Pharmacology of Intestinal Permeation II

18 Intestinal Absorption of Xenobiotics..- A. Introduction.- B. Drug Absorption and Pharmacologic Response.- C. The Side of Drug Absorption.- D. The Intestinal Barrier and its Permeability.- I. The Unstirred Water Layer.- II. The Transcellular Route.- III. The Intercellular Route.- IV. Absorption via the Lymph.- E. Factors Which Influence the Intestinal Absorption of Xenobiotics.- I. Factors Inherent to the Drug Molecule.- II. Factors Inherent of Pharmaceutical Formulation.- III. Factors Inherent to Intestinal Permeability.- IV. Factors Inherent to the Patient.- References.- 19 Role of Digestive Enzymes in the Permeability of the Enterocyte.- A. Introduction.- B. Relationship Between the Hydrolytic and Transport Systems of the Enterocytes.- I. The Basic Types of Digestion and Their Relation to Absorption..- II. Membrane Digestion and Digestive-Absorptive Functions of the Enterocyte Membrane.- III. Classification of Digestive Processes.- IV. The Enzyme Apparatus of Membrane Digestion.- V. Membrane Digestion in Normal Function of the Gastrointestinal Tract.- C. Enzyme Apparatus of the Apical Membrane of the Enterocytes.- I. Fine Location of Membrane Hydrolases.- II. The Amphipathic Structure of Membrane Enzymes.- III. Functions of the Hydrophobic Part of Intestinal Enzymes.- IV. Characterization of Hydrolases.- D. Characterization of the Transport of Free Monomers and Hydrolysis-Released Monomers.- I. Comparison of the Rates of Absorption of Oligomers and Monomers.- II. Factors Affecting the Relationship Between Oligomer and Monomer Transport.- III. Kinetic Characteristics of Oligomer and Monomer Transport.- IV. Competitive Interactions Between Free and Hydrolysis-Released Monomers.- V. Role of Na+ in the Transport of Hydrolysis-Released and Free Monomers.- E. The Enzyme Transport Complexes of the Apical Membrane of the Enterocytes.- I. Cooperative Interactions Between Enzymatic and Transport Parts.- II. Allosteric Interactions Between Enzyme and Transport Parts.- III. Possible Molecular Models.- IV. The Permeome.- F. Conclusion.- I. Adaptability and Regulation of the Enzyme Transport Complexes.- II. The Enzyme Transport Complexes of the Membrane in Pathology.- III. Concluding Remarks.- References.- 20 The Surface pH of the Intestinal Mucosa and its Significance in the Permeability of Organic Anions..- A. Introduction.- B. Intestinal pH Measurements.- C. Acidification Studies.- I. The Effect of Mucosal Glucose Concentration.- II. The Involvement of Carbonic Anhydrase.- III. Sodium Ion Exchange Mechanisms.- IV. Hydrogen-Potassium Exchange.- V. Acidification and Electrical Events.- VI. The Mechanism of Hydrogen Ion Secretion.- VII. Hormonal Effects.- VIII. Infectious Agents.- D. The Intestinal Acid Microclimate.- I. Evidence for the Microclimate Hypothesis.- II. Clinical Studies.- III. Related Phenomena.- IV. The Role of Mucus.- E. Alternative Concepts.- I. The Unstirred Layer Hypothesis.- II. Permeation of Ionised Forms.- III. Extraction Theory.- F. Absorption and the Microclimate Hypothesis: Three Paradigms.- I. Folic Acid Absorption.- II. Fatty Acid Absorption.- III. Propranolol Absorption.- G. Modelling the System.- H. Conclusion.- References.- 21 The Role of the Unstirred Water Layer in Intestinal Permeation.- A. Unstirred Water Layers: Historical and Conceptual Background.- B. Water Compartments In and Around the Intestinal Mucosal Cell.