Concepts in Biochemical Pharmacology: Part 2

ISBN-13: 9783642651793 / Angielski / Miękka / 2012 / 778 str.

Bernard B. Brodie;James R. Gillette

Opis

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 Bio- chemical 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 Clark, Director of the Pharmacology-Toxicology Program at the National Institutes of Health whose support made possible much of the work described in this volume. Contents Section Four: Methods 01 Stooging the MetoholiBm 01 Drugs Subsection A. Assay 01 Drugs and Their M etoholites Chapter 22: Basic Principles in Development of Methods for Drug Assay. B. B. BRODIE. With 2 Figures 1 1 A. Introduction . . . . . . . . . . B. Principles of Developing a Method. . . . . . 1 I. Section of Method of Assay . . . . . . 1 II. Choice of Solvent for Extraction of Drug 2 III. Adsorption of Drugs by Glass Surfaces . . . . . . . . . . . . . . 3 IV. Recoveries of Known Amounts of Compound from Biological Material. 4 V. Assessment of Sensitivity 5 VI. Assessment of Specificity 5 References. . . . . . . . . . .

Spis treści

Section Four: Methods of Studying the Metabolism of Drugs.- Subsection A. Assay of Drugs and Their Metabolites.- 22: Basic Principles in Development of Methods for Drug Assay. With 2 Figures.- A. Introduction.- B. Principles of Developing a Method.- I. Section of Method of Assay.- II. Choice of Solvent for Extraction of Drug.- III. Adsorption of Drugs by Glass Surfaces.- IV. Recoveries of Known Amounts of Compound from Biological Material.- V. Assessment of Sensitivity.- VI. Assessment of Specificity.- References.- 23: Absorption Spectrophotometry.- A. Ultraviolet Absorption Spectrophotometry.- I. Chromophores.- 1. Chromophore Coupling with Electron Fusing.- 2. Chromophore Coupling by a Saturated Link.- 3. Chromophore Coupling by Conjugated Systems.- 4. Effect of Tautomerism.- II. Environmental Influences.- 1. Effects of Solvent.- 2. Effects of Ionic Strength.- III. Applications of Ultraviolet Spectrophotometry to Drug Assay.- 1. Assays Based on a Change in pH.- 2. Assays Based on a Change of Redox State.- 3. Assays Based on Production of UV Absorption by Chemical Reaction.- 4. Blank Correction by Differential Wavelength Readings.- 5. Estimation of Drug and Metabolite at Differential Wavelengths.- B. Visible Absorption Spectrophotometry.- I. General.- II. Application of Visible Spectrophotometry to Drug Assay.- 1. Assays Based on Changes in pH.- 2. Assays Based on Changes of Redox State.- 3. Production of Visible Absorption by Chemical Reaction.- 4. Other Factors Affecting Visible Absorption.- C. Infrared Absorption Spectrophotometry.- References.- 24: Fluorometry. With 1 Figure.- A. Introduction.- B. Principles.- C. Practical Considerations.- I. Concentration.- II. Background Fluorescence.- III. Surface Adsorption of Fluorophors.- IV. Scattered Light.- D. Luminescence Analysis.- I. Types of Fluoroscence Assay Procedures.- II. Phosphorescence Analysis.- III. Application of Fluorescence Analysis to Drug Metabolism Studies.- IV. The Application of Fluorescence Spectroscopy to Drug Binding Studies.- References.- 25: Radioactive Techniques: The Use of Labeled Drugs. With 2 Figures.- A. Introduction.- B. Synthesis of Labeled Compounds.- I. Chemical Synthesis Procedures.