Pharmacology of Intestinal Permeation I by W. McD. ArmstrongPharmacology of Intestinal Permeation I by W. McD. Armstrong

Pharmacology of Intestinal Permeation I

byW. McD. Armstrong

Paperback | June 4, 2012

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The intestine, particularly the small bowel, represents a large surface (in the adult 2 human approximately 200m ) through which the body is exposed to its environment. A vigorous substrate exchange takes place across this large surface: nutrients and xenobiotics are absorbed from the lumen into the bloodstream or the lymph, and simultaneously, the same types of substrate pass back into the lumen. The luminal surface of the intestine is lined with a "leaky" epithelium, thus the passage of the substrates, in either direction, proceeds via both transcellular and intercellular routes. Simple and carrier-mediated diffusion, active transport, pinocytosis, phagocytosis and persorption are all involved in this passage across the intestinal wall. The term "intestinal permeation" refers to the process of passage of various substances across the gut wall, either from the lumen into the blood or lymph, or in the opposite direction. "Permeability" is the condition of the gut which governs the rate of this complex two-way passage. The pharmacologist's interest in the problem of intestinal permeation is twofold: on the one hand, this process determines thebioavailability of drugs and contributes significantly to the pharmacokinetics and toxicokinetics of xeno­ biotics; on the other hand, the pharmacodynamic effects of many drugs are manifested in a significant alteration of the physiological process of intestinal permeation.
Title:Pharmacology of Intestinal Permeation IFormat:PaperbackDimensions:708 pages, 24.2 × 17 × 0.17 inPublished:June 4, 2012Publisher:Springer-Verlag/Sci-Tech/TradeLanguage:English

