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10662267.Pdf https://theses.gla.ac.uk/ Theses Digitisation: https://www.gla.ac.uk/myglasgow/research/enlighten/theses/digitisation/ This is a digitised version of the original print thesis. Copyright and moral rights for this work are retained by the author A copy can be downloaded for personal non-commercial research or study, without prior permission or charge This work cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given Enlighten: Theses https://theses.gla.ac.uk/ [email protected] DRUGS and ALTERED HEPATIC BIOTRANSFORMATION: CLINICAL and EXPERIMENTAL STUDIES Dissertation submitted for the Degree of M.D. in the University of Glasgow by James Douglas Maxwell, B.Sc., M.B., M.R.C.P. (Lond. & Glas.) The work described in this thesis was undertaken during the tenure of research fellowships in the Liver Unit King's College Hospital London SE5 and Department of Medicine (Division of Gastroenterology and Clinical Pharmacology) University of California Medical Center San Francisco 94143 _ October 1977 ProQuest Number: 10662267 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a com plete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest 10662267 Published by ProQuest LLO (2017). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States C ode Microform Edition © ProQuest LLO. ProQuest LLO. 789 East Eisenhower Parkway P.Q. Box 1346 Ann Arbor, Ml 48106- 1346 AcmowMxmmrs The studies presented in this thesis were carried out while I was a research fellow in the Liver Unit, King's College Hospital London, and subsequently at the University of California Medical Center, San Francisco. My interest in drugs and the liver is due to Dr. Roger Williams who first introduced me to this field, and my warm thanks are owed to him for his interest, support and encouragement. I am also indebted to Dr. Kenneth Melmon who made it possible for me to continue with this work at the University of California, and to Dr. Urs Meyer, ny supervisor in San Francisco, for his stimulating advice, encouragement and support. Dr. Rudi Schmid kindly provided laboratory facilities. My thanks are also due to the many colleagues who cooperated with me in various projects. I greatly appreciated discussions with Dr. John Hunter, and his cooperation with studies described in chapters IV and V. Dr. Stephen Curry and Dr. David Parkes collaborated in the chlorpromazine study (chapter III), and Dr.'Mike Davis with the pregnancy study (chapter V). Invaluable technical assistance was provided by Dr. Simon Ardenan (folate assays), Mr. Graham IVfould ^chlorpromazine assay). Miss Valerie Parsons (measurement of serum calcium and alkaline phosphatase isoenzymes), Mr. David Stewart (D-glucaric acid assay), and Miss Yuhua Chang (ALA-synthetase assay). The work was generously supported by fellowships fron the ^fedical Research Council, Ciba Laboratories, and the Bay Area Heart Association. I should also like to thank Miss Glynis Phillips and Miss Marion Amos for their expert secretarial assistance. CONTENTS Title page 1 Admowledgeraents 2 Contents 3 Tables 7 Figures 8 Sumnary 10 Chapter I Hepatic Biotransformation 16 1) Historical and evolutionary aspects 17 2) General functions of biotransformation 18 3) Phases of drug metabolism 22 4) Hepatic microsomal drug metabolising systems 23 a) Mixed function oxidation b) Microsomal oxidation and electron transfer c) NADPH cytochrome c reductase d) Cytochrome P450 e) P450 binding to drugs f) Species of P450 g) Conjugation 5) Rate limiting steps in vitro 32 6) Rate limiting steps in vivo 33 a) Competitive inhibition b) Limited availability of cofactors c) Hepatic blood flow ( d) Drug distribution and protein binding ^ 7) Pharmacological consequences of drug metabolism 36 Chapter II Genetic and Environmental Influences 38 1) Genetic factors 39 a) Species differences b) Inter individual variation in drug metabolism 2) Environmental, factors 42 a) Hepatic enzyme induction b) Factors controlling drug stimulation of hepatic enzymes c) Morphological and biochemical aspects 3) Evaluating the activity of hepatic microsomal enzymes in man 47 a) Morphological techniques b) Pharmacological techniques c) Biochemical techniques in vitro - measurerænt of components of hepatic mixed function oxidases in vivo - measurement of endogenous products of ^ ^ hepatic metabolism i plasma ^ glutamyl transpeptidase ii urinary 6p hydroxy cortisol iii urinary ascorbic acid & D-glucaric acid Chapter III Tiifiueaco o f Chronic Liver Disease (Cirrhosis 1 on. Drhg 1?fetab.blism 69 1) Chronic liver disease and drug metabolism 70 a) Clinical studies b) In vitro siiudies of drug metabolism by cirrhotic liver 2) Plasma disappearance and cerebral effects of chlorprcxnazine in cirrhosis* 74 Patients and methods Results - Pharmacokinetics - Effect on EEG Discussion 3) Pathogenesis of altered drug kinetics in patients with cirrhosis 86 a) Altered hepatic blood flow b) Altered hepatic extraction c) Altered drug distribution 4) Why is metabolism of some drugs unaffected in conpensated cirrhosis? 