- 1. Procedures for 3H.- 2. Procedures for 14C.- II. Biosynthesis Procedures.- 1. In Vivo Procedures.- 2. In Vitro Procedures.- C. Stability of Labeled Compounds.- D. Measurement of Labeled Drugs.- E. Specific Procedures for the Analysis of Labeled Compounds.- F. Use of Labeled Compounds to Study Drug Metabolism.- 6. Discussion of Basic Principles.- References.- 26: Radioactive Techniques: Radioactive Isotope Derivatives of Nonlabeled Drugs.- I. Estimation of Primary or Secondary Amines.- II. Estimation of Tertiary Amines.- III. Estimation of Drugs by Chelation.- IV. Estimation of Steroids as Radioactive Derivatives.- V. Enzymatic Production of Labeled Derivatives.- VI. Potential Applications of Radiolabeled Derivatizing Reagents.- References.- 27: Gas Chromatography. With 18 Figures.- I. Introduction.- II. Theory of Gas Chromatography.- III. Columns.- IV. Detectors.- V. Techniques in Gas Chromatography.- VI. Analytical Applications of Gas Chromatography in Pharmacology.- References.- 28: Enzymatic Assays in Pharmacology. With 4 Figures.- I. Introduction.- II. Enzymatic Assays with Pharmacological Agents as Substrates.- III. Enzymatic Assays with Drugs as Inhibitors.- IV. Competitive Protein Binding Analysis.- V. Conclusion.- References.- 29: Bioassay. With 2 Figures.- A. General Considerations.- I. Specificity.- II. Accuracy.- III. Automation.- B. Individual Assays.- I. Assays Used on Grounds of Sensitivity or Specificity.- II. Assays Used for Confirmation of Biological Activity (Steroids).- III. Assays Used because Chemical Methods are not yet Available.- IV. Proteins.- C. Conclusion.- References.- 30: Immunoassay. With 2 Figures.- References.- Subsection B. Isolation and Identification of Drug Metabolites.- 31: Paper, Column and Thin Layer Chromatography, Counter-Current Distribution and Electrophoresis..- A. Introduction.- B. Extraction from Tissues.- C. Counter-Current Distribution.- I. Theory.- II. Prediction of Separability.- III. Choice of Solvent Pairs for Counter-Current Distribution.- D. Chromatography.- I. The Properties of Adsorbents Used in Column Chromatography.- II. Liquid-Liquid Partition Chromatography.- III. Paper and Thin Layer Chromatography.- 1. Introduction.- 2. Paper Chromatography.- 3. Thin Layer Chromatography.- E. Electrophoresis.- References.- 32: Isotope Dilution Analysis. With 4 Figures.- A. Introduction.- B. Isotope Dilution Analysis.- 1. Direct Methods.- 2. Inverse Methods.- C. Modifications of Isotope Dilution Analysis.- D. Some Analytic Techniques Used in Conjunction with Radioassay Methods.- 1. Conversion of Samples to a Uniform Physical State.- 2. Addition and Purity of Carrier Material.- 3. Isolation of Drugs and Drug Metabolites.- 4. Purification of Isolated Material.- 5. Concentration and Radioactivity Measurements.- E. Applications of Isotopic Dilution Techniques.- 1. Examples of Direct Methods.- a) Pentobarbital.- b) Tolbutamide.- 2. Examples of Indirect Methods.- a) Warfarin.- b) Probenecid.- c) Fluroxene.- d) Folic Acid Antagonists.- e) Cyclophosphamide.- f) Thalidomide.- g) Tartrazine.- h) Benzene and Cyclohexane.- References.- 33: Gas Chromatography-Mass Spectrometry. With 8 Figures.- A. Introduction.- B. Operation of the Combined Gas Chromatograph-Mass Spectrometer.- C. Mass Spectral Fragmentation Processes.