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ISBN - 10:3642695078

ISBN - 13:9783642695070

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Table of Contents

1 Morphology of the Intestinal Mucosa..- A. Introduction.- I. General Considerations.- II. Heterogeneity of Intestinal Epithelium.- B. Morphological Techniques.- C. The Mucosal Interface.- I. Surface Morphology of Small Intestine.- II. Surface Morphology of Large Intestine.- D. The Enterocyte.- I. The Striated Border.- II. The Apical Cell Coat and Cell Membrane.- III. The Cores of Microvilli and the Terminal Web.- IV. Other Enterocyte Surfaces.- V. The Enterocyte Cytoplasm.- VI. The Precursor Cells of the Crypt and Epithelial Dynamics.- VII. Special Features of Large Bowel Enterocytes.- E. Other Cell Types of Intestinal Mucosa.- I. Goblet Cells.- II. Intestinal Endocrine Cells.- III. Paneth Cells.- IV. Tuft Cells.- V. M Cells.- VI. Intraepithelial Lymphocytes.- VII. Globule Leukocytes.- F. Deeper Layers of the Intestine.- I. Lamina Propria.- II. Muscle Layers and Their Autonomic Innervation.- III. The Serosa.- G. Conclusion.- References.- 2 Intestinal Permeation and Permeability: an Overview..- A. Introduction.- B. Diffusion Processes.- C. The Intestine.- D. Passage of Substances Across Biologic Membranes.- I. Simple Diffusion.- II. Specific Transport Mechanisms.- III. Persorption.- E. Intestinal Permeation.- References.- 3 Permeability and Related Phenomena: Basic Concepts.- A. Introduction.- B. Passive Transport of Nonelectrolytes in Solution.- I. Nonequilibria Determining a Passive Net Flux.- II. Kinetics of Polar Solute Passage Driven by a Concentration Difference.- III. Kinetics of Nonpolar Solute Passage Driven by a Concentration Difference.- IV. Calculation of the Relative Values of the Permeability Coefficients of a Substance Across Two Membranes in Series.- C. Passive Transport of Univalent Electrolytes.- I. Kinetics of the Passive Net Transport off Univalent Electrolytes Across a Porous Membrane.- II. Transmembrane Potentials.- III. Transepithelial Potentials.- D. Transport Across Biological Membranes.- I. Passive Transport of Polar Nonelectrolytes Through Biological Membranes.- II. Passive Transport of Polar Electrolytes Through Biological Membranes.- E. Passive Transport by Carrier Facilitation.- I. Kinetics of Carrier-facilitated Transport.- II. Calculation of the Apparent Affinity Constant.- III. Saturation Kinetics.- IV. Substrate Competition.- V. Countertransport.- F. Passive Transport of Water.- I. Driving Forces.- II. The Hydrophilic Pores and Their Radius.- III. The Reflection Coefficient of Staverman.- IV. Solvent Drag.- G. Active Transport.- I. Identification.- II. Dependence of Water Transport on Metabolism.- III. Countercurrent Exchange.- IV. Thermodynamic Efficiency.- References.- 4 Methods for Investigation of Intestinal Permeability.- A. Introduction.- B. In Vivo Techniques.- I. In Conscious Animals.- II. In Anesthetized Animals.- C. In Vitro Techniques.- I. Isolated Loops.- D. Modifications of the Permeant.- I. Artificial Sugar Compounds.- II. Artificial Amino Acid Analogs.- III. Radioisotopes.- References.- 5 Vascular Perfusion of Rat Small Intestine for Permeation and Metabolism Studies.- A. Introduction.- B. Isolated Intestine with Lymph Collection.- I. Historical Aspects.- II. Development of Procedure.- III. Description of Procedure.- IV. Evidence for Sustained Viability.- V. Perfusate Composition During Recirculation.- VI. Applications.- C. Autoperfused Intestinal Segment In Vivo.- I. Description of Basic Procedure.- II. Specialized Techniques and Adaptations.- III. Applications.- D. Concluding Remarks.- I. Advantages of the Isolated Intestinal Preparation.- II. Advantages of the Autoperfused Intestinal Preparation.- References.- 6 The Use of Isolated Membrane Vesicles in the Study of Intestinal Permeation.- A. Introduction.- B. Methods for Membrane Isolation.- I. Brush Border Membranes.- II. Basolateral Plasma Membranes.- III. Enzyme and Polypeptide Content of Isolated Brush Border and Basolateral Membranes.- IV. Morphology and Orientation of Isolated Brush Border and Basolateral Membranes.- C. Methods for Analysing Transport Properties of Isolated Membrane Vesicles.- D. Transport Studies ..- I. Systems Involved in Primary Active Transport.- II. Systems Involved in Secondary Active Transport.- E. Energetics and Kinetics.