Antituberculosis Drugs by K. BartmannAntituberculosis Drugs by K. Bartmann

Antituberculosis Drugs

Contribution byK. Bartmann, H. IwainskyEditorKarl Bartmann

Paperback | December 10, 2011

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This volume deals specifically with those antituberculosis drugs which passed the preclinical phase and have been or are used in the treatment of tuberculosis and other mycobacterial diseases (except leprosy) in at least some parts of the world. Despite this restriction, there are 14 such drugs, and as a result this volume has reached rather large proportions. To prevent it from becoming even larger and more unwidely, most derivatives of antituberculotics have been omitted, especially where it is claimed that they provide only better bioavailibility or tolerability. Only in the chapter on the chemotherapy of diseases due to so-called atypical mycobacteria is the clinical use of the drugs described to a certain extent. In addition to antituberculotics, also discussed are antimicrobials which have been found to be effective against these mycobacteria. The sequence in which the drugs are described is historical, reflecting not the time of discovery but rather the first clinical application. This order was selected for reasons which are now no longer relevant. In this volume less emphasis is placed on detection, biological or synthetic production of antituberculotics, and structure-activity relationships. In contrast, emphasis is put on the degree, type, and mechanism of antimyco bacterial activity, pharmacokinetics, and biotransformation in animals and man, on experimental pharmacodynamics, and on the toxicity of antituberculotics used therapeutically.
Title:Antituberculosis DrugsFormat:PaperbackDimensions:9.61 × 6.69 × 0.07 inPublished:December 10, 2011Publisher:Springer Berlin HeidelbergLanguage:English

The following ISBNs are associated with this title:

ISBN - 10:3642728758

ISBN - 13:9783642728754

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Table of Contents

1 Historical Introduction and Chemical Characteristics of Antituberculosis Drugs.- A. p-Aminosalicylic Acid (PAS).- B. Streptomycin (SM) - Dihydrostreptomycin (DHSM).- C. Thiosemicarbazone (TSC) [Thioacetazone, Thiacetazone, p-Aminobenzaldehyde].- D. Pyrazinamide (PZA) - Morphazinamide (MZA).- E. Isoniazid (INH).- F. Tetracyclines.- I. Oxytetracycline (Terramycin, OTC).- II. Tetracycline (TC).- G. Viomycin (VM).- H. Cycloserine (CS) - Terizidone (TZ).- I. Thioamides: Ethionamide (ETH) - Protionamide (PTH).- J. Kanamycin (KM).- K. Thiocarlide (DATC).- L. Capreomycin (CM).- M. Ethambutol (EMB).- N. Rifampicin (RMP).- References will be found on each end of Paragraphs.- 2 Experimental Evaluation of Efficacy.- A. Introduction.- B. Methods, Their Limitations, Advantages, and Disadvantages.- I. In-vitro Tests.- 1. Determination of Minimal Inhibitory Concentrations (MIC).- 2. Cross-Resistance.- 3. Type of Action.- II. Animal Experiments.- III. Cell- and Tissue Cultures.- References.- C. Drugs and Treatment Regimens.- I. p-Aminosalicylic Acid (PAS).- 1. Antimicrobial Spectrum in Vitro.- 2. Antimycobacterial Activity.- Activity in Artificial Media in Vitro.- Bacterial Resistance.- Type of Action.- Effects in Cell and Tissue Cultures.- Activity in Experimental Tuberculosis and Development of Resistance in Vivo.- 3. Concluding Remarks.- References.- II. Streptomycin (SM) - Dihydrostreptomycin (DHSM).- 1. Antimicrobial Spectrum in Vitro.- 2. Antimycobacterial Activity.- Activity in Artificial Media in Vitro.- Bacterial Resistance to, and Dependence on SM.- Type of Action.