- D. Applications of Mass Spectrometry to the Problem of Identifying Drug Metabolites.- 1. Ethanol.- 2. Aspirin.- 3. Phenacetin.- 4. Tremorine.- 5. Siduron.- 6. Naphthalene.- 7. Probenecid.- 8. Brief Accounts of Mass Spectral Studies of Miscellaneous Compounds of Interest to Pharmacologists and Toxicologists.- a) Limonene.- b) Phytanic Acid.- c) Isoprene.- d) Acetylcholine.- e) The “Pink Spot” in Urine from Schizophrenics.- f) Bee Scent.- g) Trans-stilbene.- h) Pteridines.- i) Tetracycline.- j) Polychlorinated Biphenyls (PCB’s).- k) DDT.- E. Forensic Applications.- References.- 34: The Application of Various Spectroscopies to the Identification of Drug Metabolites. With 5 Figures.- A. Introduction.- B. Sample Requirements and Isolation Procedures.- C. Mass Spectrometry.- D. Nuclear Magnetic Resonance Spectroscopy.- E. Infrared Spectroscopy.- F. Ultraviolet Spectroscopy.- G. Optical Rotatory Dispersion and Circular Dichroism.- H. Diazepam Metabolites.- J. Triprolidine Metabolites.- References.- Section Five: Sites of Drug Metabolism.- 35: Introduction: Pathways of Drug Metabolism.- A. The Biphasic Metabolism of Drugs.- B. Phase I Reactions.- I. Oxidative Reactions.- 1. The Oxidation of Aromatic Rings.- 2. The Oxidation of Alkyl Chains.- 3. Oxidative Dealkylation.- 4. N-Oxidation.- 5. Sulphoxidation.- 6. Replacement of S by O.- 7. Epoxidation.- II. Reductions.- III. Hydrolyses.- C. Conjugations or Phase II Reactions.- I. Types of Conjugation Reactions.- 1. Glucuronic Acid Conjugation.- 2. Glucoside Conjugation.- 3. Hippuric Acid Synthesis.- 4. Mercapturic Acid Synthesis.- 5. Ornithuric Acid Synthesis.- 6. Glutamine Conjugation.- 7. Ethereal Sulphate Synthesis.- 8. The Cyanide Detoxication.- 9. Methylation.- 10. Acetylation.- II. Mechanism of Conjugation.- D. Compounds which are not Metabolized.- E. Spontaneous Reactions.- F. The Excretion of Foreign Compounds.- References.- Subsection A: Microsomal Enzymes.- 36: Some Morphological Characteristics of Hepatocyte Endoplasmic Reticulum and Some Relationships between Endoplasmic Reticulum, Microsomes, and Drug Metabolism.- I. Some Morphological Considerations.- II. Some Structure-activity Correlations.- III. Some Problems in Correlating ER Structure and Microsomal Enzyme Activity.- IV. Localization of Drug Metabolizing Enzymes in Submicrosomal Fractions.- References.- 37: Model Systems in Studies of the Chemistry and the Enzymatic Activation of Oxygen. With 9 Figures.- A. Introduction.- B. Chemical Properties of the Active Oxygen in Enzymatic Monooxygenations.- I. Hydroxylations of Aliphatic CH-Bonds.- II. Monooxygenation of the Isolated Double Bond.- III. Monooxygenation of Aromatic Systems.- IV. Monooxygenation at Heteroatoms.- C. Model Reactions for the Enzymatic Active Oxygen.- D. Model Systems for Oxygen Activation by Monooxygenases.- References.- 38: Cytochrome P-450 — Its Function in the Oxidative Metabolism of Drugs. With 23 Figures.- I. Discovery of Cytochrome P-450.- II. Function of Cytochrome P-450.- III. How Does Cytochrome P-450 Function ?.- IV. Cytochrome P-450: Monomorphous or Polymorphous?.- V. The Enzymatic Reduction of Cytochrome P-450.- VI. The Organization of the Microsomal Electron Transport Chain.- Summary.- Addendum.- References.- 39: Enzymatic Oxidation at Carbon.