Pharmacology of Intestinal Permeation II PDF
Preview Pharmacology of Intestinal Permeation II
Handbook of Experimental Pharmacology Continuation of Handbuch der experimentellen Pharmakologie Vol. 70111 Editorial Board G.y' R.Born,London· A.Farah,Rensselaer,NewYork H. Herken, Berlin· A. D. Welch, Bethesda, Maryland Advisory Board S. Ebashi· E. G. Erdos· V. Erspamer· U. S. von Euler· W S. Feldberg G. B. Koelle· M. Rocha e Silva· 1. R. Vane· P. G. Waser Pharmacology of Intestinal Permeation II Contributors J. G. Banwell . P. Bass' T. Z. Csaky . A. M. Dawson' J. M. Dietschy K. Ewe' G. W. Gullikson' T. R. Hendrix' S. Hughes N. N. Jezuitova . F. Lauterbach· M. Lucas' J. S. McKay K. J. Moriarty· G. Nell· W. Rummel· L. F. Smimova . M. Staritz A. B. R. Thomson' L. A. Tumberg . A. M. Ugolev . V.Varr6 R. Wanitschke . D. Winne Editor T.Z. Csaky Springer-Verlag Berlin Heidelberg New York Tokyo 1984 TIHAMER Z. CSAKY, M.D. Professor of Pharmacology Department of Pharmacology University of Missouri-Columbia School of Medicine Columbia, MO 65212 USA With 149 Figures Library of Congress Cataloging in Publication Data. Main entry under title: Phannacology of intestinal penneation. (Handbook of experimental phannacology; vol. 70/1-11) Includes bibliographical references and index. I. Intestinal absorption. 2. Gastrointestinal agents - Physiological effect. I. Annstrong, W. McDennott (William McDennott) II. Csaky, T. Z. III. Series: Handbook of experimental phannacology; v. 70/1-11. [DNLM: I. Intestinal Absorption. 2. Intestines - metabolism. 3. Cell Membrane Penneability - drug effects. 4. Drugs - metabolism. WI HA51L v. 70 pt. 1-2/WI 402 P536] QP905.H3 vol. 70/1-11 615'.1 s 84-5558 [QPI56] [612'.33] ISBN-13: 978-3-642-69510-0 e-ISBN-13: 978-3-642-69508-7 DOl: 10.1007/978-3-642-69508-7 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically those of translation, reprinting, re-use of illustrations, broadcasting, reproduction by photocopying machine or similar means, and storage in data banks. Under § 54 of the Gennan Copyright Law, where copies are made for other than private use, a fee is payable to "Verwertungsgesellschaft Wort", Munich. © by Springer-Verlag Berlin Heidelberg 1984 Softcover reprint of the hardcover 1s t edition 1984 The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product Liability: The publisher can give no guarantee for infonnation about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other phannaceuticalliterature. 2122/3130-543210 List of Contributors J. G. BANWELL, Department of Medicine, Division of Gastroenterology, Case Western School of Medicine, Cleveland, OH 44106, USA P. BASS, School of Pharmacy, University of Wisconsin, 425 N. Charter Street, Madison, WI 53706, USA T. Z. CSAKY, Professor of Pharmacology, Department of Pharmacology, Uni versity of Missouri-Columbia, School of Medicine, Columbia, MO 65212, USA A. M. DAWSON, Department of Gastroenterology, St. Bartholomew's Hospital, West Smithfield, London, ECIA 7BE, Great Britain J. M. DIETSCHY, Department of Internal Medicine, University of Texas, Health Science Center, Southwestern Medical School, Dallas, TX 75235, USA K. EWE, I. Medizinische Klinik und Poliklinik, Johannes Gutenberg Universitat, Postfach 3960, LangenbeckstraJ3e 1, 6500 Mainz, FRG G. W. GULLIKSON, Research Investigator, Department of Biological Research, Searle Research and Development, Division ofG. D. Searle & Co., Box 5110, Chicago, IL 60680, USA T. R. HENDRIX, Department of Medicine, Chief Gastroenterology Division, The John Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21205, USA S. HUGHES, Department of Medicine, Hope Hospital, (University of Manchester School of Medicine), Eccles Old Road, Salford M68HD, Great Britain N. N. JEZUITOVA, J.