- Effects in Combination with Other Antituberculotics.- Effects in Cell- and Tissue Cultures.- Activity in Experimental Tuberculosis and Development of Resistance in Vivo.- Continuous Monotherapy.- Intermittent Monotherapy.- SM in Combined Chemotherapy.- 3. Concluding Remarks.- References.- III. Thiosemicarbazones (TSC) [Thiacetazone, Thioacetazone].- 1. Antimicrobial Spectrum in Vitro.- 2. Antimycobacterial Activity.- Activity in Artificial Media in Vitro.- Bacterial Resistance.- Type of Action.- Effects in Combination with Other Antituberculotics.- Effects in Cell- and Tissue Cultures.- Activity in Experimental Tuberculosis and Development of Resistance in Vivo.- TSC in Combined Chemotherapy.- 3. Concluding Remarks.- References.- IV. Pyrazinamide (PZA) and Morphazinamide (MZA).- 1. Antimicrobial Spectrum in Vitro.- 2. Antimycobacterial Activity.- Activity in Artificial Media in Vitro.- Bacterial Resistance.- Type of Action.- Effects in Cell- and Tissue Cultures.- Activity in Experimental Tuberculosis and Development of Resistance in Vivo.- Monotherapy.- PZA in Combined Chemotherapy.- 3. Concluding Remarks.- References.- V. Isoniazid (INH).- 1. Antimicrobial Spectrum in Vitro.- 2. Antimycobacterial Activity.- Activity in Artificial Media in Vitro.- Bacterial Resistance.- Type of Action.- Effects in Combination with Other Antituberculotics.- Effects in Cell- and Tissue Cultures.- Effects in Embryonated Eggs.- Activity in Experimental Tuberculosis and Development of Resistance in Vivo.- Efficacy in Special Animal Models.- INH in Combined Chemotherapy.- Intermittent Treatment with INH Alone and in Combination.- Treatment in Phases.- 3. Concluding Remarks.- References.- VI. Tetracyclines.- 1. Antimicrobial Spectrum in Vitro.- 2. Antimycobacterial Activity.- Activity in Artificial Media in Vitro.- Bacterial Resistance.- Type of Action.- Effects in Combination with Other Antituberculotics.- Effects in Cell- and Tissue Cultures.- Activity in Experimental Tuberculosis.- 3. Concluding Remarks.- References.- VII. Viomycin (VM).- 1. Antimicrobial Spectrum in Vitro and in Vivo.- 2. Antimycobacterial Activity.- Activity in Artificial Media in Vitro.- Bacterial Resistance.- Type of Action.- Effects in Combination with Other Antituberculotics.- Effects in Cell- and Tissue Cultures.- Activity in Experimental Tuberculosis.- Monotherapy.- VM in Combined Chemotherapy.- 3. Concluding Remarks.- References.- VIII. Cycloserine (CS) and Terizidone (TZ).- 1. Cycloserine (CS).- Antimicrobial Spectrum in Vitro.- Antimycobacterial Activity.- Activity in Artificial Media in Vitro.- Bacterial Resistance.- Type of Action.- Effects in Cell- and Tissue Cultures.- Activity in Experimental Tuberculosis.- Monotherapy.- CS in Combined Chemotherapy.- 2. Terizidone (TZ).- Activity in Experimental Tuberculosis.- Activity in Artificial Media in Vitro.- 3. Concluding Remarks.- References.- IX. Thioamides: Ethionamide (ETH), Protionamide (PTH).- 1. Antimicrobial Spectrum in Vitro.- 2. Antimycobacterial Activity.- Activity in Artificial Media in Vitro.- Type of Action.- Bacterial Resistance.- Effects in Cell- and Tissue Cultures.- Activity in Experimental Tuberculosis and Development of Resistance in Vivo.- Continuous Monotherapy.- Intermittent Monotherapy.- ETH in Combined Chemotherapy.- 3. Concluding Remarks.- References.- X. Kanamycin (KM) and Amikacin.- 1. Kanamycin - Antimicrobial Spectrum in Vitro.- 2. Kanamycin - Antimycobacterial Activity.- Activity in Artificial Media in Vitro.- Bacterial Resistance.- Type of Action.- Effects in Cell- and Tissue Cultures.- Activity in Experimental Tuberculosis.- Monotherapy.- KM in Combined Chemotherapy.