- A. Introduction.- B. Aliphatic Hydroxylation.- I. Hydroxylation at the Terminal Methyl Group.- II. Hydroxylation at the Penultimate Methylene Group.- III. Hydroxylation at the Benzylic Position.- IV. Hydroxylation at the Allylic Position.- V. Hydroxylation of Alicyclic Rings.- VI. Hydroxylation at Carbon ?- to a Heteroatom.- VII. Hydroxylation at Carbon ?- or ?- to a Carbonyl Group.- VIII. Mechanistic Studies.- C. Peroxidation.- D. Epoxidation.- I. Epoxidation of Conjugated and Unconjugated Olefins.- II. Epoxidation of Aromatic Double Bonds.- III. Epoxide Hydrase.- E. Aromatic Oxidation.- I. Hydroxylation of Substituted Benzenes.- II. Hydroxylation of Bicyclic and Polycyclic Aromatic Compounds.- III. The NIH Shift.- IV. Arene Oxides.- F. Summary.- References.- 40: N-Oxidation Enzymes. With 2 Figures.- I. Introduction.- II. N-Hydroxylation in Vitro.- III. Formation of N-Hydroxy Derivatives by Biochemical Reduction.- IV. Formation and Reactions of Tertiary Amine and Heterocyclic N-Oxides.- V. Conclusions.- References.- 41: Enzymatic N-, 0-, and S-Dealkylation of Foreign Compounds by Hepatic Microsomes. With 4 Figures.- A. N-Dealkylation.- I. Relationship of the N-Alkyl Substituent to the Rate of Dealkylation.- II. Relative Rates of N-Dealkylation of Secondary and Tertiary Amines.- 1. In Vivo.- 2. In Vitro.- III. Multiple Microsomal N-Demethylases.- IV. Mechanism of Microsomal N-Dealkylation.- 1. Cytochrome P-450.- 2. N-Oxide Formation.- 3. Isotope Effects on Microsomal Dealkylation.- V. Stereospecificity in N-Dealkylation.- VI. Fate of Aldehydes Formed during Metabolic Dealkylation of Drugs.- B. O-Dealkylation.- I. Relationship of the O-Alkyl Substituent to the Rate of Dealkylation.- II. Mechanism of Microsomal O-Dealkylation.- C. S-Dealkylation.- D. Summary.- References.- 42: Reductive Enzymes. With 6 Figures.- A. Introduction.- B. Reduction of Nitro Compounds.- I. Enzymatic Mechanisms in Liver.- II. Enzymatic Reduction of Nitro Compounds in Other Mammalian Tissues.- III. Nitro Reduction by Bacterial Enzymes.- IV. Semi-nonenzymatic Reactions.- C. Azo Reduction.- I. Azo Reduction in Liver.- II. Semi-nonenzymatic Reactions.- III. Azo Reduction in Other Mammalian Tissues.- IV. Bacterial Enzymes.- V. Relative Importance of Azo Reductases.- References.- 43: Oxidative Desulfuration and Dearylation of Selected Organophosphate Insecticides.- References.- 44: Metabolism of Halogenated Compounds. With 7 Figures.- I. General Consideration of the Halogen-Carbon Bond.- 1. Chemical Reactivity of Aromatic Halogen Derivatives.- 2. Chemical Reactivity of Aliphatic Halogen Derivatives.- II. Metabolism of Halogenated Aromatic Hydrocarbons.- III. Metabolism of Aliphatic Halogenated Compounds.- IV. Indirect Tests of Dehalogenation.- V. Dehalogenation of Insecticides.- Summary and Conclusions.- References.- 45: Glucuronide-Forming Enzymes. With 1 Figure.- A. Mechanism of Glucuronide Biosynthesis.- I. Transference from Uridine Diphosphate Glucuronic Acid.- II. Other Enzymic Pathways of Glucuronide Biosynthesis.- III. Non-Enzymic Pathways of Glucuronide Biosynthesis.- IV. Study of Glucuronide Biosynthesis.- B. UDPGlucuronic Acid.- C. UDPGlucuronyltransferase.- I. Occurence of UDPGlucuronyltransferase in Species.- II. Occurence of UDPGlucuronyltransferase in Tissues.