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1 the Maternal and Neonatal Disposition of Pethidine And 1 THE MATERNAL AND NEONATAL DISPOSITION OF PETHIDINE AND BUPIVACAINE ADMINISTERED IN CHILDBIRTH Submitted by Lidia Josephine Notarianni M.Sc. for the degree of Doctor of Philosophy of the University of London 1979 Department of Biochemical Pharmacology St. Mary's Hospital Medical School Paddington, London W.2 COPYRIGHT "Attention is drawn to the fact that copyright of this thesis rests with its author. This copy of the thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with its author and that no quotation from the thesis and no information derived from it may be published without the prior consent of the author." This thesis may be photocopied, microfilmed or lent to other libraries for the purpose of consultation 2 To my parents with love and gratitude "Let it, then be distinctly understood, that the popular unprofessional use of ether and chloroform is both immoral and injurious; that it is highly dangerous and may produce death." (W. Charming; in 'A Treatise on Etherization in Childbirth' 1848). 4 CONTENTS Page Abstract 10 Acknowledgements 12 List of figures 13 List of tables 18 Chapter One. Perinatal pharmacology and obstetric analgesia 1.1 Introduction 23 1.1.1 Historical background 23 1.1.2 Analgesic drugs used in obstetric practice 25 1.2 The passage of maternally administered drugs to 26 the fetus 26 1.2.1 Drugs and the fetus 27 1.2.2 Placental structure and transplacental transfer 35 1.2.3 Drug distribution in the fetus 41 1.2.4 Pharmacokinetics of placental transfer at term 46 1.3 Perinatal drug metabolism 52 1.3.1 General metabolism 52 1.3.2 Drug metabolism during pregnancy 54 1.3.3 Drug retabolism by the placenta 58 1.3.4 Drug metabolism by the fetus 60 1.3.5 Drug metabolism by the neonate 63 1.4 Obstetric analgesia 69 1.4.1 Pethidine 70 1.4.2 Xylidide local anaesthetics 75 1.5 Scope of the present work 89 5 Page Chapter Two. Materials and methods (bupivacaine) 92 Compounds 92 Syntheses 92 Animals 97 Preparation of rats with biliary fistulae 97 Human volunteers 98 Storage of biological samples 98 Spectra 99 Radiochemical techniques 99 Isotope dilution procedures 100 Chromatography 102 Visualization of compounds 103 Treatments of urine prior to analysis 104 Concentration of urinary metabolites 105 Gas-liquid chromatography (GC) 105 Mass spectrometry (MS) 105 Gas chromatography - mass spectromety (GC-MS) 106 Estimation of bupivacaine by GC and GC-MS 106 Extraction of urinary metabolites 108 Chapter Three. Materials and methods (pethidine) 111 Compounds 112 Syntheses 112 Animals 113 Administration of compounds 114 Collection of urine and faeces 114 Collection of 14CO2 in expired air of rodents 114 6 Page Human volunteers 115 Administration of norpethidine and pethidinic acid 116 Storage of excreta 116 Collection of 14CO2 in expired air of humans 116 Radiochemical techniques 116 Quantitation of 14C in animal carcasses 117 Thin layer chromatography 117 Gas-liquid chromatography (GC) 117 Mass spectrometry (MS) 119 Gas chromatography - mass spectrometry (GC-MS) 119 Acetylation of metabolites 119 Estimation of pethidine and norpethidine by GC 119 Estimation of total pethidinic and norpethidinic acids 120 by GC Estimation of free pethidinic and norpethidinic acids 121 Estimation of pethidine-N-oxide 122 General procedure for the separation, identification and 122 quantitation of metabolites Chapter Four(a) The maternal and neonatal disposition of bupivacaine administered during childbirth 125 Introduction 126 Subjects, drug administration and sample collections; 126 Results 127 (i)Mernal and neonatal cord levels at delivery 127 (ii)I`eonatal elimination 132 Discussion 134 7 Page Chapter Four(b) The maternal and neonatal disposition of pethidine administered in childbirth Introduction 144 Subjects, drug administration and sample collection 144 Results 145 (i)maternal and neonatal cord levels at delivery 145 (ii)N.eonatal elimination 150 Discussion 153 Comparison of the placental transfer of bupivacaine 161 and pethidine Chapter Five The effects of maternal analgesia (pethidine and bupivacaine) on the fetus and neonate 165 Introduction 166 Patients and methods 166 Selection of population studied 166 Obstetric management 166 Assessment of neonate 167 Results 168 Effect of maternal analgesia on the fetal cardio- 168 vascular system Effect of maternal analgesia on neonatal behaviour 170 Discussion 175 Implications of the results 177 Chapter Six The metabolism of bupivacaine in rat and man 182 183 Introduction Identification of metabolites 183 Rat urine 183 8 Page Sequential extraction of rat urine 184 Rat bile 191 Human urine 194 Sequential extraction of human urine 197 Results 199 Rat urine 199 Rat bile 203 Human urine 208 Discussion 213 Chapter Seven The identification of urinary metabolites of pethidine in adult volunteers 227 Introduction 228 Analysis of urinary metabolites 230 Results 241 Discussion 248 Chapter Eight The metabolism of pethidine in adult volunteers and human neonates 253 Introduction 254 Analysis of