-O. Pavlov Institute of Physiology, The Academy of Sciences of the USSR, Nab. Makarova, 6, Leningrad, 199164, USSR F. LAUTERBACH, Institut fUr Pharmakologie und Toxikologie, Ruhr-Universitiit Bochum, Postfach 102148,4630 Bochum 1, FRG M. LUCAS, Institute of Physiology, The University of Glasgow, Glasgow, W.2 Great Britain J. S. McKAY, Department of Medicine, Hope Hospital, (University of Manches ter School of Medicine), Eccles Old Road, Salford M6 8HD, Great Britain K. J. MORIARTY, Department of Gastroenterology, St. Bartholomew's Hospital, West Smithfield, London, ECIA 7BE. Present address: Department of Medicine, Hope Hospital (University of Manchester School of Medicine), Eccles Old Road, Salford M6 8HD, Great Britain VI List of Contributors G. NELL, Institut fiir Pharmakologie und Toxikologie der Universitiit des Saarlandes, 6650 Homburg (Saar), FRG W. RUMMEL, Institut fUr Pharmakologie und Toxikologie der Universitat des Saarlandes, 6650 Homburg (Saar), FRG L. F. SMIRNOVA, I. P. Pavlov Institute of Physiology, The Academy of Sciences of the USSR, Nab. Makarova, 6, Leningrad, 199164, USSR M. STARITZ, I. Medizinische Klinik und Poliklinik, LangenbeckstraBe 1, 6500 Mainz, FRG A. B. R. THOMSON, University of Alberta, Edmonston, Alberta, CDN L. A. TURNBERG, Department of Medicine, Hope Hospital, (University of Manchester School of Medicine), Eccles Old Road, Salford M6 8HD, Great Britain A. M. UGOLEV, I. P. Pavlov Institute of Physiology, The Academy of Sciences of the USSR, Nab. Makarova, 6, Leningrad, 199164, USSR V. VA RR6, First Department of Medicine, University Medical School, P.B. 469, 6701 Szeged, Hungary R. WANITSCHKE, I. Medizinische Klinik und Poliklinik, Johannes-Gutenberg Universitat, Postfach 3960, LangenbeckstraBe 1,6500 Mainz, FRG D. WINNE, Abt. fUr Molekularpharmakologie, Pharmakologisches Institut der Universitat Tiibingen, WilhelmstraBe 56, 7400 Tiibingen 1, FRG Preface The intestine, particularly the small bowel, represents a large surface (in the adult human approximately 200 m2) 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. The material in these volumes was collected in order to present some of the fundamental aspects of the permeability and the permeation of the intestine. An attempt has been made to include morphological, physicochemical, physiologic, biophysical, biochemical, pharmacologic and toxicologic aspects. Clearly, intesti nal permeation cannot be properly studied from the perspective of one or a few disciplines; the subject cuts across a wide spectrum of disciplines. Consequently, it is hoped that the information provided in these volumes will be useful to scientists working in a variety of specialties. I would like to express my thanks to those colleagues who accepted my invitation and contributed to this publication. It is somewhat unfortunate that the collection of the material required a considerable amount of time, but in a publication of this size, with a large number of contributors, some delay is inevitable. One prospective contributor was prevented from completing his task by a fatal heart attack, while others had to be excused because they failed to find enough time for the work. Fortunately, outstanding replacements were secured, but not without some holdup. Our knowledge of fundamental principles seldom changes in a revolutionary fashion, thus, despite the spread in time, it is hoped VIII Preface that these volumes will provide the reader with the information necessary to form a correct contemporary image of the complex process of intestinal permeation and the conditions of permeability. Finally, I would like to thank my wife for lending me a helping hand, admist her own professional duties, in various aspects of the editorial work. T.Z. CSAKY Contents CHAPTER 18 Intestinal Absorption of Xenobiotics. T. Z. CSAKY. With 5 Figures A. Introduction . . . . . . . . . . . . . . . 