Table Of ContentHandbuch der
experimentellen Pharmakologie
Handbook of
Experimental Pharmacology
Hefl"ter-Heubner New Series
Herausgegeben von/Edited by
O.Eichler A.Farah H. Herken A. D. Welch
Heidelberg Rensselaer, NY Berlin New Brunswick, NJ
Beirat/ Advisory Board
G. Acheson· E. J. Ariens . Z. M. Bacq . P. Calabresi . S. Ebashi . E. G. Erdos
v.
Erspamer . U. S. von Euler· W. Feldberg· R. Furchgott . A. Goldstein
G. B. Koelle· O. Krayer . H. Raskova . M. Rocha e Silva· F. Sakai· P. Waser
W. Wilbrandt
Volume XXVIII/l
Concepts in
Biochemical Pharmacology
Part 1
Contributors
W.P. Argy, Jr., A.H. Beckett, C.F. Chignell, R.M. Featherstone,
M. Finster, H. Foreman, L. T. Greene, S. Hegeman, C.A.M. Hogben,
R.D. Hossie, M. Katz, P. Keen, l.J. Kopin, J.F. Maher, L.c. Mark,
B.J. Poulsen, D.P. RaIl, H. Rackow, F. Rasmussen, L.J. Roth,
L. S. Schanker, J. Schou, G. E. Schreiner, W. Settle, L. Siegel,
R.L. Smith, H.M. Solomon, LM. Weiner
Editors
B. B. Brodie and J. R. Gillette
Assistant Editor
Helen S. Ackerman
With 143 Figures
Springer-Verlag Berlin· Heidelberg· New York 1971
DR. BERNARD B. BRODIE - DR. JAMES R. GILLETTE
Department of Health, Education and Welfare,
National Institutes of Health, Bethesda, MD 20014jUSA
ISBN-13: 978-3-642-65054-3 e-ISBN-13: 978-3-642-65052-9
DOl: 10.1007/978-3-642-65052-9
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
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Under § 64 of the German Copyright Law where copies are made for other than private use, a fee Is payable to
the publisher, the amount of the fee to be detelmined by agreement with the publisher.
© by Springer·Verlag Berlin' Heidelberg 1971. Library of Congress Catalog Card Number 79·135957.
Softcover reprint of the hardcover 1s t edition 1971
The use of general descriptive names, trade names, trade marks, etc. In this publication, even If the
former are not especially identified, is not to be taken as a sign that such names, as understood by the Trade Marks
and Merchandise Marks Act, may accordingly be used freely by anyone.
Druck: Joh. Roth sel. Ww., MQnchen
Preface
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 . . . . . .. 21
X. Physiological Factors and Dosage Forms of Drugs as Related to Absorption
from the Gastrointestinal Tract . . . . . . 22
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Chapter 3:
Buccal Apsorption of Drugs. A. H. BECKETT and R. D. HOSSIE. With 23 Figures 25
A. General Considerations. . . . . . . . . . . 25
B. Administration of Drugs via the Buccal Route . . . 26
C. Buccal Absorption Characteristics of Drugs. . . . . 27
I. General Method for the Buccal Absorption Test 28
II. Results of the Buccal Absorption Test . . . . 28
III. Absorption of Basic Drugs . . . . . . . . . 31
IV. Absorption of Acidic Drugs . . . . . . . . . . 34
V. Correlation with Partition Coefficients of Acidic and Basic Drugs. 36
VI. Kinetics of Buccal Absorption of some Acids and Bases. . . . . 39
D. Distribution and Excretion of some Basic Drugs after Buccal Absorption in Man 42
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Chapter 4:
Subcutaneous and Intramuscular Injection of Drugs. J. SCHOU. With 7 Figures 47
A. Introduction . . . . . 47
B. Anatomy of Injections. . 48
Local Events. . . . 48
C. Mechanism of Absorption 49
1. Blood Flow Measurement 50
2. Absorption Kinetics 51
3. Pellet Absorption 52
4. Dynamic Events . 52
5. Molecular Weight 53
D. Biological Factors . . . . 54
1. Blood Flow . . . 55
2. Connective Tissue 56
3. Glucocorticoids 58
4. Release of Biogenic Substances. 58
E. Injection Solutions . . . . . . . . . 59
1. Injection Volume and Concentration 59
2. Tonicity . . . . . . . . . 59
3. Hydrogen Ion Concentration. . . . 60
VIII Contents
F. Delayed Uptake ...•.... 60
1. Prolonged Local Effect . . 60
2. Prolonged Systemic Effect 61
G. Complications with Injections ..... 61
1. Microbiological Contamination . 62
2. Nerve Damage 62
3. Carcinogenesis. 62
H. Conclusion . .. 62
References. . . . . . . . 63
Chapter 5:
Absorption, Distribution and Excretion of Gaseous Anesthetics. H. RACKOW.