- C. Comparison of Dimensions of the Unstirred Water Layer with Morphological Parameters.- D. The Glycocalyx and Mucus as Diffusion Barriers.- E. Intestinal Membrane Structure.- F. Movement of Solutes Across Biologic Membranes: General Principles.- G. Effects of Aqueous Diffusion Barriers on Solute Movement.- H. A Consideration of Surface Areas.- J. Consequences of Failure to Correct for the Unstirred Water Layer and Passive Permeation.- K. Diffusion Barriers of Greater Complexity.- L. Possible Functional Heterogeneity of the Villus.- M. Effect of Carrier Molecules, Solubility of Probe, and Metabolism in the Cytosolic Compartment.- N. Effect of Membrane Polarity on Penetration of Passively Transported Molecules.- O. Anomalous Behavior of Diffusion of Certain Solutes Across the Intestine.- P. Methods Available for the Measurement of the Dimensions of the Unstirred Water Layer.- I. Effective Thickness of the Unstirred Water Layer.- II. Effective Surface Area of the Unstirred Water Layer.- Q. Examples of the Effect of Unstirred Water Layers on Intestinal Transport.- I. Estimates of the Temperature Coefficient.- II. Estimates of Kinetic Constants of Carrier-Mediated Transport..- III. Permeation of Weak Electrolytes: Acid Microclimate.- IV. Effect of Volume Flow, "Sweeping Away" Effects, and Unstirred Layers on the Estimation of Effective Osmotic Pressure Across a Membrane.- V. Membrane "Pores"18 Intestinal Absorption of Xenobiotics..- A. Introduction.- B. Drug Absorption and Pharmacologic Response.- C. The Side of Drug Absorption.- D. The Intestinal Barrier and its Permeability.- I. The Unstirred Water Layer.- II. The Transcellular Route.- III. The Intercellular Route.- IV. Absorption via the Lymph.- E. Factors Which Influence the Intestinal Absorption of Xenobiotics.- I. Factors Inherent to the Drug Molecule.- II. Factors Inherent of Pharmaceutical Formulation.- III. Factors Inherent to Intestinal Permeability.- IV. Factors Inherent to the Patient.- References.- 19 Role of Digestive Enzymes in the Permeability of the Enterocyte.- A. Introduction.- B. Relationship Between the Hydrolytic and Transport Systems of the Enterocytes.- I. The Basic Types of Digestion and Their Relation to Absorption..- II. Membrane Digestion and Digestive-Absorptive Functions of the Enterocyte Membrane.- III. Classification of Digestive Processes.- IV. The Enzyme Apparatus of Membrane Digestion.- V. Membrane Digestion in Normal Function of the Gastrointestinal Tract.- C. Enzyme Apparatus of the Apical Membrane of the Enterocytes.- I. Fine Location of Membrane Hydrolases.- II. The Amphipathic Structure of Membrane Enzymes.- III. Functions of the Hydrophobic Part of Intestinal Enzymes.- IV. Characterization of Hydrolases.- D. Characterization of the Transport of Free Monomers and Hydrolysis-Released Monomers.- I. Comparison of the Rates of Absorption of Oligomers and Monomers.- II. Factors Affecting the Relationship Between Oligomer and Monomer Transport.- III. Kinetic Characteristics of Oligomer and Monomer Transport.- IV. Competitive Interactions Between Free and Hydrolysis-Released Monomers.- V. Role of Na+ in the Transport of Hydrolysis-Released and Free Monomers.- E. The Enzyme Transport Complexes of the Apical Membrane of the Enterocytes.- I. Cooperative Interactions Between Enzymatic and Transport Parts.- II. Allosteric Interactions Between Enzyme and Transport Parts.- III. Possible Molecular Models.- IV. The Permeome.- F. Conclusion.- I. Adaptability and Regulation of the Enzyme Transport Complexes.