- 3. Amikacin - Antimycobacterial Activity.- 4. Concluding Remarks.- References.- XI. Thiocarlide (DATC).- 1. Antimicrobial Spectrum in Vitro.- 2. Antimycobacterial Activity.- Activity in Artificial Media in Vitro.- Bacterial Resistance.- Type of Action.- Effects in Cell- and Tissue Cultures.- Activity in Experimental Tuberculosis.- Monotherapy.- DATC in Combined Chemotherapy.- 3. Concluding Remarks.- References.- XII. Capreomycin (CM).- 1. Antimicrobial Spectrum in Vitro.- 2. Antimycobacterial Activity.- Activity in Artificial Media in Vitro.- Type of Action.- Bacterial Resistance.- Effects in Cell- and Tissue Cultures.- Activity in Experimental Tuberculosis and Development of Resistance in Vivo.- Monotherapy.- CM in Combined Chemotherapy.- 3. Concluding Remarks.- References.- XIII. Ethambutol (EMB).- 1. Antimicrobial Spectrum in Vitro.- 2. Antimycobacterial Activity.- Activity in Artificial Media in Vitro.- Type of Action.- Bacterial Resistance.- Effects in Cell- and Tissue Cultures.- Activity in Experimental Tuberculosis and Development of Resistance in Vivo.- Monotherapy.- EMB in Combined Chemotherapy.- 3. Concluding Remarks.- References.- XIV. Rifampicin (RMP).- 1. Antimicrobial Spectrum in Vitro.- 2. Antimycobacterial Activity.- Activity in Artificial Media in Vitro.- Bacterial Resistance.- Type of Action.- Effects in Combination with Other Antituberculotics.- Effects in Cell- and Tissue Cultures.- Activity in Experimental Tuberculosis and Development of Resistance in Vivo.- Continuous Monotherapy.- Intermittent Monotherapy.- RMP in Combined Chemotherapy (Continuous, Intermittent, in Phases).- 3. Concluding Remarks.- References.- 3 Experimental Evaluation of Chemoprophylaxis and Preventive Treatment in Animals.- A. Definitions.- B. Objectives of Laboratory Experiments.- C. Results of Animal Experiments.- I. Experiments with Monkeys.- II. Experiments with Guinea Pigs.- III. Experiments with Cattle.- D. Discussion of Experimental Data.- I. Technique of Infection.- II. Infective Dose.- III. Animal Species Differences.- IV. The Drug as Factor.- E. Preventive Treatment in Animals.- I. Experiments with Guinea Pigs.- II. Experimental Studies with Mice.- III. Mink and Rabbits.- IV. Intermittent Treatment.- V. Preventive Treatment in Cattle.- F. Immunological Questions of Chemoprophylaxis and Vaccine Prophylaxis.- Combination of Chemoprophylaxis and Immune Prophylaxis.- INH Resistant BCG.- References.- 4 Experimental and Clinical Activity of Antituberculosis Drugs and Other Antimicrobial Agents Against Mycobacteria Other than Tubercle Bacilli, Except M. Leprae.- A. Introduction.- B. Possible Reasons for the Lower Sensitivity of MOTT to many Antituberculotics Compared to M. tuberculosis.- C. Efficacy of Antituberculosis Drugs and Other Antimicrobial Agents Against the Various MOTT Species.- I. Group I. Photochromogenic Mycobacteria.- 1. M. Kansasii (Yellow Bacillus, M. Luciflavum).- Types of Disease.- Activity of Antituberculosis Drugs in Vitro.- Activity of Other Antimicrobial Agents in Vitro.- Activity of Antituberculosis Drugs and Other Antimicrobial Agents in Animals.- Treatment of Infections in Man.- 2. M. Marinum (M. Balnei).- Types of Disease.- Activity of Antituberculosis Drugs in Vitro.- Activity of Other Antimicrobial Agents in Vitro.- Activity of Antituberculosis Drugs and Other Antimicrobial Agents in Animals.- Treatment of Infections in Man.- 3. M. Simiae.- Types of Disease.- Activity of Antituberculosis Drugs in Vitro.- Treatment of Infections in Man.- 4. M. Asiaticum.- Types of Disease.- Activity of Antituberculosis Drugs in Vitro.- Treatment of Infections in Man.