination of Drugs.- A. Effect on Distribution and Activity.- 1. The Drug-Protein Complex.- 2. Tissue Distribution.- 3. Pharmacodynamic Activity.- 4. Antibacterial Activity.- 5. Entry into Transmembrane Compartments.- B. Effect on Elimination.- 1. Renal Excretion.- 2. Excretion into Bile.- 3. Salivary Excretion.- 4. Drug Metabolism.- C. Effect on Pharmacokinetics.- 1. A Model.- 2. Distribution.- 3. Kinetics.- D. Conclusions.- References.- 11: Competition between Drugs and Normal Substrates for Plasma and Tissue Binding Sites.- I. Introduction.- II. Bilirubin.- III. Thyroxine.- IV. Steroids.- V. Fatty Acids.- VI. Summary.- References.- 12: Drug Entry into Brain and Cerebrospinal Fluid With.- A. Introduction.- B. Anatomical Basis of Blood, Brain and CSF Barriers.- C. Blood-CSF Relationships.- D. CSF-Brain Relationships.- E. Drug Entry into CSF and Brain from Blood.- F. Methods for Studying Drug Entry and Exit.- G. Pathological Situations.- References.- 13: Translocation of Drugs into Bone.- I. Introduction.- II. The Nature of Bone.- III. Bone Mineral.- IV. Bone Mineral Dynamics and Ion Binding.- V. Binding of Heterogeneous Materials.- 1. Tetracyclines.- 2. Other Org…