1 B. Drug Absorption and Pharmacologic Response 1 C. The Side of Drug Absorption. . . . . . 2 D. The Intestinal Barrier and its Permeability 3 I. The Unstirred Water Layer. 4 II. The Transcellular Route . 5 III. The Intercellular Route . . 10 IV. Absorption via the Lymph . 11 E. Factors Which Influence the Intestinal Absorption of Xenobiotics 12 I. Factors Inherent to the Drug Molecule. . . . . 12 II. Factors Inherent of Pharmaceutical Formulation 13 III. Factors Inherent to Intestinal Permeability 13 IV. Factors Inherent to the Patient 13 References. . . . . . . . . . . . . . . . . . 23 CHAPTER 19 Role of Digestive Enzymes in the Permeability of the Enterocyte A. M. UGOLEV, N. N. IEZUITOVA, and L. F. SMIRNOVA. With 26 Figures A. Introduction . . . . . . . . . . . . . . . . . . . . . . .. 31 B. Relationship Between the Hydrolytic and Transport Systems of the Enterocytes . . . . . . . . . . . . . . . . . . . . . . . . . 32 I. The Basic Types of Digestion and Their Relation to Absorption. 32 II. Membrane Digestion and Digestive-Absorptive Functions of the Enterocyte Membrane . . . . . . . . . . . . 34 III. Classification of Digestive Processes . . . . . . . . . . . . . 37 IV. The Enzyme Apparatus of Membrane Digestion. . . . . . . . 38 V. Membrane Digestion in Normal Function of the Gastrointestinal Tract . . . . . . . . . . . . . . . . . . . . . . . 47 C. Enzyme Apparatus of the Apical Membrane of the Enterocytes 49 I. Fine Location of Membrane Hydrolases . . . . . . . . 49 II. The Amphipathic Structure of Membrane Enzymes . . . 53 III. Functions of the Hydrophobic Part of Intestinal Enzymes 58 IV. Characterization of Hydrolases . . . . . . . . . . . . 61 x Contents D. Characterization of the Transport of Free Monomers and Hydrolysis- Released Monomers. . . . . . . . . . . . . . . . . . . {j6 I. Comparison of the Rates of Absorption of Oligomers and Monomers. . . . . . . . . . . . . . . . . . . . . 67 II. Factors Affecting the Relationship Between Oligomer and Monomer Transport. . . . . . . . . . . . . . . . . 78 III. Kinetic Characteristics of Oligomer and Monomer Transport 80 IV. Competitive Interactions Between Free and Hydrolysis-Released Monomers. . . . . . . . . . . . . . . . . . . . . . .. 81 V. Role of Na + in the Transport of Hydrolysis-Released and Free Monomers. . . . . . . . . . . . . . . . . . . . . . .. 84 E. The Enzyme Transport Complexes of the Apical Membrane cif the Enterocytes . . . . . . . . . . . . . . . . . . . . . . . .. 86 I. Cooperative Interactions Between Enzymatic and Transport Parts 87 II. Allosteric Interactions Between Enzyme and Transport Parts 89 III. Possible Molecular Models . 93 IV. The Permeome . . . . . . . . . . . . . . . . . . . . 93 F. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . 95 I. Adaptability and Regulation of. the Enzyme Transport Complexes 96 II. The Enzyme Transport Complexes of the Membrane in Pathology 97 III. Concluding Remarks 98 References. . . . . . . . . . . . . . . . . . . . . . . . . . .. 