- F. Studies with Isolated Membrane Vesicles on the Physiological Regulation of Transepithelial Transport.- G. Conclusions.- References.- 7 The Transport Carrier Principle.- A. The Carrier Concept in Relation to Intestinal Transport.- I. Early Development of the Carrier Concept.- B. The Kinetic Approach to Membrane Carriers.- I. The Simple Pore and Simple Carrier.- II. Coupled Transport Systems.- III. Chemiosmotic Coupling.- C. The Thermodynamics and Energetics of Membrane Carrier Systems.- I. Carrier Asymmetry.- II. Energetics of Countertransport Systems.- III. Energetics of Cotransport.- References.- 8 Energetics of Intestinal Absorption.- A. Introduction.- B. Special Fuels as Sources of Energy.- C. Membrane Transport and Oxidative Phosphorylation.- D. General Features of Energy Utilization.- E. Basal Energy Requirements of Tissues.- F. The Energetics of Absorption Are the Energetics of Movement Along a Multistep Pathway.- G. Variable Patterns of Fuels Available to the Small Intestine.- H. Intestinal Metabolism of Nutrients During Absorption.- I. Energetics of Brush Border Transport Processes.- K. Influence off Circulation of Epithelial Transport: General Principles.- I. Convective Transport.- II. Cellular Transport: Influence of Vascular Flow on Power Requirements.- III. A Simple Model.- L. Effects of Circulation on Epithelial Transport in the Steady State.- M. Influence of Circulation on Wash-out from Epithelium.- N. Influence of Circulation on Sodium Fluxes Across Vascularly Perfused Intestine.- I. Na Fluxes Across the Small Intestine.- II. Na Fluxes Across the Colon.- III. Factors Affecting Na Fluxes Across Frog Intestine.- O. Effects of Vascular Flow on Size of Tissue Fluid Compartments.- I. Measurement of Extracellular and Interstitial Space.- II. Influence of Vascular Flow on Permeability of the Pathway Between Epithelium and Blood.- P. Conclusions.- References.- 9 Polarity of Intestinal Epithelial Cells: Permeability of the Brush Border and Basolateral Membranes.- A. Introduction.- B. Functionally Polarized and Unpolarized Cells.- C. The Epithelial Layer as a Selective Barrier.- D. Brush Border Membrane: Morphology, Chemical Composition, and Biochemical Characteristics.- I. Morphology.- II. Chemical Composition.- III. The Brush Border as a Selective Membrane.- E. Basolateral Membrane: Chemical and Biochemical Organization.- I. Chemical Composition.- II. Enzyme Content.- F. Permeability of Brush Border and Basolateral Membranes.- G. Factors Affecting Membrane Permeability.- H. Concluding Remarks.- References.- 10 Electrical Phenomena and Ion Transport in the Small Intestine.- A. Introduction.- B. Transepithelial Electrical Parameters and Ionic Fluxes in the Small Intestine.- I. Ionic Conductance and its Structural and Functional Correlates . 316 II. Ionic Fluxes.- C. Pathways of Ion Transport in the Small Intestine.- I. The Cellular Pathway.- II. The Paracellular Pathway.- D. Analysis of Intestinal Electrical Parameters in Terms of Electrical Equivalent Circuits.- E. Na+-Coupled Transport of Organic Solutes by the Small Intestine.- I. Transepithelial Effects: The Na+ Gradient Hypothesis.- II. Intracellular Effects: The Electrical Potential Profile of the Absorptive Cell.- III. Equivalent Circuit Analysis: Is the Na+/K+ Exchange Pump Rheogenic?.- IV. Transapical Sugar Transport: Energetics and Stoichiometry.- F. The Regulation of Ion Transport in the Small Intestine.- I. Cyclic Nucleotides and Intestinal Transport: Secretion.- G. Conclusion.- References.- 11 Intestinal Permeation of Water.- A. Introduction.- B. Historical Concepts of Intestinal Fluid Absorption.- C. Formal Description of Water Transfer.- I. General Principles.- II. Diffusion.- III. Filtration.- IV. Osmosis.- V. Interaction Between Solute and Solvent Fluxes.- D. Passive Water Transport.- I. Diffusional Water Permeability.- II. Osmotic Water Permeability.- III. Rectification of Osmotic Water Flow.- IV. Route of Diffusional and Osmotic Water Flow.- V. Water Flow Driven by a Hydrostatic Pressure Gradient.- E. Active Water Transport.- I. The Series Membrane Model.- II. Hypertonic Interspace Mechanisms (Local Osmosis Theories) 431 III. Countercurrent Exchanger Model.- F. Relation Between Intestinal Blood Flow and Water Absorption.- G. Conclusion.- References.- 12 Intestinal Permeability to Calcium and Phosphate.- A. Introduction.- B. Calcium Transport.- I. Brush Border Membrane.