- II. The Enzyme Transport Complexes of the Membrane in Pathology.- III. Concluding Remarks.- References.- 20 The Surface pH of the Intestinal Mucosa and its Significance in the Permeability of Organic Anions..- A. Introduction.- B. Intestinal pH Measurements.- C. Acidification Studies.- I. The Effect of Mucosal Glucose Concentration.- II. The Involvement of Carbonic Anhydrase.- III. Sodium Ion Exchange Mechanisms.- IV. Hydrogen-Potassium Exchange.- V. Acidification and Electrical Events.- VI. The Mechanism of Hydrogen Ion Secretion.- VII. Hormonal Effects.- VIII. Infectious Agents.- D. The Intestinal Acid Microclimate.- I. Evidence for the Microclimate Hypothesis.- II. Clinical Studies.- III. Related Phenomena.- IV. The Role of Mucus.- E. Alternative Concepts.- I. The Unstirred Layer Hypothesis.- II. Permeation of Ionised Forms.- III. Extraction Theory.- F. Absorption and the Microclimate Hypothesis: Three Paradigms.- I. Folic Acid Absorption.- II. Fatty Acid Absorption.- III. Propranolol Absorption.- G. Modelling the System.- H. Conclusion.- References.- 21 The Role of the Unstirred Water Layer in Intestinal Permeation.- A. Unstirred Water Layers: Historical and Conceptual Background.- B. Water Compartments In and Around the Intestinal Mucosal Cell.- C. Comparison of Dimensions of the Unstirred Water Layer with Morphological Parameters.- D. The Glycocalyx and Mucus as Diffusion Barriers.- E. Intestinal Membrane Structure.- F. Movement of Solutes Across Biologic Membranes: General Principles.- G. Effects of Aqueous Diffusion Barriers on Solute Movement.- H. A Consideration of Surface Areas.- J. Consequences of Failure to Correct for the Unstirred Water Layer and Passive Permeation.- K. Diffusion Barriers of Greater Complexity.- L. Possible Functional Heterogeneity of the Villus.- M. Effect of Carrier Molecules, Solubility of Probe, and Metabolism in the Cytosolic Compartment.- N. Effect of Membrane Polarity on Penetration of Passively Transported Molecules.- O. Anomalous Behavior of Diffusion of Certain Solutes Across the Intestine.- P. Methods Available for the Measurement of the Dimensions of the Unstirred Water Layer.- I. Effective Thickness of the Unstirred Water Layer.- II. Effective Surface Area of the Unstirred Water Layer.- Q. Examples of the Effect of Unstirred Water Layers on Intestinal Transport.- I. Estimates of the Temperature Coefficient.- II. Estimates of Kinetic Constants of Carrier-Mediated Transport..- III. Permeation of Weak Electrolytes: Acid Microclimate.- IV. Effect of Volume Flow, "Sweeping Away" Effects, and Unstirred Layers on the Estimation of Effective Osmotic Pressure Across a Membrane.- V. Membrane "Pores"18 Intestinal Absorption of Xenobiotics..- A. Introduction.- B. Drug Absorption and Pharmacologic Response.- C. The Side of Drug Absorption.- D. The Intestinal Barrier and its Permeability.- I. The Unstirred Water Layer.- II. The Transcellular Route.- III. The Intercellular Route.- IV. Absorption via the Lymph.- E. Factors Which Influence the Intestinal Absorption of Xenobiotics.- I. Factors Inherent to the Drug Molecule.- II. Factors Inherent of Pharmaceutical Formulation.- III. Factors Inherent to Intestinal Permeability.- IV. Factors Inherent to the Patient.- References.- 19 Role of Digestive Enzymes in the Permeability of the Enterocyte.- A. Introduction.- B. Relationship Between the Hydrolytic and Transport Systems of the Enterocytes.- I. The Basic Types of Digestion and Their Relation to Absorption..