Pharmacokinetics Antibiotics and Chemotherapy Vol. 25 Series Editors H. SCHNFELD, Grenzach; R. W. BROCKMAN, Birmingham, Ala, and F.E. HAHN, Washington, D.C. S. Karger Basel Mnchen. Paris London New York Sydney Pharmacokinetics Volume Editor H. SCHNFELD, Grenzach 58 figures and 70 tables, 1978 S. Karger Basel Mnchen Paris London New York Sydney Antibiotics and Chemotherapy Vol. 23: Fundamentals in Cancer Chemotherapy. Anticancer Symposium held in Connection with the 10th International Congress of Chemotherapy, Zurich, September 1977. Ed.: F. M. SCHABEL, Jr. (Birmingham, Ala.). VIII +3 04 p., 62 fig., 1 cpl., 91 tab., 1978 ISBN 3-8055-2830-2 Vol. 24: Application of Cancer Chemotherapy. Anticancer Symposium held in Connection with the 10th International Congress of Chemotherapy, Zurich, September 1977. Ed.: F.M. SCHABEL, Jr. (Birmingham, Ala). VIII + 242 p., 42 fig., 96 tab., 1978 ISBN 3-8055-2831-0 Cataloging in Publication Pharmacokinetics Volume editor, H. Schnfeld. - Basel, New York, Karger, 1978. (Antibiotics and chemotherapy, vol. 25) 1. Kinetics 2. Pharmacology 1. Schnfeld, HANS, ed. II. Title III. Series WI AN855G v.25/qv 38 P533 ISBN 3-8055-2752-7 All rights reserved.
No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Copyright 1978 by S.Karger AG, 4011 Basel (Switzerland), Arnold-Bocklin-Strasse 25 Printed in Switzerland by Genossenschaftsdruckerei, Zurich ISBN 3-8055-2752-7 Contents Penicillins T. BERGAN (Oslo)... 1 Introduction... 2 History... 3 Molecular Synthesis... 3 Chemical Structure of Penicillin... 10 Chemical Properties of Penicillins... 10 Methods of Determination... 17 Evaluation... 24 Influence of Chemical Structure on Pharmacokinetics of Penicillin... 25 Synergism... 30 Biopharmaceutics... 32 Metabolism... 34 Protein Binding... 36 Pharmacokinetics... 39 Penetration of Penicillins... 40 Renal Function and Excretion... 45 Characteristics of the Different Penicillins... 50 Adicillin.... 50 Amoxycillin... 50 Ampicillin... 57 Ancillin... 58 Azidocillin... 59 Azlocillin... 60 Bacampicillin... 61 Bacmecillinam... 63 Basic Penicillins... 63 Benzylpenicillin... 63 Early Penicillins... 65 Phenoxymethylpenicillin... 67
Phenoxyalkylpenicillins... 70 Contents VI Betacin... 71 Carbenicillin... 72 Carfecillin... 77 Clometocillin... 78 Cyclacillin... 78 Epicillin... 79 Guanylureidopenicillin... 79 Hetacillin... 80 Indanylcarbenicillin (Carindacillin)... 81 Isoxazolypenicillins... 82 Mecillinam... 85 Metampicillin... 89 Methicillin... 90 Mezlocillin... 91 Nafcillin... 91 Pirbenicillin... 93 Piperacillin... 93 Pirazocillin... 94 Pivampicillin... 94 Pivmecillinam... 98 Quinacillin... 98 Sulfocillin (Sulbenicillin)... 98 Suncillin... 99 Talampicillin... 99 Ticarcillin... 100 Appendix... 101 References... 102 Pharmacokinetics of Cephalosporin Antibiotics J. M. BROGARD, F. CoMTE and M. PINGET (Strasbourg)... 123 Cephalothin... 126 Absorption... 126 Distribution... 126 Elimination... 127 Cephaloridine... 128 Absorption... 128 Distribution... 129
Elimination... 130 Cephacetrile... 131 Absorption... 131 Distribution... 131 Elimination... 132 Cefazolin... 133 Absorption... 133 Distribution... 134 Elimination... 135 Contents VII Cephradine... 136 Absorption... 136 Distribution... 137 Elimination... 137 Cephapirin... 138 Absorption... 139 Distribution... 139 Elimination... 139 Cephanone... 140 Absorption... 141 Distribution... 141 Elimination... 141 Cefamandole... 141 Absorption... 142 Distribution... 142 Elimination... 142 Cefoxitin... 143 Absorption... 143 Distribution... 144 Elimination... 144 Cefuroxime... 145 Absorption... 145 Distribution... 145 Elimination... 146 Cefatrizine... 146 Absorption... 146 Distribution... 147 Elimination... 147 Ceftezole... 147 Cefazaflur... 148