With 18 Figures. . . . . . . . 67
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
Chapter 6:
Aerosols. L. T. GREENE 88
I. Properties of Aerosols.. ..... . 88
II. Measurement of Aerosols . . . . . . 89
III. Generation of Aerosols . . . . . . . . . . . 89
IV. Deposition of Aerosols in the Respiratory Tract 91
V. Absorption of Aerosols - Absorptive Surfaces 93
VI. Absorption Studies . 95
VII. Summary .. ........... . 97
References. . . . . . . . . . . . . . . . . . . . 97
Chapter 7:
Absorption of Drugs through the Skin. M. KATZ and B.J. POULSEN. With 16 Figures 103
Preface ......... . 103
A. Anatomy and Physiology. . . 103
I. Evolution. . . . . . . 103
II. Some Facts and Figures . 104
III. Anatomy . . . . . . 104
1. Epidermis 105
2. The Dermis (Corium) 108
3. Subcutaneous Tissue 109
4. Appendages . 110
5.pH ...... . 111
IV. Dermatitis .... . 112
1. Pathology 112
2. Structure Changes 112
3. Inflammation . . 113
4. Patterns . . . . 113
B. Pathways of Percutaneous Absorption 114
I. Introduction. . . . 114
II. Alternate Pathways ..... . 114
III. General Conclusions. . . . . . 116
C. Factors Affecting Percutaneous Absorption 117
I. Introduction. . . . . 117
II. Drug-skin Interactions 118
1. Skin Hydration . . 118
2. Circulatory Effects . 118
3. Skin Metabolism. . . 119
4. Binding of Drugs by Skin 121
III. Vehicle-Skin Interactions . 121
1. Effect on Skin Hydration 121
2. Temperature Effects . • 124
3. Solvent Effects . . . • 125
IV. Drug-Vehicle Interactions. 130
1. Release from Solutions . 131
2. Release from Suspensions • 132
3. Other Factors Influencing Release 134
Contents IX
V. Drug-Vehicle-Skin Interactions. 134
1. Diffusion Constant . 136
2. Partition Coefficient . 136
3. Drug Concentration. . . . . 139
VI. Summary • . . . . . . . . . 141
D. Methods for Studying Percutaneous Absorption 141
I. In Vitro . .............. . 141
1. Diffusion Methods without a Membrane . 141
2. Diffusion Methods with Membranes . 142
II. In Vivo . ...... . 144
1. Animal Models 144
2. Remainder Analysis . 145
3. Human Skin Window. 145
4. Histology . . . . . . 145
5. Direct Observation. . . 146
6. Systematic Observation . 147
7. Dermal Perfusion. . . . 148
E. Drugs and Methods for Percutaneous Absorption Studies 148
F. Treatment .................. . 148
I. Dermatologic Medications. . . . . . . . . . 148
II. Anti-Inflammatory Agents - Topical Corticoids 159
III. Vehicles. 160
References. . . . . . . . . . . . . . . . . . . . . 162
Section Two: Sites of Drug Transport and Disposition
Chapter 8:
The Nature of Drug-Protein Interaction. W. SETTLE, S. HEGEMAN, and R.M. FEATHER-
STONE. With 5 Figures . . . . . . . . 175
A. Protein Structures. . . . . . . . . . . . . . 175
B. Maintenance Forces of Protein Structure . . . . 178
C. Protein Structure and Binding of Small Molecules . . . . . . . . . 178
I. Alterations of Structure at the Site of Binding of Small Molecules . . . . . 178
II. Alterations of Protein Structure at Sites Remote from the Binding Site of Small