- II. Group II. Scotochromogenic Mycobacteria.- 1. Introductory Remarks Including Types of Disease.- 2. Publications on Group II Without Identification of the Species.- Activity of Antituberculosis Drugs in Vitro.- Activity of Other Antimicrobial Agents in Vitro.- Activity of Antituberculosis Drugs in Animals.- Treatment of Infections in Man.- 3. M. Flavescens.- Types of Disease and Treatment in Man.- 4. M. Gordonae.- Activity of Antituberculosis Drugs in Vitro.- Activity of Other Antimicrobial Agents in Vitro.- Treatment of Infections in Man.- 5. M. Scrofulaceum (M. Marianum, M. Parafnicum).- Activity of Antituberculosis Drugs in Vitro.- Activity of Other Antimicrobial Agents in Vitro.- Treatment of Infections in Man.- 6. M. Szulgai.- Types of Disease.- Activity of Antituberculosis Drugs in Vitro.- Activity of Other Antimicrobial Agents in Vitro.- Treatment of Infections in Man.- 7. M. Xenopi (M. Littorale, M. Xenopei).- Types of Disease.- Activity of Antituberculosis Drugs and Other Antimicrobial Agents in Vitro.- Treatment of Infections in Man.- III. Group III.- 1. M. Avium Complex, Including M. Avium and M. Intracellulare ("Battey Bacillus").- Introductory Remarks Including Types of Disease.- Activity of Antituberculosis Drugs in Vitro.- Activity of Other Antimicrobial Agents in Vitro.- Activity of Antituberculosis Drugs in Animals.- Treatment of Infections in Man.- 2. M. Haemophilum.- Types of Disease, Activity of Antituberculosis Drugs in Vitro, and Treatment of Infections in Man.- 3. M. Malmoense.- Types of Disease, Activity of Antituberculosis Drugs in Vitro, and Treatment of Infections in Man.- 4. M. Nonchromogenicum Complex (Including M. Nonchromogenicum, M. Terrae, M. Novum, M. Triviale).- Types of Disease, Activity of Antituberculosis Drugs and Other Antimicrobial Agents in Vitro, and Treatment of Infections in Man.- 5. M. Ulcerans (M. Buruli).- Types of Disease.- Activity of Antituberculosis Drugs in Vitro.- Activity of Other Antimicrobial Agents in Vitro.- Activity of Antituberculosis Drugs and Other Antimicrobial Agents in Animals.- Treatment of Infections in Man.- IV. Group IV.- 1. M. Fortuitum Complex (Including M. Fortuitum and M. Chelonei with Subspecies Abscessus).- Types of Disease.- Activity of Antituberculosis Drugs and Other Antimicrobial Agents in Vitro and in Vivo.- Treatment of Infections in Man.- 2. M. Smegmatis.- Types of Disease.- Activity of Antituberculosis Drugs and Other Antimicrobial Agents in Vitro and in Vivo.- 3. M. Thermoresistibile.- Types of Disease, Activity of Antituberculosis Drugs, and Treatment of Infection in Man.- References.- 5 Experimental Pharmacology and Toxicology of Antituberculosis Drugs.- A. Introduction.- B. The Drugs.- I. p-Aminosalicylic Acid (PAS).- 1. Respiration, Circulation, Heart.- 2. Acute Toxicity.- 3. Subchronic and Chronic Toxicity.- References.- II. Streptomycin - Dihydrostreptomycin (SM - DHSM).- 1. Respiration, Circulation, Heart.- 2. Neuromuscular Blocking Effects of SM, DHSM, and Other Basic Antibiotics.- 3. Smooth Muscles.- 4. Ganglion Blocking Effects.- 5. Further Pharmacologic Effects.- 6. Acute Toxicity.- Attempts at Reducing the Acute Toxicity.- 7. Subchronic Toxicity.- 8. Ototoxicity of the Aminoglycoside Antibiotics.- Morphology.- Pathophysiology.- Causes: Pharmacokinetics and Biochemical Effects.- Species Related Sensitivity Differences and Differences in the Activity of the Various Antibiotics.- Attempts to Reduce Ototoxicity.- 9. Nephrotoxicity.- 10. Reproductive Toxicity.- 11. Biochemical Effects of SM.- References.- III. Thiosemicarbazone - Thiacetazone, Thioacetazone (TSC).- 1. Acute Toxicity.- 2. Subchronic and Chronic Toxicity.