Cefalexin... 148 Absorption... 148 Distribution... 149 Elimination... 149 Cephaloglycin... 152 Absorption... 153 Distribution... 153 Elimination... 153 References... 154 Pharmacokinetics of Aminoglycosides in Subjects with Normal and Impaired Renal Function A. LEROY, G. HUMBERT, G. OKSENHENDLER and J.P. FILLASTRE (Rouen)... 163 I. Introduction... 163 II. General Pharmacokinetic Properties of Aminoglycoside Antibiotics.. 164 Contents VII III. Pharmacokinetic Parameters of Aminoglycoside Antibiotics... 166 A. Subjects with Normal Renal Function... 166 B. Uraemic Patients... 170 C. In Haemodialyzed Patients... 172 D. Correlations... 172 1. Correlation between Serum Elimination Half-Lives (TYo) and Serum Creatinine Levels... 172 2. Linear Correlation between Overall Elimination Rate Constant (Ke) and Endogenous Creatinine Clearances (Ccr)... 173 IV. Dosage Schedules... 173 A. In Normal Healthy Individuals... 175 B. In the Uraemic Patient.... 175 C. In the Haemodialyzed Patient... 177 V. Conclusion... 178 Summary... 178 References... 178 Pharmacokinetics of Erythromycin in Man J. T. WILSON and C.J. VAN BOXTEL (Nashville, Tenn)... 181 I. Absorption... 182 II. Distribution... 187 III. Elimination... 191
IV. Miscellaneous Information... 193 References... 198 Lincomycin and Clindamycin D.M.D. RIMMER and S.E.L. SALES... 204 Clindamycin... 204 Solubility... 205 Bioavailability Studies... 205 1. Clindamycin HCI Hydrate... 205 2. Clindamycin Palmitate HCl... 205 3. Clindamycin Phosphate... 206 Protein Binding... 207 Concentration of Clindamycin in Human Tissues and Fluids... 207 Biological Half-Life... 207 Excretion of Clindamycin... 207 Lincomycin... 210 Solubility Data... 210 Lincomycin - BioavaiIability Studies... 210 Lincomycin Hydrochloride Solution... 210 Lincomycin Hydrochloride Syrup... 211 Contents IX Protein Binding... 211 Concentrations of Lincomycin Hydrochloride in Various Human Tissues and Fluids... 213 Biological Half-Life... 213 Excretion of Lincomycin... 213 References... 215 The Combination Trimethoprim-Sulphamethoxazole I. HANSEN (Copenhagen)... 217 Absorption... 218 Distribution... 219 Metabolism... 222 Elimination... 222 Interaction with Other Substances... 225 Physico-Chemical Properties... 225 Method of Determination... 226 TMP... 226 SMZ... 227
References... 227 The Pharmacokinetics of Nitrofurantoin and its Related Bioavailability J.D. CoNKLIN (Norwich, N.Y.)... 233 Introduction... 233 Physical Properties... 234 Drug Analysis... 235 Absorption... 236 Distribution... 237 Excretion... 239 Metabolism... 241 Bioavailability... 242 Summary... 245 Acknowledgements... 246 References... 246 Antifungal Agents E. DROUHET (Paris)... 253 Introduction... 254 Polyene Antifungal Antibiotics... 256 Contents XI 1. Chemical Structure and Physico-Chemical Properties... 256 2. Biological Properties... 258 Nystatin... 260 1. Chemical and Miscellaneous Data... 260 2. Absorption, Distribution, Elimination... 261 Amphotericin... 262 1. Chemical and Miscellaneous Data... 262 2. Absorption... 263 3. Distribution... 265 4. Elimination... 266 5. Local Injections... 266 Hamycin... 267 Saramycetin... 267 Griseofulvin... 268 1. Chemical and Miscellaneous Data... 268 2. Absorption... 269 3. Distribution and Elimination... 270