- II. Membrane Digestion and Digestive-Absorptive Functions of the Enterocyte Membrane.- III. Classification of Digestive Processes.- IV. The Enzyme Apparatus of Membrane Digestion.- V. Membrane Digestion in Normal Function of the Gastrointestinal Tract.- C. Enzyme Apparatus of the Apical Membrane of the Enterocytes.- I. Fine Location of Membrane Hydrolases.- II. The Amphipathic Structure of Membrane Enzymes.- III. Functions of the Hydrophobic Part of Intestinal Enzymes.- IV. Characterization of Hydrolases.- D. Characterization of the Transport of Free Monomers and Hydrolysis-Released Monomers.- I. Comparison of the Rates of Absorption of Oligomers and Monomers.- II. Factors Affecting the Relationship Between Oligomer and Monomer Transport.- III. Kinetic Characteristics of Oligomer and Monomer Transport.- IV. Competitive Interactions Between Free and Hydrolysis-Released Monomers.- V. Role of Na+ in the Transport of Hydrolysis-Released and Free Monomers.- E. The Enzyme Transport Complexes of the Apical Membrane of the Enterocytes.- I. Cooperative Interactions Between Enzymatic and Transport Parts.- II. Allosteric Interactions Between Enzyme and Transport Parts.- III. Possible Molecular Models.- IV. The Permeome.- F. Conclusion.- I. Adaptability and Regulation of the Enzyme Transport Complexes.- II. The Enzyme Transport Complexes of the Membrane in Pathology.- III. Concluding Remarks.- References.- 20 The Surface pH of the Intestinal Mucosa and its Significance in the Permeability of Organic Anions..- A. Introduction.- B. Intestinal pH Measurements.- C. Acidification Studies.- I. The Effect of Mucosal Glucose Concentration.- II. The Involvement of Carbonic Anhydrase.- III. Sodium Ion Exchange Mechanisms.- IV. Hydrogen-Potassium Exchange.- V. Acidification and Electrical Events.- VI. The Mechanism of Hydrogen Ion Secretion.- VII. Hormonal Effects.- VIII. Infectious Agents.- D. The Intestinal Acid Microclimate.- I. Evidence for the Microclimate Hypothesis.- II. Clinical Studies.- III. Related Phenomena.- IV. The Role of Mucus.- E. Alternative Concepts.- I. The Unstirred Layer Hypothesis.- II. Permeation of Ionised Forms.- III. Extraction Theory.- F. Absorption and the Microclimate Hypothesis: Three Paradigms.- I. Folic Acid Absorption.- II. Fatty Acid Absorption.- III. Propranolol Absorption.- G. Modelling the System.- H. Conclusion.- References.- 21 The Role of the Unstirred Water Layer in Intestinal Permeation.- A. Unstirred Water Layers: Historical and Conceptual Background.- B. Water Compartments In and Around the Intestinal Mucosal Cell.- C. Comparison of Dimensions of the Unstirred Water Layer with Morphological Parameters.- D. The Glycocalyx and Mucus as Diffusion Barriers.- E. Intestinal Membrane Structure.- F. Movement of Solutes Across Biologic Membranes: General Principles.- G. Effects of Aqueous Diffusion Barriers on Solute Movement.- H. A Consideration of Surface Areas.- J. Consequences of Failure to Correct for the Unstirred Water Layer and Passive Permeation.- K. Diffusion Barriers of Greater Complexity.- L. Possible Functional Heterogeneity of the Villus.- M. Effect of Carrier Molecules, Solubility of Probe, and Metabolism in the Cytosolic Compartment.- N. Effect of Membrane Polarity on Penetration of Passively Transported Molecules.- O. Anomalous Behavior of Diffusion of Certain Solutes Across the Intestine.- P. Methods Available for the Measurement of the Dimensions of the Unstirred Water Layer.