- 3. Liver Toxicity.- References.- IV. Pyrazinamide (PZA) and Morphazinamide (MZA).- 1. Pyrazinamide (PZA).- Respiration and Blood Pressure.- Acute and Subchronic Toxicity.- Liver Toxicity, Carcinogenicity.- References.- 2. Morphazinamide (MZA).- Acute and Subchronic Toxicity.- References.- V. Isoniazid (INH).- 1. Respiration, Circulation, Heart.- 2. Smooth Muscles.- 3. Other Pharmacological Effects.- 4. Central Stimulation Effects.- 5. INH and Vitamin B6 Metabolism.- 6. INH and the ?-Aminobutyric Acid Metabolism.- 7. Protective Action of Various Substances.- 8. Acute Toxicity.- 9. Subchronic and Chronic Toxicity.- 10. Liver Toxicity.- 11. Neurotoxic Effects.- 12. Ototoxicity.- 13. Reproductive Toxicity.- 14. Carcinogenic Effects.- 15. Cytostatic Effects.- 16. Mutagenic Effects.- 17. Lathyrogenic Activity.- References.- VI. Tetracyclines: Tetracycline, Oxytetracycline (TC, OTC).- 1. Respiration, Circulation, Heart.- 2. Neuromuscular Blocking Effects of Tetracyclines.- 3. Smooth Muscles.- 4. Acute Toxicity.- 5. Subacute Toxicity.- 6. Liver Toxicity.- 7. Nephrotoxicity.- 8. Effects on the Intestinal Epithelium.- 9. Tetracyclines and Bone Metabolism.- 10. Reproductive Toxicity.- 11. Inhibition of Protein Synthesis.- 12. Ototoxicity.- 13. Phototoxicity.- References.- VII. Viomycin (VM).- 1. Respiration, Blood Pressure.- 2. Neuromuscular Blocking Effect.- 3. Ganglion Blocking Effect.- 4. Smooth Muscles.- 5. Acute Toxicity.- 6. Subacute Toxicity.- 7. Nephrotoxicity.- 8. Ototoxicity.- References.- VIII. Cycloserine (CS) and Terizidone (TZ).- 1. d-Cycloserine (CS).- Respiration, Circulation, Heart.- Smooth Muscles.- Central Nervous Effects.- Other Pharmacological Effects.- Acute Toxicity.- Subchronic Toxicity.- Chronic Toxicity.- Nephrotoxicity, Ototoxicity.- Local Tolerability.- 2. Terizidone (TZ).- Acute Toxicity.- Subacute and Chronic Toxicity.- References.- IX. Thioamides (Ethionamide, Protionamide).- 1. Ethionamide (ETH).- Circulation, Heart.- Acute, Subchronic and Chronic Toxicity.- Reproductive Toxicity.- Carcinogenicity.- 2. Protionamide (PTH).- Acute and Subchronic Toxicity.- Reproductive Toxicity.- Carcinogenicity.- References.- X. Kanamycin (KM).- 1. Respiration, Circulation, Heart.- 2. Neuromuscular Blocking Effects.- 3. Smooth Muscles.- 4. Other Pharmacologic Effects.- 5. Acute Toxicity.- 6. Subchronic and Chronic Toxicity.- 7. Ototoxicity.- 8. Nephrotoxicity.- 9. Reproductive Toxicity.- References.- XI. Thiocarlide (DATC).- 1. Acute Toxicity.- 2. Subacute Toxicity.- 3. Chronic Toxicity.- 4. Reproductive Toxicity.- References.- XII. Capreomycin (CM).- 1. Respiration, Circulation, Heart.- 2. Acute Toxicity.- 3. Chronic Toxicity.- 4. Reproductive Toxicity.- 5. Ototoxicity.- 6. Nephrotoxicity.- References.- XIII. Ethambutol (EMB).- 1. Acute Toxicity.- 2. Chronic Toxicity.- 3. Reproductive Toxicity.- 4. Ototoxicity.- 5. Pharmacology.- References.- XIV. Rifampicin (RMP).- 1. Acute Toxicity.- 2. Subchronic Toxicity.- 3. Chronic Toxicity.- 4. Microsomal Enzyme Induction.- 5. Reproductive Toxicity.- 6. Ototoxicity.- 7. Carcinogenicity.- 8. Mutagenicity.- 9. Interactions with Other Drugs.- References.- 6 Mode of Action, Biotransformation and Pharmacokinetics of Antituberculosis Drugs in Animals and Man.- A. General Part.- I. Mode of Action of Antituberculosis Drugs.- 1. Type of Effect and Primary Site of Attack.- 2. Transport of Antituberculotics to the Site of Action.- 3. Mode of Action of Antituberculosis Drugs.- Nucleic Acid and Protein Synthesis as Primary Site of Attack.- Biosynthesis of the Microbial Cell Wall as Primary Site of Attack.- II. Biotransformation.