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Pharmacokinetics and Metabolism of Barbiturates

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Pharmacokinetics and Metabolism of Barbiturates PHARMACOKINETICS AND METABOLISM OF BARBITURATES TJONG DING YIH PHARMACOKINETICS AND METABOLISM OF BARBITURATES Promotor: Prof. Dr. J.M. van Rossum. PHARMACOKINETICS AND METABOLISM OF BARBITURATES PROEFSCHRIFT TER VERKRIJGING VAN DE GRAAD VAN DOCTOR IN DE WISKUNDE EN NATUURWETENSCHAPPEN AAN DE KATHOLIEKE UNIVERSITEIT TE NIJMEGEN, OP GEZAG VAN DE RECTOR MAGNIFICUS PROF. DR. A.J.H. VENDRIK VOLGENS BESLUIT VAN HET COLLEGE VAN DECANEN IN HET OPENBAAR TE VERDEDIGEN OP VRIJDAG 10 SEPTEMBER 1976 DES NAMIDDAGS OM 2 UUR PRECIES DOOR TJONG DING YIH GEBOREN TE UTRECHT 1976 DRUK: STICHTING STUDENTENPERS NIJMEGEN The investigations were earned out in the Department of Pharmacology, University of Nijmegen, Nijmegen, The Netherlands and have been partly supported by grants of the Dutch Organization for Purely Scientific Research (ZWO/FUNGO). Voor Liesbeth ACKNOWLEDGEMENTS The author is greatly indebted to all persons who contributed to the realization of this study. Thanks are expressed to the staffs of the Pharmacological Department, especially the members of the group of Pharmacokinetics for support, valuable discussions and friendship. The author wishes to thank: Drs. H.C.J. Ketelaars for his help in the mass spectrometric analysis; Dr. F. Seutter-Berlage and Dr. P.Th. Hender­ son for their helpful advice and criticism during the preparation of the manuscript; Dr. G. Ziv for corrections to the english text; Miss S. Tom for her unfailing help with the preparation of the liver perfusions and the analysis of so many samples, often during off-duty hours; Mrs. E.L. Klok for her invaluable assistance in the computer analysis of the data; Mr. P.L.J, van Gemert for his help with the synthesis and recrystalliza- tion procedures of the barbiturates; Mr. C.G. van den Vorstenbosch for his help with the preparation of microsomes and recording of difference spectra; Mr. J.A.L. Jansen, Mr. W.B. Hoeboer, Mr. Smulders and the members of the Department of Glass-works for technical assistance; Mr. T.H.M. Arts and co-operators of the Central Animal Laboratory for their aid in the animal experiments; the students who have worked on barbiturates: S. Graafsma, R. van den Heuvel, A.W. Boxman and P.B. ten Kortenaer; Mr. J.G. Wiese and co-workers of the Department of Medical Illustration; Mr. A.Th.A. Reynen and co-workers for their artful photography; Mr. E. de Graaf and co-workers for bibliographic aid; Dr. J.M.A. Sitsen (Utrecht) for gifts of 5-ethyl-5-(2,3-dimethylbutyl) barbituric acid; Dr. L.A. Her­ mans (Utrecht) for gifts of hydroxyzine and helpful suggestions; U.C.B. (Belgium) for gifts of brallobarbital; Hommel A.G. (Switzerland) for gifts of 2-allyl-4-valerolacton; Cassella-Riedel Pharma (W. Germany) for gifts R R of Noctal and Eunarcon ; Miss M.P.M. Jansstr ;-jr her invaluable typing aid. CONTENTS ABBREVIATIONS 9 GENERAL INTRODUCTION 11 SECTION I PHARMACOKINETICS CHAPTER 1 KINETICS OF DRUG DISTRIBUTION AND ELIMINATION 16 INTRODUCTION 16 PHARMACOKINETIC MODELS 17 FLOW-LIMITED ELIMINATION OF DRUGS 23 CAPACITY-LIMITED ELIMINATION OF DRUGS 23 PHARMACOKINETIC ANALYSIS 24 CHAPTER 2 ENZYME KINETICS ON HEPATOCYTES AND MICROSOMES 25 SECTION II MATERIALS AND METHODS CHAPTER 