- I. Effective Thickness of the Unstirred Water Layer.- II. Effective Surface Area of the Unstirred Water Layer.- Q. Examples of the Effect of Unstirred Water Layers on Intestinal Transport.- I. Estimates of the Temperature Coefficient.- II. Estimates of Kinetic Constants of Carrier-Mediated Transport..- III. Permeation of Weak Electrolytes: Acid Microclimate.- IV. Effect of Volume Flow, "Sweeping Away" Effects, and Unstirred Layers on the Estimation of Effective Osmotic Pressure Across a Membrane.- V. Membrane "Pores".- VI. Potential Role of the Intestinal Unstirred Water Layer in Disease.- References.- 22 Intestinal Permeation of Organic Bases and Quaternary Ammonium Compounds.- A. Introduction.- B. Absorption of Organic Bases and Quaternary Ammonium Compounds.- I. Dependence on Polarity.- II. Dependence on Concentration.- III. Dependence on Time.- C. Intestinal Secretion of Organic Cations.- I. Secretion by the Isolated Mucosa of Guinea-Pig Small Intestine..- II. Substrate Specificity.- III. Localization of the Secretory System in the Enterocyte.- IV. In Vivo Secretion.- D. A Concept for the Intestinal Permeation of Organic Cations.- E. Comparative Aspects of Organic Cation Secretion.- I. Intestinal Secretion of Other Xenobiotics.- II. Secretion of Organic Cations by Other Organs.- F. Conclusions.- References.- 23 Role of Blood Flow in Intestinal Permeation.- A. Introduction.- B. Methods.- C. Theoretical Considerations.- D. Experimental Data.- I. Dependence of Intestinal Absorption on Total Intestinal Blood Flow Rate.- II. Dependence of Intestinal Absorption on Intramural Blood Flow Pattern.- III. Role of Villous Countercurrent Exchange in Intestinal Absorption.- E. Concluding Remarks.- References.- 24 Hormonal Effects on Intestinal Permeability.- A. Introduction.- B. Gastrin.- I. In Vitro Studies.- II. In Vivo Studies.- C. Cholecystokinin.- D. Vasoactive Intestinal Polypeptide.- I. In Vitro Studies.- II. In Vivo Studies.- III. VIP-Secreting Tumors.- E. Secretin.- F. Insulin.- I. Influence of Exogenous Insulin on Intestinal Permeability.- G. Glucagon.- I. Effect on Intestinal Water and Electrolyte Movements.- II. Endogenous Hyperglucagonemia.- III. Effect on Sugar and Amino Acid Absorption In Vivo.- IV. Effect on Sugar and Amino Acid Transfer In Vitro.- V. Effect on Portal Glucose Transport.- VI. Changes of Mucosal cAMP and cGMP Levels After Glucagon Treatment in the Rat Small Intestine.- VII. Intestinal Mucosal Adaptation to Glucagon.- H. Other Gastrointestinal Polypeptides.- I. Gastric Inhibitory Polypeptide.- II. Pancreatic Polypeptide.- III. Somatostatin.- IV. Sorbin.- J. General Remarks on the Effects of Gastrointestinal Hormones on Intestinal Permeation.- References.- 25 The Influence of Opiates on Intestinal Transport.- A. Introduction.- B. In Vivo Studies.- C. In Vitro Studies.- I. Opiate Receptors.- II. Possible Neural Mediation.- D. Ion Flux Responses.- E. Antisecretory Activity.- F. Summary.- References.- 26 Effect of Cholera Enterotoxin on Intestinal Permeability.- A. Introduction.- B. Cholera Enterotoxin-Intestinal Interaction.- I. The Enterotoxin.- II. Enterotoxin-Enterocyte Interaction.- III. Enterotoxin Activation of Adenylate Cyclase.- IV. Cyclic AMP and Intestinal Secretion.- C. Role of Increased Filtration in the Production of Cholera-Induced Intestinal Secretion.- I. Increased Intestinal Permeability.- II. Increased Driving Force.- D. Conclusion.- References.