- 1. Site of the Biotransformation.- 2. Possible Reactions.- 3. Factors Influencing Biotransformation.- 4. Influence of the Inductive Effect of RMP on the Biotransformation of Other Drugs.- 5. Antituberculosis Treatment and Biotransformation.- III. Pharmacokinetics.- 1. Absorption of Antituberculosis Drugs.- 2. Factors Influencing the Absorption.- Changes in Absorption due to a Different Mode of Administration.- Influence of Structural Modifications of the Drugs.- Influence of Galenic Processing.- Influence of Food Consumption.- 3. Binding of Antituberculosis Drugs to Proteins and Blood Cells.- 4. Distribution of Antituberculosis Drugs in the Body.- 5. Excretion of Antituberculosis Drugs.- Routes of Excretion.- Influence of Age.- Influence of Kidney Function.- Influence of Liver Diseases.- 6. Factors Influencing the Pharmacokinetics of Antituberculosis Drugs.- Influence of Sex and Age.- Influence of Administration Intervals and Dose.- Influence of Combination of Antituberculosis Drugs.- 7. Serum-Concentrations of Antituberculosis Drugs as Parameter of Treatment Efficacy.- Coverage.- Half-Life.- Area Under the Curve.- IV. General Medical Relevance of the Results Obtained in the Field of Tuberculosis.- 1. Studies on the Mode of Action.- 2. Studies on Biotransformation Processes.- 3. Studies on Pharmacokinetics.- References.- B. Special Part - The Antituberculosis Drugs.- I. PAS.- 1. Mode of Action.- 2. Biotransformation.- 3. Pharmacokinetics.- References.- II. SM.- 1. Mode of Action.- 2. Biotransformation.- 3. Pharmacokinetics.- References.- III. TSC.- 1. Mode of Action.- 2. Biotransformation.- 3. Pharmacokinetics.- References.- IV. PZA.- 1. Mode of Action.- 2. Biotransformation.- 3. Pharmacokinetics.- References.- V. INH.- 1. Mode of Action.- Incorporation of INH in Mycobacteria.- Biotransformation of INH by Mycobacteria.- Uptake of INH by Resistant Mycobacteria.- Mode of Action.- 2. Biotransformation.- Biotransformation Patterns in Man and in Animals.- Biotransformation and Antituberculotic Activity.- Determination of INH and Its Biotransformation Products.- Genetically Fixed Polymorphism of INH and Other Drugs.- Possible Ways of Differentiating Between Rapid and Slow INH Biotransformation.- Biotransformation of INH Derivatives and INH Retard Preparations.- Factors Affecting Biotransformation.- Race Dependent Biotransformation.- Biotransformation in Animals.- Influence of Biotransformation on Efficacy and Side Effects.- 3. Pharmacokinetics.- References.- VI. Tetracyclines.- 1. Mode of Action.- 2. Biotransformation.- 3. Pharmacokinetics.- References.- VII. VM.- 1. Mode of Action.- 2. Biotransformation.- 3. Pharmacokinetics.- References.- VIII. CS.- 1. Mode of Action.- 2. Biotransformation.- 3. Pharmacokinetics.- References.- IX. ETH/PTH.- 1. Mode of Action.- 2. Biotransformation.- Possibilities of Assay of ETH, PTH and Their Biotransformation Products.- Reversible Conversion of ETH and PTH into the Corresponding Sulphoxides.- Biotransformation Products of ETH and PTH.- Biotransformation of ETH and PTH in Man and Animals.- 3. Pharmacokinetics.- References.- X. KM.- 1. Mode of Action.- 2. Biotransformation.- 3. Pharmacokinetics.- References.- XI. DATC.- 1. Mode of Action.- 2. Biotransformation.- 3. Pharmacokinetics.- References.- XII. CM.- 1. Mode of Action.- 2. Biotransformation.- 3. Pharmacokinetics.- References.- XIII. EMB.- 1. Mode of Action.- 2. Biotransformation.- 3. Pharmacokinetics.- References.- XIV. RMP.- 1. Mode of Action.- 2. Biotransformation.- Biotransformation Pattern in Man and in Animals.- Modification of the Biotransformation Rate by Auto-Induction.- 3. Pharmacokinetics.- References.