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Metabolism of Contraceptive Steroids. a Thesis For

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Metabolism of Contraceptive Steroids. a Thesis For 1. I fit-- 'IN VITRO ' METABOLISM OF CONTRACEPTIVE STEROIDS. A THESIS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN THE UNIVERSITY OF LONDON 1976 . FIRYAL SULTANAUkAN.MSc. THE ROYAL POSTGRADUATE MEDICAL SCHOOL, LONDON. 2. A B S T R A C T. A comparative in vitro' investigation of the effect of various substituent groups on the structurally related synthetic 19-norprogestogens (norethisterone norgestrel, lynestrenol and their esterified derivatives) in the rabbit hepatic and extrahepatic tissues is described. Using total tissue homogenates, the study indicated that various structural modifications of the progestogens resulted in compounds with varying degrees of resistance to metabolism. (The esterified derivatives were metabolised at a comparatively slower rate than the non-esterified progestogens). However, the route of metabolism was not affected by these modifications as compared to natural steroids. Amongst the extrahepatic tissues small intestine, lung and skeletal muscle tissue metabolised the progestogens but at a slower rate than in the liver. Mainly ring-A reduced metabolites were identified. In contrast to the study with total liver homogenates, in the microsomal fraction of rabbit liver ring-A reduced and hydroxylated products were identified from d-, dl- and 1-norgestrel. d-norgestrel followed the reductive and oxidative pathways equally, whereas dl- and 1-norgestrel were mainly hydroxylated. In comparison to testosterone d-, dl- and 1-norgestrel were metabolised at a slower rate. As compared to dehydroepiandrosterone and ethynyloestradiol, the rate of sulphate conjugation of the 19-norprogestogens was relatively slower in the liver. Gastrointestinal and lung tissues also sulphated these compounds. The 19-norprogestogens were conjugated at C-17, dehydroepiandrosterone at C-3 and ethynyloestradiol at both C-3 and C-17 in the liver. 14 The tin vivo' investigation of the metabolism .of (4- C) norethisterone oxime (racemate, 'anti'- and 'syn'-isomers) indicated that after intra- peritoneal administration these compounds were excreted mainly in the uriney in the glucuronide fraction.' Small amounts of radioactivity were excreted in the faeces. In plasma, peak levels of norethisterone oxime were seen at two hours and the levels of radioactivity declined gradually. The major metabolite identified from the urine and faeces was unchanged norethisterone oxime. 3. In the tin vitro' study the oxime derivatives of norethisterone and d—norgestrel were metabolised more slowly than the parent compounds. Gastrointestinal and lung tissues also metabolised these compounds at a similar rate to that in the liver. The metabolites identified were hydrolysed and ring—A reduced products. 4. TRIVIAL AND SYSTEMATIC NAMES OF STEROIDS. TRIVIAL NAME SYSTEMATIC NAME.(IUPAC 1971) Cholestenone 4-Cholesten-3-one. Dehydroepiandrosterone 3p-Hydroxy-5-androsten-17-one. Dehydroepiandrosterone Sulphate 38-Sulphato-androst-5-en-17-one. Dihydronorgestrel 1704-Ethyny1-17p-hydroxy-18-methy1-504 - estrane-3-one. 6E -Hydroxynorgestrel 170(-Ethyny1-6e ,17p-dihydroxy-18-methy1- 4-estren-3-one. 1604-Hydroxynorgestrel 17N-Ethyny1-1604,17P-dihydroxy-18-methyl- 4-estren-3-one. 16P-Hydroxynorgestrel 1704-Ethyny1-16P,17)3-dihydroxy-18-methyl- 4-estren-3-one. Ethynyloestradiol 1704-Ethyny1-1,3,5-estratriene-3, 17P-diol. Ethynyloestradiol-3-sulphate 1704-Ethyny1-1,3,5-estratriene-17P- ol-3-sulphate. Ethynyloestradiol-17-sulphate 1704-Ethyny1-1,3,5-estratriene-17P- sulphato-3P-ol. Ethynyloestradiol-3,17-sulphate 1704-Ethyny1-1,3,5-estratriene-3, 17-sulphate. Lynestrenol 170(-Ethyny1-4-estren-17,13-ol. Lynestrenol acetate 1704-Ethyny1-4-esten-17P-acetate. Lynestrenol sulphate 1704-Ethyny1-4-estren-17p-sulphate. Norethisterone 17m-Ethyny1-17P-hydroxy-4-estren-3-one. Norethisterone acetate 17q-Ethyny1-17p-acetoxy-4-estren-3-one. Norethisterone oenanthate 17x-Ethyny1-17P-heptonate-4-estren-3-one. Norethisterone oxime 3-Hydroxyimino-1704-Ethyny1-17P-hydroxy- 4-estrene. Norethisterone sulphate 1704-Ethyny1-17P-sulphato-4-estren-3-one d-Norgestrel D-17o(-Ethyny1-17p-hydroxy-18-methy1-4- estren-3-one. dl-Norgestrel DL-1704-Ethyny1-17P-hydroxy-18-methy1-4- estren-3-one. 1-Norgestrel L-17a-Ethyny1-17p-hydroxy-18-methy1-4- estren-3-one. dl-Norgestrel acetate 0L-17x-Ethyny1-17P-acetoxy-18-methyl-4- estren-3-one. Norgestrel oxime 3-Hydroxyimino-170c-Ethyny1-17.0-hydroxy- 18-methy1-4-estren-3-one. 5. Norgestrel sulphate 17a—Ethyny1-17p—sulphato—:.8—methyl- 4—estren-3—one. 19—Nortestosterone 17p—Hydroxy-4—estren-3—one. Testosterone 177—Hydroxy-4—androsten-3—one. Tetrahydronorethisterone 170.