- III. Location of UDPGlucuronyltransferase in the Cell.- IV. Purification of UDPGlucuronyltransferase.- V. Catalytic Center.- VI. Specificity of UDPGlucuronyltransferase.- VII. Factors Affecting Observed UDPGlucuronyltransferase Activity in Vitro.- D. Factors Affecting Overall Glucuronidation in Vivo.- I. Age.- II. Diet.- III. Hormones.- IV. Genetic Factors.- V. Administration of Drugs and Steroids.- VI. Environmental Factors.- VII. Toxicological and Pathological Factors.- References.- 46: Metabolism of Normal Body Constituents by Drug-Metabolizing Enzymes in Liver Microsomes.- A. Introduction.- B. Steroid Hormones.- I. Factors Influencing Steroid Hydroxylation.- II. Effect of Enzyme Induction on Steroid Action.- III. Effect of Enzyme Induction on Steroid Hydroxylation in Man.- C. Cholesterol.- I. Biosynthesis.- II. Metabolism to Bile Acids.- D. Fatty Acids.- I. ?-Oxidation.- II. Desaturation.- E. Thyroxin.- F. Bilirubin.- G. Miscellaneous.- I. Indoles.- II. Sympathomimetic Amines.- III. Heme.- IV. Kynurenine and Anthranilic Acid.- V. Methylated Purines.- H. Concluding Remarks.- References.- 47: Tissue Distribution Studies of Polycyclic Hydrocarbon Hydroxylase Activity.- I. Introduction.- II. Histochemical Studies of Polycyclic Hydrocarbon Hydroxylase Systems.- III. Quantitative Studies of Polycyclic Hydrocarbon Hydroxylase Systems.- IV. Implications of Extra-Hepatic Distribution of Drug Metabolizing Systems.- References.- 48: Mechanisms of Induction of Drug Metabolism Enzymes. With 9 Figures.- A. Introduction.- B. Effects of Polycyclic Hydrocarbons and Phenobarbital on Protein Synthesis.- C. Enzyme Induction and the Gene-Action System.- D. Effect of Inducers on the Turnover and Activity of Microsomal Proteins.- E. Effects of Inhibitors on the Induction of Enzyme Activities in Vivo.- I. Enzyme Induction in Vivo.- II. Enzyme Induction in Isolated Perfused Rat Liver.- F. Enzyme Induction in Cell Culture.- I. Estimation of Half-Life of Induced Aryl Hydroxylase Activity.- II. Effects of Metabolic Inhibitors on Inducible Aryl Hydroxylase.- III. A Translation-independent Phase of Aryl Hydrocarbon Hydroxylase Induction.- G. The Effect of Inducers on RNA Metabolism.- References.- 49: Inhibition of Drug Metabolism. With 1 Figure.- A. Methods of Determining Inhibition of Drug Metabolism.- I. In Vivo Methods.- II. In Vitro Methods.- III. Combined in Vivo-in Vitro Methods.- B. Implication of a Common Drug Metabolizing System.- C. Inhibition of the Metabolism of One Drug by Another Drug in Vivo.- D. SKF 525-A and other Prolonging Agents.- E. Role of Binding of Inhibitors to Cytochrome P-450.- F. Some Applications of Inhibitors.- G. Therapeutic Implications of Inhibition of Drug Metabolism.- References.- Subsection B: Nonmicrosomal Enzymes.- 50: Esterases of Human Tissues. With 2 Figures.- A. Introduction.- B. Properties of Different Types of Esterases.- C. Blood Esterases.- 1. Serum Esterases.- 2. Erythrocyte Esterases.- D. Tissue Esterases.- 1. Liver.- 2. Kidney.- 3. Skeletal and Smooth Muscle.- 4. Brain.- 5. Esterases of Other Human Tissues.- E. Hydrolysis of Drugs Containing Ester Groups in Man.- Summary.- References.- 51: Enzymatic Oxidation and Reduction of Alcohols, Aldehydes and Ketones.- A. Oxido-Reductases.- I. Liver Alcohol Dehydrogenase.