5-F1uorocytosine or 5-Flucytosine... 271 1. Chemical and Miscellaneous Data... 271 2. Absorption... 273 3. Distribution... 274 4. Elimination... 275 Imidazole Antifungals... 277 Clotrimazole... 277 1. Chemical and Miscellaneous Properties... 277 2. Systemic Administration.... 278 a) Absorption... 278 b) Distribution... 279 c) Elimination... 279 3. Dermal Application... 279 Miconazole... 280 1. Chemical and Miscellaneous Data... 280 2. Absorption... 280 3. Distribution... 281 4. Elimination... 281 Econazole... 282 1. Chemical and Miscellaneous Data... 282 2. Absorption, Distribution, Elimination... 282 References... 284 Interactions between Antibiotics and Other Drugs A.J. BINT and D.S. REEVES (Bristol)... 289 I. Classification of Interactions... 291 II. Absorption... 291 Contents XI A. Complexation... 291 1. Tetracyclines - Metals... 291 2. Lincomycin - Kaolin-Pectin... 293 3. Lincomycin - Cyclamate... 293 B. Alteration of Motility... 293 1. Isoniazid - Antacids... 293 2. Para-Aminosalicyclic Acid (PAS) - Diphenhydramine... 294 C. Induced Malabsorption States... 294 1. Neomycin - Digoxin... 294 2. Para-Aminosalicyclic Acid (PAS) - Rifampicin... 294 3. Neomycin - Penicillin... 295
D. Parenteral... 295 1. Sulphonamides - Local Anaesthetics... 295 III. Distribution... 295 1. Sulphonamides - Tolbutamide... 296 2. Sulphonamides - Methotrexate... 296 3. Sulphonamides - Warfarin... 296 4. Sulphonamides - Thiopentone... 296 5. Sulphonamides - Diphenylhydantoin (DPH)... 297 6. Nalidixic Acid - Warfarin... 297 7. Sulphonamides - Displacing Agents... 297 8. Penicillins - Displacing Agents... 297 IV. Sites of Action... 298 1. Aminoglycosides - Muscle Relaxants... 298 2. Colistin - Muscle Relaxants... 299 3. Aminoglycosides - Diuretics... 299 4. Aminoglycosides - Cephalosporins... 299 5. Cephalosporins - Diuretics... 300 6. Tetracycline - Methoxyflurane... 300 7. Aminoglycosides - Methoxyflurane... 301 8. Colistin - Cephalothin... 301 9. Tetracycline - Diuretics... 301 10. Rifampicin - Halothane... 301 11. Rifampicin - Isoniazid... 301 12. Ampicillin - Allopurinol... 302 13. Co-Trimoxazole - Pyrimethamine... 302 V. Metabolism... 302 A. Increased Metabolism... 303 1. Rifampicin - Warfarin... 303 2. Rifampicin - Tolbutamide... 303 3. Rifampicin - Oral Contraceptives... 303 4. Rifampicin - Corticosteroids... 304 5. Doxycycline - Antiepileptic Drugs and Barbiturates... 304 B. Decreased Metabolism... 304 1. Sulphonamides - Diphenylhydantoin (DPH)... 304 2. Sulphonarnides - Tolbutamide... 305 3. Sulphonamides - Warfarin... 305 Contents XII 4. Chloramphenicol - Diphenylhydantoin (DPH)... 305 5. Chloramphenicol - Tolbutamide... 305 6. Chloramphenicol - Dicoumarol... 305
7. Chloramphenicol- Cyclophosphamide... 306 8. Triacetyloleandomycin - Carbamazepine... 306 9. Isoniazid, Para-Aminosalicylic Acid - Diphenylhydantoin (DPH)... 306 10. Para-Acetylsalicylic Acid (PAS) - Isoniazid... 306 11. Isoniazid - Disulfiram... 307 12. Metronidazole - Disulfiram... 307 13. Metronidazole - Alcohol... 307 14. Furazolidone - Monoamine Oxidase Inhibitors, etc.... 307 VI. Excretion... 308 1. Penicillins and Cephalosporins - Probenecid... 308 2. Penicillin - Other Drugs... 309 3. Para-Aminosalicyclic Acid (PAS) - Probenecid... 309 VII. Miscellaneous... 309 1. Antibiotics - Oral Contraceptives... 309 2. Neomycin - Warfarin... 310 3. Penicillins - Coumarins... 310 4. Rifampicin - Probenecid... 310 5. Pyrazinamide - Para-Aminosalicylic Acid (PAS), etc.... 311 6. Sulphamethoxypyridazine - Multiple Drug Therapy... 311 VIII. Conclusion... 311 References... 315