- 27 Aspects of Bacterial Enterotoxins Other than Cholera on Intestinal Permeability.- A. Introduction.- B. Escherichia coli.- I. Heat-Labile Toxin.- II. Heat-Stable Toxin.- III. Relationship of Surface Adhesion (Colonization Factors) to Fluid Secretion.- IV. Surface Mucosal Invasion (Enteroadherence).- C. Shigella.- D. Prostaglandin Released from Inflamed Tissue and Fluid and Electrolyte Secretion.- E. Salmonella.- I. Salmonella Enteritis.- II. Role of Increased Capillary Hydrostatic Pressure and Transmucosal Permeability.- III. Role for a Salmonella Enterotoxin.- F. Pseudomonas aeruginosa.- G. Campylobacter fetus.- H. Yersinia enterocolitica.- J. Noncoliform Enterobacteriaceae.- I. Klebsiella pneumoniae Toxin.- II. Enterobacter cloacae Toxin.- III. Aeromonas hydrophila Toxin.- K. Food Poisoning Organisms.- I. Bacillus cereus Toxin.- II. Clostridial Toxin.- L. Staphylococcus.- M. Additional Mechanisms for Toxin-Mediated Permeation Defects.- I. Evidence for a Role for Calcium.- II. Filtration Secretion.- References.- 28 Mechanisms of Action of Laxative Drugs.- A. Introduction.- B. Intestinal Tract Smooth Muscle Response to Laxatives.- C. Effects of Laxatives on Fluid and Electrolyte Movement.- I. Cellular and Mucosal Damage.- II. Enhanced Mucosal Permeability.- III. Role of cAMP in the Actions of Laxatives.- IV. Effects of Laxatives on NA+, K+-ATPase and Energy Metabolism.- V. Hormones as Mediators of Laxative Action.- D. Bulk and Dietary Fibers.- I. Water-Retaining Properties.- II. Role of Bacteria in the Action of Bulk Laxatives.- III. Altered Transit Time.- IV. Fiber Interaction.- V. Carbohydrate Laxative Drugs.- E. Summary.- References.- 29 Action Mechanisms of Secretagogue Drugs.- A. Introduction.- B. Theoretical Considerations.- I. Inhibition of Active Absorption.- II. Active Secretion.- III. Filtration.- C. Triarylmethane and Anthraquinone Derivatives.- I. Effect on Intestinal Fluid and Electrolyte Transfer.- II. Chemistry, Structure-Activity Relationship, and Pharmacokinetics.- III. Proposed Action Mechanisms.- IV. Conclusion.- D. Surfactants.- I. Effect on Intestinal Fluid and Electrolyte Transfer.- II. Structure-Activity Relationship.- III. Proposed Action Mechanisms.- IV. Conclusions.- E. General Summary and Concluding Remarks.- References.- 30 Use and Abuse of Cathartics.- A. Introduction.- B. Classification.- I. Bulking Agents.- II. Contact Cathartics.- III. Stool Softeners.- IV. Osmotic Laxatives.- V. Per Rectum Evacuants.- C. Indications for Use.- I. Constipation.- II. The Irritable Bowel Syndrome.- D. Laxative Abuse.- I. Habitual Abuse.- II. Surreptitious Abuse.- E. Summary.- References.- 31 Intestinal Permeability Studies in Humans.- A. Introduction.- B. Methods for Studying Intestinal Permeability in Humans.- I. Intestinal Perfusion.- II. Intestinal Permeability Studied by Test Molecules.- III. Electrical Transmucosal Potential Difference.- C. Permeability Characteristics of the Human Gut.- I. Studies Employing Intestinal Intubation and Perfusion.- II. Selectivity of Cation Permeability.- III. Transcellular Intestinal Permeability.- IV. Unstirred Water Layer and Intestinal Permeability.- V. Intestinal Permeability to Peptide Macromolecules.- VI. Persorption of Particles.- D. Influence of Drugs on Intestinal Permeability.- I. Influence on Electrolyte and Water Transfer.- II. Change in Intestinal Permeability by Cytostatic Treatment.- E. Intestinal Permeability in Disease.- I. Coeliac Disease.- II. Inflammatory Bowel Disease.- References.