98 CHAPTER 20 The Surface pH of the Intestinal Mucosa and its Significance in the Permeability of Organic Anions. M. LUCAS. With 14 Figures A. Introduction . . . . . . . 119 B. Intestinal pH Measurements . . . . . . . . . . . 121 C. Acidification Studies. . . . . . . . . . . . . . . 122 I. The Effect of Mucosal Glucose Concentration. 122 II. The Involvement of Carbonic Anhydrase 122 III. Sodium Ion Exchange Mechanisms 123 IV. Hydrogen-Potassium Exchange .... 124 V. Acidification and Electrical Events. . . 124 VI. The Mechanism of Hydrogen Ion Secretion 125 VII. Hormonal Effects . . . . 126 VIII. Infectious Agents . . . . . . . . . . . 126 D. The Intestinal Acid Microclimate . . . . . . . 127 I. Evidence for the Microclimate Hypothesis 127 II. Clinical Studies . . 134 III. Related Phenomena 135 IV. The Role of Mucus 137 E. Alternative Concepts . . 137 I. The Unstirred Layer Hypothesis. 137 II. Permeation of Ionised Forms 141 III. Extraction Theory. . . . . . . 142 Contents XI F. Absorption and the Microclimate Hypothesis: Three Paradigms 143 I. Folic Acid Absorption . 143 II. Fatty Acid Absorption. 145 III. Propranolol Absorption 148 G. Modelling the System 149 H. Conclusion. 154 References. . . . . . . 155 CHAPTER 21 The Role of the Unstirred Water Layer in Intestinal Permeation A. B. R. THOMSON and J. M. DIETSCHY. With 55 Figures A. Unstirred Water Layers: Historical and Conceptual Background. 165 B. Water Compartments In and Around the Intestinal Mucosal Cell 168 C. Comparison of Dimensions of the Unstirred Water Layer with Morphological Parameters . . . . . . . . . . 170 D. The Glycocalyx and Mucus as Diffusion Barriers . . . . . . 173 E. Intestinal Membrane Structure . . . . . . . . . . . . . . 173 F. Movement of Solutes Across Biologic Membranes: General Principles 175 G. Effects of Aqueous Diffusion Barriers on Solute Movement. . . . . 178 H. A Consideration of Surface Areas. . . . . . . . . . . . . . . . 180 J. Consequences of Failure to Correct for the Unstirred Water Layer and Passive Permeation . . . . . . . . . . . . 185 K. Diffusion Barriers of Greater Complexity. . . . . . . . . . . . . 190 L. Possible Functional Heterogeneity of the Villus . . . . . . . . . . 190 M. Effect of Carrier Molecules, Solubility of Probe, and Metabolism in the Cytosolic Compartment . . . . . . . . . . . . . . . . . . . . 193 N. Effect of Membrane Polarity on Penetration of Passively Transported Molecules . . . . . . . . . . . . . . . . . . . . . . .. 197 O. Anomalous Behavior of Diffusion of Certain Solutes Across the Intestine. . . . . . . . . . . . . . . . . . . . . . . .. 202 P. Methods Available for the Measurement of the Dimensions of the Unstirred Water Layer. . . . . . . . . . . . . . . . 204 I. Effective Thickness of the Unstirred Water Layer . . . . 204 II. Effective Surface Area of the Unstirred Water Layer. . . 213 Q. Examples of the Effect of Unstirred Water Layers on Intestinal Transport . . . . . . . . . . . . . . . . . . . . . . . 216 I. Estimates of the Temperature Coefficient. . . . . . . . 216 II. Estimates of Kinetic Constants of Carrier-Mediated Transport 218 III. Permeation of Weak Electrolytes: Acid Microclimate. . . .. 250 IV. Effect of Volume Flow, "Sweeping Away" Effects, and Unstirred Layers on the Estimation of Effective Osmotic Pressure Across a Membrane. . . . . . . . . . . . . . . . . . . . . . . . 254 V. Membrane "Pores" . . . . . . . . . . . . . . . . . . . . 255 VI. Potential Role of the Intestinal Unstirred Water Layer in Disease 258 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
The list of books you might like