88 5) Altered sensitivity to sedative drugs in cirrhosis 89 6) Critique of clinical studies 90 a) Study design b) Patient selection c) Analytical læthodology d) Choice of test drug e) Drug interactions f) Pharmacokinetic considerations g) Future studies Chapter IV Effect of Hepatic Enzyiæ Inducing Drugs on Plasma Bilirubin and Bile Flow 98 1) Effect of phenobarbitone on plasma bilirubin in jaundiced patients 99 a) Clinical studies b) Effect on bilirubin kinetics 2) Soiæ possible mechanisms for bilirubin lowering effect of phenobarbitone 107 3) Experimental! studies in man and the rat* 109 Methods - Wistar rats Gunn rats Investigations:uin man Results - Animal studies Clinical studies Discussion - Drug dosage in conparative studies Effects on hepatic enzymes Effects on bile flow Species variation Qiapter V Clinical Implications of Enhanced Bfepatic Biotransformation 122 1) Drugs and liver hypertrophy: Adaptive or toxic response? 123 2) Stimulation of hepatic biotransformation in man. 123 a) Drug mediated enzyme induction b) Non-drug stimulants 3) Possible therapeutic applications of enzyme induction 125 a) Jaundice b) Cushing's syndrome c) Gallstone dissolution d) Enhancement of drug efficacy e) Elimination of toxic drugs and chemicals f) Treatment of inherited enzyme defects 4) Adverse consequences of hepatic enzyme induction 131 a) Altered drug pharmacokinetics b) Enhanced drug toxicity c) Vitamin deficiency i Vitamin D 135 Lin^ield Calcium Study* Subjects and methods 137 Results Discussion ii Folate 147 Is folate deficiency after drugs an effect of enzyme induction? Alternative hypotheses for drug related folate deficiency lingfield Folate Study* 153 Subjects and methods Results Discussion iii Vitamin K 159 Neonatal haemorrhage following maternal anti­ convulsant therapy d) Enzyme induction and teratogenesis 5) Induction of hepatic enzymes during noimal human pregnancy 162 Pregnancy study* 162 Patients and methods Results Discussion Chapter VI Drug Sensitivity in the Hereditary Hepatic Porphyrias 167 1) Hereditary hepatic porphyrias 168 a) Pharmacogenetics b) Clinical features and enzyme defects - Intermittent Acute Porphyria - Hereditary Coproporphyria - Variegate Porphyria “ Porphyria Cutanea Tarda c) Biochemical basis for clinical features 2) Drugs and hepatic porphyria 177 a) Precipitation of acute attacks by drugs b) Toxic and experimental porphyria 3) A model for drug sensitivity in intermittent acute ' porphyria 184 Studies with experimental partial blocks in heme synthesis* 186 Animals Methods Results - ALA synthetase activity - Urinary ALA excretion - Drug metabolism in vitro and in vivo Discussion 3) Coirmon basis for human and e^^rimental porphyria 202 a) Dual requirenents for massive induction of ALA synthetase b) Role of enzyme inducing agents in acute human porphyria References 211 * denotes original clinical/laboratory study TABLES 1. Relative drug metabolising activity of various organs from rat, guinea-pig and rabbit. 19 2. Relative drug metabolising ability of various fractions and reconbinations of liver hanogenate. , 21 3. Mixed function oxidase (Phase I) reactions, with examples of drugs metabolised by each. 24 4. Ifethods for evaluating the activity of hepatic microsomal enzymes. 48 5. Soire studies showing lack of effect of chronic liver disease on drug metabolism in man. 71 6. Clinical and biochemical details of patients with cirrhosis in chloipromazine study. 75 7. Chlorpromazine study: Cooposition of clinical groups and calculated kinetic constants for drug in plasma. 82 8. Some studies suggesting inpaired drug metabolism in patients with chronic liver disease. , 91 9. Some studies on the efficacy of phenobarbitone in congenital non-haemolytic hyperbilirubinaemia. 101 10. Some studies on the efficacy of phenobarbitone in hyperbilirubinaemia of neonatal jaundice. 103 11. Some studies on the efficacy of phenobarbitone
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