- 1. General Properties.- 2. Substrate Selectivity of LADH.- 3. Stereochemistry and Mechanism.- II. Other Alcohol Dehydrogenases.- III. Reductases.- 1. 4-Ketoproline Reductase.- 2. Aromatic Aldehyde-Ketone Reductase.- 3. Pig Liver Reductase.- 4. ?-?-Unsaturated Ketone Reductase.- 5. Kidney Lactaldehyde Reductase.- 6. Retinal Reductase from Rat Intestine.- 7. Aromatic ?-Keto Acid Reductase.- 8. Other Reductases.- B. Aldehyde Oxidation.- I. Aldehyde Dehydrogenases.- II. Aldehyde Oxidase.- III. Xanthine Oxidase.- C. Summary.- References.- 52: Amine Oxidases.- Monoamine Oxidases.- 1. Isolation of MAO.- 2. Molecular Properties of MAO.- 3. Methods of Measurement of MAO Activities.- a) In Vitro Procedures.- b) Determination of MAO Activity in Materials Obtained from Living Persons.- 4. Substrate Specificity and Multiple Forms of MAO.- 5. Kinetic Studies.- 6. MAO Inhibitors.- a) List of Inhibitors.- b) Substrates as Inhibitors and Inhibitors as Substrates.- c) Propargylamine Derivatives.- d) ?-Alkylamines.- e) Cyclopropylamine Derivatives.- f) Hydrazine Derivatives.- g) Acylhydrazides.- h) Furazolidones.- i) Aromatic Amines and N-Heterocyclic Compounds.- j) Alcohols, Phenol, and Ethers.- k) Effect of the Substrate on Modality and Efficiency of MAO Inhibition.- 7. Mechanism of Interaction between MAO and its Substrates.- 8. Interaction between Inhibitors and MAO.- 9. On the Biological Function of MAO.- a) Occurrence of MAO in the Mammalian Organism.- b) Ontogenetic Changes in MAO Activity.- c) Effect of Hormones on MAO.- d) Protective Function of MAO.- e) Specific Functions of MAO.- References.- 53: Sulphate Conjugation Enzymes. With 3 Figures.- A. General Introduction.- B. The Activation of Sulphate.- I. The Sulphate-Activating System.- II. ATP-Sulphurylase.- III. APS-Kinase.- C. The Hydrolysis of Adenylyl Sulphates.- D. Sulphotransferases.- I. General Considerations.- II. Phenol Sulphotransferase.- III. Alcohol Sulphotransferase.- IV. Steroid Sulphotransferases.- 1. Introduction.- 2. Oestrone Sulphotransferase.- 3. Androstenolone Sulphotransferase.- 4. Aetiocholanolone Sulphotransferase.- 5. Testosterone Sulphotransferase.- 6. Desoxycorticosterone Sulphotransferase.- V. Arylamine Sulphotransferase.- E. The Synthesis of Sulphate Esters in Vivo.- References.- 54: Acetylating, Deacetylating and Amino Acid Conjugating Enzymes. With 3 Figures.- A. Acetylation and Deacetylation Enzymes.- 1. Acetylator Phenotyping.- 2. Assay Methods for N-Acetyltransferase in Mammalian Tissues.- 3. Properties of Mammalian Liver N-Acetyltransferase.- 4. Mechanism of Acetylation.- 5. Comparison of Liver N-Acetyltransferases from Rapid and Slow INH Acetylators.- 6. Comparison of Liver N-Acetyltransferases from Adult and Developing Rabbits.- 7. Evidence for Multiple N-Acetyltransferases.- 8. Deacetylation Enzymes.- 9. Comments on Evaluating the Relative Importance of Acetylating and Deacetylating Enzymes in Different Species.- B. Amino Acid Conjugating Enzymes.- 1. Properties of the Acyl Activating Enzyme System.- 2. Properties of the Acyltransferases.- C. Concluding Remarks.- References.- 55: Mercapturic Acid Conjugation. With 1 Figure.- I. Sources of the Cysteine Group that have been Proposed.- II. Glutathione as the Source of Cysteine.- III. Conversion of Glutathione Conjugates into Mercapturic Acids.