Molecules . . . . . . . . . . . . . 180
D. Forces in Protein-Small Molecule Interactions 181
I. Bond Types . . . . . . . 181
II. "Hydrophobic Bonds" . . 183
III. Free Energy Considerations 184
IV. Environmental Effects 184
E. Albumins. . . . . . . . . . . 184
I. Structure of Albumin. . . 185
II. Albumin-Drug Interactions 185
Conclusion.. .... 185
References. . . . . . . . . . . . 185
Chapter 9:
Physical Methods for Studying Drug-Protein Binding. C.F. CHIGNELL. With 10 Figures 187
A. Nonspectroscopic Techniques . . 188
I. Rapid (or Kinetic) Dialysis 188
II. Gel Filtration . . . . . . 189
III. Heatburst Microcalorimetry 189
B. Spectroscopic Techniques. . . . . . . . . . . . . 190
I. Ultraviolet and Visible Absorption Spectroscopy 190
II. Fluorescence Spectroscopy. . . . . . . . . . . 193
III. Optical Rotatory Dispersion and Circular Dichroism 197
IV. Nuclear Magnetic Resonance ...... 203
V. Other Spectroscopic Techniques . . . . . 206
VI. Stopped Flow and Relaxation Spectrometry 208
References. . . . . . . . . . . . . . . . . . . 209
x Contents
Chapter 10:
Eft'ect of Binding to Plasma Proteins on the Distribution, Activity and E1imination of
Drugs. P. KEEN. With 9 Figures. . 213
A. Effect on Distribution and Activity 213
1. The Drug-Protein Complex 213
2. Tissue Distribution. . . . 215
3. Pharmacodynamic Activity 217
4. Antibacterial Activity. . . . . 218
5. Entry into Transmembrane Compartments 220
B. Effect on Elimination . . . 222
1. Renal Excretion . . 222
2. Excretion into Bile . 223
3. Salivary Excretion . 223
4. Drug Metabolism. . 223
C. Effect on Pharmacokinetics . 224
1. A Model. . . 224
2. Distribution . 224
3. Kinetics. 227
D. Conclusions. . 230
References. . . . . 230
Chapter 11:
Competition between Drugs and Normal Substrates for Plasma and Tissue Binding Sites.
H. M. SOLOMON . . 234
I. Introduction. 234
II. Bilirubin . 234
III. Thyroxine 235
IV. Steroids . 236
V. Fatty Acids 237
VI. Summary 238
References. . . . . 238
Chapter 12:
Drug Entry into Brain and Cerebrospinal Fluid. D.P. RALL. With 6 Figures 240
A. Introduction . . . . . . . . . . . . . . . . . 240
B. Anatomical Basis of Blood, Brain and CSF Barriers. 241
C. Blood-CSF Relationships. . . . . . . . . 242
D. CSF-Brain Relationships. . . . . . . . . 243
E. Drug Entry into CSF and Brain from Blood . 244
F. Methods for Studying Drug Entry and Exit . 246
G. Pathological Situations. . 247
References. . . . . . . . . . . . . . . . . 248
Chapter 13:
Translocation of Drugs into Bone. H. FOREMAN. 249
I. Introduction. . . . . . . . . . . . . 249
II. The Nature of Bone . . . . . . . . . 249
III. Bone Mineral . . . . . . . . . . . . 250
IV. Bone Mineral Dynamics and Ion Binding 250
V. Binding of Heterogeneous Materials 251
1. Tetracyclines . . . 251
2. Other Organic Drugs 254
3. Fluorides 254
References. . . . . . . . . . 255
Chapter 14:
Translocation of Drugs and Other Exogenous Chemicals into Adipose Tissue. L. C. MARK.