urinary metabolites 254 Adult panel study 254 Neonatal study 255 Results 255 Adult panel study 255 Neonatal study 262 Discussion 267 9 Page Chapter Nine Species variation in the metabolism of pethidine 279 Introduction 280 Analysis of urinary metabolites 280 Non-human primates 280 Sub-primate mammals 281 Results 282 Non-human primates 282 Sub-primate mammals 286 Discussion 289 *References 303 Appendix A: Formulae for the dioxan and Triton based 294 scintillants used in the study. Appendix B(1): Maternal, umbilical and neonatal blood 295 concentrations of bupivacaine; neonatal blood elimination half-life;maternal dose and last dose-delivery interval for all individuals in the bupivacaine study. Appendix B(2): Maternal, umbilical and neonatal blood 298 concentrations of pethidine; neonatal blood elimination half-life; maternal dose and last dose-delivery interval for all individuals in the pethidine study. Appendix C: Estimation of total drug exposure of the 301 fetus/neonate to maternally administered pethidine or bupivacaine. Appendix D: Estimation of rate constants for the elimination of pethidine and metabolites. 302 *The first citation of any work in this thesis will be referred to in the text by all authors names and the year of publication. Subsequent references to the same work will only include the first author and year of publication. 10 ABSTRACT (1) The maternal and neonatal disposition of bupivacaine (n=58) and pethi- dine(n=51)administered to the mother during childbirth has been studied. (2) Both drugs readily pass the placenta, pethidine more extensively than bupivacaine, and at birth the neonatal body burden of the drug used depends partly on the time interval between the last maternally administered dose and delivery. (3) The infant eliminates both these drugs very slowly which, in the case of pethidine at least, is largely due to impaired metabolism since the blood elimination half-life of the drug is increased by a factor of 6.1 and pethidine metabolism impaired by a factor of 9.1 compared to the adult. (4) The judicious use of bupivacaine and pethidine in childbirth does not have detrimental effects on fetal physiology, but both drugs have been shown to affect neonatal behaviour for at least the first six weeks of life. (5) The metabolism of bupivacaine in rat and man has been studied. The major metabolic pathway in the rat is aromatic hydroxylation yielding 2 isomeric phenolic metabolites of bupivacaine. In man, the major metabolites have not been elucidated, and although the results suggest that they are phenolic in nature, they are not 3' and 4'-hydroxybupivacaine. 11 (6) The metabolism of pethidine in human adults has been investigated using a mixture of [ 14C] /[2H5] -pethidine to aid mass spectrometric ident- ification- of the metabolites. The major metabolic routes of pethidine in man are ester hydrolysis and N-demethylation yielding pethidinic and norpethidinic acids and norpethidine. Two minor metabolites, 4'-hydroxypethidine and pethidine-N-oxide have been quantitated for the first time. (7) The metabolism of pethidine in a small group (15) of adults has been studied which has shown large inter-individual diff- erences in its metabolism. Ester hydrolysis and N-demethylation are competing pathways, and N-demethylation is apparently not under the same genetic control as the aromatic, alicyclic and aliphatic carbon oxidation of drugs such as guanoxan, phenacetin and debrisoquine. (8) The metabolism of pethidine in 5 neonates was studied showing impaired metabolic ability and evidence of differential onto- genesis of the mixed function microsomal oxidase system was obtained. (9) Inter-species variation in the metabolism of pethidine was studied in 4 species of non-human primates and 3 species of sub-primate mammals. Due to the large inter-individual diff- erences in metabolism observed in humans, no one species was a consistently good metabolic model for man. 12 ACMNOWLEDGEMENTS I would like to take this opportunity to express my gratitude to Professor Robert Smith and Dr. John Caldwell for their invaluable advice and guidance throughout this work and their useful suggestions and comments on the contents of this thesis. My thanks are also due to my colleagues and technical staff of the Pharmacology Department, Professor Ted Hawes and Mr. Lawrence Wakile for their assistance in the pethidine assay, the Biophysics Department for making available the mass spectrometry facility and in particular Mr. Graham Correy for his help in obtaining the mass spectra. My gratitude also extends to all those too numerous to mention by name who were involved in the obstetric/neonatal study for the collection of blood and urine samples and the testing of babies at anti-social hours which made this study possible. Finally, but most of all, I wish to thank my parents for their love and support throughout my long education ( I hope they are not too disappointed by the result ) and my f iancē Robin for his constant help and encouragement during this work and the writing of this thesis.
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