- IV. Glutathione S-Transferases.- V. Glutathione S-Aryltransferase.- VI. Glutathione S-Epoxidetransferase.- VII. Glutathione S-Alkyltransferase.- VIII. Glutathione S-Aralkyltransferase.- IX. Glutathione S-Alkenetransferases.- X. Other Mercapturic Precursors.- 1. Arylamines.- 2. Urethane.- 3. Benzothiazole-2-Sulfonamide.- 4. Alkyl Methanesulfonates.- 5. 3,5-Di-tert-butyl-4-hydroxytoluene.- 6. Isovalthine.- 7. Bis-?-chloroethyl Sulfide.- 8. Nitrofurans.- Conclusion.- References.- 56: Methyltransferase Enzymes in the Metabolism of Physiologically Active Compounds and Drugs.- I. Catechol-O-Methyltransferase (COMT).- II. Phenol-O-Methyltransferase.- III. O-Methylation of Hydroxamic Acid.- IV. Hydroxyindole-O-Methyl Transferase (HIOMT).- V. Phenylethanolamine N-Methyl Transferase (PNMT).- VI. Histamine N-Methyltransferase.- VII. Non-Specific N-Methyltransferase.- VIII. Enzymatic Formation of Methanol from S-Adenosylmethionine.- References.- 57: Enzymes that Inactivate Vasoactive Peptides. With 2 Figures.- A. Introduction.- B. Inactivation of Kinins.- I. Kininases in Blood.- II. Carboxypeptidase N.- III. Kininase II.- IV. Converting Enzyme.- V. Kininases in Blood Cells.- VI. Kininases in Other Biological Fluids.- VII. Kininases in Tissues.- VIII. Inactivation of Kinins by Purified Proteases.- IX. Administration of Carboxypeptidase B.- X. Venoms.- XI. Microbial Kininases.- XII. Fate of Kinins in Vivo.- XIII. Inhibitors of Kininases.- XIV. Inhibition of Kininases in Vivo.- XV. Changes in Kininase Activity.- XVI. Enzymatic Conversion of Kinins.- C. Inactivation of Angiotensins.- I. Angiotensinases in Blood Plasma.- II. Angiotensinases in Blood Cells.- III. Angiotensinases in Other Biological Fluids.- IV. Angiotensinases in Tissues.- V. Use of Purified Proteases in the Determination of Angiotensin Structure.- VI. Fate of Angiotensins in Vivo.- VII. Inhibitors of Angiotensinases.- VIII. Changes in Angiotensinase Activity.- IX. Inactivation of Angiotensin in Vivo by Exogenous Enzymes.- D. Epilogue: The Importance of the Enzymes.- References.- 58: The Metabolism of Analogs of Endogenous Substrates: Wider Application of a Limited Concept. With 15 Figures.- A. Introduction.- B. Metabolism of Purine and Pyrimidine Analogs by Pathways of Normal Substrates.- I. General Background.- II. Metabolism of a Pyrimidine Analog: 5-Fluorouracil.- 1. The Pathways of Metabolism.- 2. General Interrelationship of Action and Metabolism of FU.- 3. Actions of Specific Metabolites of FU.- 4. Evaluation of Pharmacological Significance of Various Metabolic Routes.- III. Comparative Metabolism of 5-Halouracil Derivatives.- IV. Metabolism of a Purine Analog: 6-Thioguanine.- V. Metabolism of Other Purine and Pyrimidine Analogs.- VI. Clinical Applications of Knowledge on Metabolism of Purine and Pyrimidine Antimetabolites.- 1. Enhancement of Metabolism.- 2. Attempts to Increase Cell Penetrability of Active Metabolites.- 3. Selectively Increasing the Availability of Active Analog Metabolites.- 4. Spacing of Doses.- 5. Combination Therapy.- 6. Supplying Rescue Agents.- C. Metabolism of Other Analogs by Pathways for Normal Substrates.- D. The Metabolism of Substrate Analogs Along Routes Used by “Conventional” Drugs.- E. Summary.- References.- Author Index.