With 4 Figures. . . . . . . . . . . . . . . 258
Adipose Tissue as a Unique Body Compartment. . 260
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272
Chapter 15:
Placental Transfer of Drugs and their Distribution in Fetal Tissues. M. FINSTER, and
L. C. MARK. With 3 Figures . . . 276
I. Physicochemical Properties . . . . . . . . . . . . . . . . . . . . . . 276
Contents XI
II. Maternal Hemodynamics and Pharmacokinetics 277
1. Maternal Hemodynamics . 277
2. Maternal Pharmacokinetics . 277
3. Special Considerations . . . 277
III. The Placenta . . . . . . . . 278
1. Anatomic Considerations . . 278
2. Hemodynamic Considerations 279
3. Other Considerations 280
IV. The Fetal Circulation. 280
Practical Applications 282
References. . . . . . . . . . 283
Chapter 16:
The Use of Autoradiography in Experimental Pharmacology. L.J. ROTH. With 16 Figures 286
A. Introduction . . . . . . . . . . 286
B. Light Microscope Autoradiography. . . . . . . . . . . . . . . . . . . . . . 291
I. Extracellular Space ......................... 291
II. 3H Nicotine in Ganglia . . . . . . . . . . . . . . . . . . . . . . . . 294
III. Estradiol in Uterine Tissue - Localization by Autoradiographic and Biochemi-
cal Techniques. . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
IV. 3H Estradiol in Nervous Tissue .................... 299
V. Neuromuscular Junction - Measurement of Active AchE Enzyme Sites in End-
plates. . . . . . . . . . . . . . 300
1. Curare Alkaloids. . . . . . .. . 301
2. Decamethonium . . . . . . . . . . 301
3. Diisopropylfluorophosphate (DFP) . . 301
C. Electron Microscope Autoradiography (E~IAR) 305
I. DFP at Motor Endplates . . . . . .. . 305
II. Norepinephrine at Sympathetic Nerve Terminals 307
D. Organ and Whole Body Autoradiography. . . . 308
References. . . . . . . . . . . . . . . . . . . . . 313
Chapter 17:
Accumulation of Drugs at Sympathetic Nerve Endings. I.J. KOPIN. With 2 Figures. 317
A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317
B. Accumulation of Amines in Adrenergic Neurones . . . . . . . . . . . . . 317
C. Functional Significance of Amine Accumulation in Sympathetic Nerve Endings 320
D. Effects on Norepinephrine Synthesis. . . . . . . 322
E. Chemical Sympathectomy with 6-Hydroxydopamine 322
F. Uptake of Other Cyclic Bases 323
Summary . . . . . . . . . . . . . . . 324
References. . . . . . . . . . . . . . . . . . . . 324
Section Three: Sites of Drug Excretion
Chapter 18:
Excretion of Drugs by the Kidney. I.M. WEINER. With 6 Figures 328
Introduction. . . . . . . . . . . . . . . . . . . . . . . . 328
I. The Components of the Renal Excretory System. . . . 329
II. Assessment of Tubular Function. . . . . . . . . . . 332
III. Characteristics of Clearances Determined Mainly by Passive Processes 334
IV. The Secretory System .................... 339
1. Organic Anion Mechanism ................. 339
2. The Organic Cation Mechanism . . . . . . . . . . . . . . . 343
3. Other Components and Compounds Apparently Secreted by Two Mechanisms 344
V. The Reabsorptive Systems: Bidirectional Transport . . . . . . 345
VI. Analogous Aspects of Studies of Drug Metabolism and Excretion. 346
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347
Chapter 19:
Excretion of Drugs in Bile. R. L. SMITH. With 5 Figures 354
A. Introduction . . 354
B. Historical Aspects . . . . . . . . . . . . . . . 354