3 SYNTHESIS OF BARBITURATES 28 CHAPTER 4 INTACT ANIMAL EXPERIMENTS 30 CHAPTER 5 THE ISOLATED PERFUSED RAT LIVER 32 CHAPTER 6 9000 g RAT LIVER SUPERNATANT 40 CHAPTER 7 ISOLATED RAT HEPATOCYTES 44 CHAPTER 8 PARTITION COEFFICIENTS 49 CHAPTER 9 SPECTRAL DISSOCIATION CONSTANTS (Ks) 51 CHAPTER 10 ANALYSIS 52 SECTION III PHARMACOKINETICS OF BARBITURATES CHAPTER 11 5-ETHYL-5-ALKYL SUBSTITUTED BARBITURATES IN THE RAT AND THE LIVER PERFUSION 60 CHAPTER 12 5-ALLYL- AND 5-BROMOALLYL-5-ALKYL SUBSTITUTED BARBITURATES IN THE RAT AND THE LIVER PERFUSION 74 CHAPTER 13 RING-SUBSTITUTED BARBITURATES IN THE RAT AND THE LIVER PERFUSION 86 CHAPTER 14 PHARMACOKINETICS OF BARBITURATES IN THE ISOLATED RAT HEPATOCYTE SUSPENSION 98 CHAPTER 15 PHARMACOKINETICS OF BARBITURATES IN A SUBCELLULAR SYSTEM OF RAT LIVER 104 CHAPTER 16 THE DISSOCIATION CONSTANTS (Ks) OF THE BINDING OF BARBITURATES TO CYTOCHROME Ρ 450 OF RAT LIVER AND THE MICHAELIS-MENTEN CONSTANTS OF A NUMBER OF BARBITURATES 111 SECTION IV METABOLISM OF BARBITURATES CHAPTER 17 PHARMACOKINETICS OF BARBITURATE METABOLITES 122 CHAPTER 18 METABOLIC DIFFERENCES BETWEEN THE ISOLATED HEPATOCYTE SUSPENSION AND THE 9000 g RAT LIVER SUPERNATANT 130 CHAPTER 19 IDENTIFICATION OF BARBITURATES AND THEIR METABOLITES 13 5 SECTION V INTRAVENOUS AND ORAL ADMINISTRATION OF BARBITURATES CHAPTER 20 PHARMACOKINETICS OF BUTOBARBITAL AND CYCLOBARBITAL FOLLOWING INTRAVENOUS AND ORAL ADMINISTRATION 144 CHAPTER 21 PECULIAR PHARMACOKINETICS OF BRALLOBARBITAL AS A SOURCE OF COMPLICATIONS IN VESPARAXR INTOXICATION 149 SECTION VI SPECIES AND SEX DIFFERENCES ELIMINATION OF BARBITURATES CHAPTER 22 COMPARISON OF THE PHARMACOKINETIC DATA OF BARBITURATES IN MAN AND RAT 166 CHAPTER 23 SEX DIFFERENCES IN THE ELIMINATION OF HEXOBARBITAL AND HEPTABARBITAL IN THE RAT 169 SUMMARY 171 SAMENVATTING 177 REFERENCES 183 CURRICULUM VITAE 191 LIST OF ABBREVIATIONS OF THE BARBITURATES USED Alio : allobarbital, 5,5-diallyl barbituric acid Apro : aprobarbital, 5-allyl-5-isopropyl barbituric acid Bral : brallobarbital, 5-allyl-5-(2-bromoallyl) barbituric acid m-Bral : l-N-methyl-5-allyl-5-(2-bromoallyl) barbituric acid DnrBral : 1.a-N.N'-dimethyl-S-allyl-S-CZ-bromoallyl) barbituric acid Butyl : butobarbital, 5-ethyl-5-butyl barbituric acid Dnr-But : 5-ethyl-5-(2>3-diniethylbutyl) barbituric acid Cyclo : cyclobarbital, 5-ethyl-5-(l-cyclohexen-l-yl) barbituric acid ш-Cyclo : l-N-methyl-5-ethyl-5-(l-cyclohexen-l-yl) barbituric acid Dm-Cyclo : 1 .S-N.N'-dimethyl-S-ethyl-S-O-cyclohexen-l-yl) barbituric acid R Cyclop : Cyclopal , 5-allyl-5-(2-cyclopenten-l-yl) barbituric acid m-Cyclop : l-N-methyl-5-allyl-5-(2-cyclopenten-l-yl) barbituric acid Eunarc : Eunarcon , l-N-methyl-5-(2-bromoallyl-5-isopropyl) barbi­ turic acid Hepta : heptabarbital, 5-ethyl-5-(I-cyclohepten-l-yl) barbituric acid m-Hepta : ]-N-methyl-5-ethyl-5-(l-cyclohepten-l-yl) barbituric acid Dm-Hepta : 1.S-N.N'-dimethyl-S-ethyl-S-Cl-cyclohepten-l-yl) barbituric acid Heptyl : 5-ethyl-5-heptyl barbituric acid m-Heptyl : l-N-methyl-5-ethyl-5-heptyl barbituric acid Hexo : hexobarbital, l-N-methyl-5-methyl-5-(l-cyclohexen-l-yl) barbituric acid m-Hexo : 1,3-N-dimethyl-5-methyl-5-(l-cyclohexen-I-yl) barbituric acid Hexyl : Ortal , 5-ethyl-5-hexyl barbituric acid m-Hexyl : |-N-methyl-5-ethyl-5-hexyl barbituric acid Dm-Hexyl : 1jS-N.N'-dimethyl.S-ethyl-S-hexyl barbituric acid Hydroxy-Hexo: l-N-methyl-5-(l-cyclohexen-l-yl-3-hydroxy) barbituric acid Keto-Hexo : ]-N-methyl-5-(l-cyclohexen-l-yl-3-keto) barbituric acid Neal : nealbarbital, 5-allyl-5-neopentyl barbituric acid R Noct : Noctal , 5-(2-bromoallyl)-5-isopropyl barbituric acid 9 Nonyl 5-ethyl-5-nonyl barbituric acid m-Nonyl l-N-methyl-5-ethyl-5-nonyl barbituric acid Nor-Hexo 5-methyl-5-(l-cyclohexen-l-yl) barbituric acid Octyl 5-ethyl-5-octyl barbituric acid m-Octyl l-N-methyl-5-ethyl-5-octyl barbituric acid Pentyl 5-ethyl-5-pentyl barbituric acid i-Pentyl amobarbital, 5-ethyl-5-(3-methylbutyl) barbituric acid s-Pentyl pentobarbital, 5-ethyl-5-(l-methylbutyl) barbituric acid Pem Pernocton , 5-(2-bromoallyl)-5-(l-methylpropyl) barbituric acid nr-Pem l-N-methyl-5-(2-bromoallyl)-5-(l-methylpropyl) barbituric acid m-Pheno Prominal , l-N-methyl-5-etnyl-5-phenyl barbituric acid Propryl 5-ethyl-5-propyl barbituric acid Reet Rectidon , 5-(2-bromoallyl)-5-(l-methylbutyl) barbituric acid Rep Reposal , 5-еіЪу1-5-(.ЫсусІо-3,2 , l-oct-2-en-2-yl) barbitu­ ric acid m-Rep l-N-methyl-5-ethyl-5-(bicyclo-3,2,l-oct-2-en-2-yl) barbi­ turic acid Seco secobarbital, 5-allyl-5-(l-ioethylbutyl) barbituric acid ρ Tal Talbutal , 5-allyl-5-(l-methylbutyl) barbituric acid Vinylbital 5-vinyl-5-(l-methylbutyl) barbituric acid 10 GENERAL INTRODUCTION The total body clearance is the kinetic parameter characterizing the elimination of drug from the body. Especially for lipophilic drugs' the liver plays an important role in the elimination so that for many drugs the total body clearance equals the metabolic clearance. The metabolic clearance depends on the kinetics of the metabolic enzymes in the liver. This implies that there must be a relationship between the parameters governing enzymatic conversion of drugs in the liver and the metabolic clearance or total body clearance. The object of this study is to explore the relationship between total body clearance in vivo and enzymatic processes in vitro. For this purpose the kinetics of series of barbiturates were studied in the intact rat and preparations of rat liver. The in vitro methods range from studies on the intact perfused rat liver via isolated liver cells (hepatocytes) to liver microsomes and the enzyme cytochrome Ρ 450. See figure. These studies allow us to gain information on the relevance of blood flow through the liver, the rate of penetration of drugs within the liver cells, access to the microsomes and finally binding to and biotransforma­ tion by the liver enzymes with respect to the rate of metabolic degrada­ tion. The barbiturates were chosen because the compounds are strongly re­ lated but nevertheless they show diverse pharmacological properties. The discovery of the hypnotic properties of 5,5-diethyl barbituric acid (barbital) by Fischer and Von Mehring in 1903 led to the synthesis of numerous barbituric acid derivatives. Numerous barbiturates and barbitu­ rate combinations have been introduced into practice as hypnotics, seda­ tives and anaesthetics (Bobranski, 1972). The consumption of barbiturates amounts still to enormous proportions so that many cases of barbiturate poisoning and fatalities have been reported. In early studies with rats and mice it has been found that the "hypnotic effect", often expressed as minimum anaesthetic dose (M.A.D.), could be changed markedly by varying the substituents.
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