- II. Basolateral Membranes.- C. Phosphate Transport.- D. Mechanism of Action of 1,25-Dihydroxycholecalciferol.- I. Pharmacology of the Receptors for 1,25-Dihydroxycholecalciferol 479 II. Regulation of Transport Mediated by a Nuclear Action of Vitamin D.- III. Regulation of Lipid Metabolism by Vitamin D.- IV. Calcium Binding Proteins.- V. Membrane-Bound Calcium Binding Protein.- VI. Calcium-Dependent Adenosine Triphosphatase.- VII. Adenylate Cyclase.- E. Vitamin D-Independent Regulation of Intestinal Calcium Absorption.- F. Summary.- References.- 13 Protein-Mediated Epithelial Iron Transfer.- A. Introduction.- B. Mucosal Uptake, Storage, and Transfer of Iron.- I. Experimental Models.- II. Choice of the Experimental Conditions and Iron Test Doses.- III. Molecular Aspects of Iron Absorption: Search for Mucosal Iron Carriers.- IV. Studies in Purified Fractions of Mucosal Epithelium and Mucosal Cell Suspension.- V. Morphological Studies.- C. Regulation of Iron Absorption.- I. The Significance of Mucosal Iron Binding Proteins.- II. Luminal Factors.- D. Heavy Metal Interaction with the Iron Transfer System: Sites of Interaction.- E. Conclusions.- References.- 14 Intestinal Absorption of Heavy Metals.- A. Introduction.- B. Experimental Problems.- C. General Characteristics of Heavy Metal Absorption.- I. Kinetics.- II. Role of Mucosal Metal Retention.- III. Specificity of Absorption Mechanisms.- IV. Chemical Form of Absorbed Metals.- V. Effects of Age.- D. Absorption of Some Individual Metals.- I. Cadmium.- II. Zinc.- III. Lead.- IV. Copper.- V. Mercury.- VI. Other Metals.- E. Summary and Conclusions.- References.- 15 Intestinal Permeability of Water-Soluble Nonelectrolytes: Sugars, Amino Acids, Peptides.- A. General Functions of the Enterocyte.- B. Intestinal Permeability to Sugars.- I. Simple Diffusion.- II. Facilitated Diffusion and Active Transport.- III. Enzymes Related to Sugar Transport.- IV. Sugar Binding Sites.- V. The Role of Brush Border and Basolateral Membranes in Sugar.- Transport.- VI. Energetics of Sugar Transport.- C. Intestinal Permeability to Amino Acids and Peptides.- I. Specific Transport Systems of l- and D-Amino Acids.- II. Interactions Between Amino Acid and Sugar Transport.- III. Absorption and Transport of Peptides.- D. Concluding Remarks.- References.- 16 Pharmacologic Aspects of Intestinal Permeability to Lipids (Except Steroids and Fat-Soluble Vitamins).- A. Introduction.- B. Brief Outline of the Physiology of Intestinal Permeability to Lipids.- I. Permeation from the Intestinal Lumen (Fat Absorption).- II. Permeation from the Plasma Pool (Uptake and Metabolism of Plasma Free Fatty Acids).- C. Mechanisms by which Drugs May Affect the Intestinal Permeability to Lipids.- I. Interference with Intraluminal Events of Fat Absorption.- II. Disturbance of Intestinal Mucosal Integrity.- III. Interference with Intracellular Events of Intestinal Lipid and Lipoprotein Metabolism.- IV. Interactions with Intestinal Metabolism of Plasma Free Fatty Acids.- D. Agents which Affect the Intestinal Permeability to Lipids in a More Complex Manner.- I. Ethanol.- II. Hormones.- III. Cytostatic Agents.- IV. Dietary Fiber.- E. Concluding Remarks.- References.- 17 Intestinal Absorption of the Fat-Soluble Vitamins: Physiology and Pharmacology.- A. Introduction.- B. Lipid Digestion and Absorption.- C. The Fat-Soluble Vitamins.- I. Vitamins A.- II. Vitamins D.- III. Vitamins E.- IV. Vitamins K.- D. Hydrolysis of Esters of the Fat-Soluble Vitamins.- I. Intraluminal Digestion.- II. Membrane Digestion of Fat-Soluble Vitamin Esters.- E. Role of Bile Salts in Fat-Soluble Vitamin Absorption.- F. Route of Transport of Fat-Soluble Vitamins from the Intestine.- I. Lymphatic Route.- II. Portal Venous Route.- G. Enterohepatic Circulation of the Fat-Soluble Vitamins.- H. Intestinal Uptake of the Fat-Soluble Vitamins.- I. Vitamin A.- II. Vitamin D.- III. Vitamin E.- IV. Vitamin K.- V. Absorption of the Ubiquinones.- J. Summary of Intestinal Absorption of Fat-Soluble Vitamins.- K. Nonnutrient Substances which Interfere with Fat-Soluble Vitamin Absorption.- I. Bile Salt Sequestrants.- II. Nonabsorbale Lipids.- III. Drugs Affecting Small Intestinal Mucosal Morphology and Metabolism.- IV. Other Drugs Which Cause Steatorrhoea.- L. Other Effects of Drugs on Fat-Soluble Vitamin Absorption.- M. Summary of Drug Effects on Fat-Soluble Vitamin Absorption.- References.