The intestine, particularly the small bowel, represents a large surface (in the adult 2 human approximately 200 m ) through which the body is exposed to its environ­ ment. 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 the bioavailability 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 signigicant alteration of the physiological process of intestinal permeation.

Inhalt

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. Eff…