—Ethyny1-17p—hydroxy—estrane. Tetrahydronorgestrel 17a—Ethyny1-17p—hydroxy-18—methyl—estrane. 6. ABBREVIATIONS ABBREVIATIONS FOR STEROIDS. 19-port. 19-nortestosterone DHA dehydroepiandrosterone dehydroepiandrosterone sulphate DHA-SO4 E oestradiol 2 E -3-50 oestradiol-3-sulphate 2 4 E -17-S0 oestradiol-17-sulphate 2 4 E -3-17-50 oestradio1-3-17-sulphate 2 4 EE ethynyloestradiol EE-3-SO ethynyloestradiol-3-sulphate 4 EE-17-SO ethynyloestradiol-17-sulphate 4 EE-3-17-SO ethynyloestradiol-3-17-sulphate 4 Lyn lynestrenol Lyn-AC lynestrenol acetate Lyn-SO4 lynestrenol sulphate NET norethisterone NET-AC norethisterone acetate NET-OX norethisterone oxime NET-EN norethisterone oenanthate NET-SO norethisterone sulphate 4 d-,dl-, and 1-Ng. d-, dl-, and 1-norgestrel d, dl-, and 1-Ng-AC d-, dl-, and 1-norgestrel acetate d-, dl-, and 1-Ng-SO4 d-, dl-, and 1-norgestrel sulphate d-Ng-OX d-norgestrel oxime T testosterone THNET tetrahydronorethisterone THNg tetrahydronorgestrel DHNET dihydronorethisterone OTHER ABBREVIATIONS ATP adenosine 5'-triphosphate A ampere A.R. analytical reagent cm centimeter CV coefficient of variation c.p.m. counts per minute Ci Curie degrees celcius EDTA ethylenediaminetetra acetate 7. g.l.c. gas—liquid chromatography g gram g unit of the gravitational field (9.81 m.s-2) h hour I.D. internal diameter KC1 potassium chloride K SO potassium sulphate 2 4 KH PO potassium dihydrogen orthophosphate 2 4 3 1 litre (dm ) -6 micro (10 x) Ng microgram -6 prrl micron (10 m) mCi milli Curie m,u millimicron -3 m milli (10 m) mg milligram MgC12 magnesium chloride MgSO4 magnesium sulphate MnC1 manganese chloride 2 ml millilitre mM milli molar min minute (60 s) molar mol mole mol. wt. molecular weight -9 n nano (10 x) NaC1 sodium chloride ng nannogram NAD' nicotinamide—adenine dinucleotide NADP nicotinamide—adenine dinucleotide phosphate NADPH nicotinamide—adenine dinucleotide phosphate, reduced per cent 0 probability PAPS adenosine 3I—phosphate 5t—phosphosulphate p.c. paper chromatography psi pounds per square inch r.p.m. rev per minute R T retention time RR relative retention time T s seconds '(time) S.D. standard deviation 8. sp. act. specific activity t.l.c. thin—layer chromatography TMS ethers trimethylsilyl ethers Tris 2—Amino-2—hydroxymethyl—propane-1,3—dial. vol. volume v volume to volume by vol. by volume wavelength wt. weight weight to volume v sum of is less than is greater than 9. INDE PAGE ABSTRACT 2 Trivial and systematic names of steroids. 4 Abbreviations. 6 Index. 9 Index of figures and tables. 18 INTRODUCTION 22 REVIEW OF THE LITERATURE. 23 Development of the synthetic progestational steroids 23 related to testosterone. Metabolic alterations ofanaturally occurring steroid 26 hormone, testosterone. Metabolic alterations of 19—nortestosterone. 29 a)'In viva' and 'in vitro' metabolism in man. 29 b)'In vitro' metabolism in animals. 31 Metabolic alterations of the synthetic progestogens 32 structurally related to testosterone. Metabolism of norethisterone. 32 a)'In vivo' metabolism in man. 32 b)'In viva' and 'in vitro' metabolism in rabbit. 34 Metabolism of norgestrel. 35 a)'In vivo' metabolism in man. 37 b)'In vivo' metabolism in rabbit. 38 Metabolism of lynestrenol. 39 a)'In vivo' metabolism in man. 39 b) 'In vivo' and 'in vitro' metabolism in rabbit. 41 Metabolism of esterified derivatives of synthetic 43 19—norprogestogens. Comparison of the 'in vivo' and 'in vitro' metabolic 44 studies of synthetic 19—norprogestogens. Additional comments. 44 Comparison of the metabolism of synthetic 19—norprogestogens 45 in man and rabbit. 10. SECTION 1. CHAPTER 1. RING—A REDUCTION OF 19—NORPROGESTOGENS. 47 INTRODUCTION. 47 MATERIAL AND METHODS. 48 1. Animals 48 2. Chemicals. 48 a)Steroids 48 b)Organic solvents. 48 c)Other chemicals. 48 d)Cofactors. 48 e)Gas—liquid chromatographic materials. 50 f)Scintillation fluid for estimation of 50 .radioactivity. 3. Washing of glassware. 50 4. Purification of substrates. 50 5. 'In vitro' methodology. 51 a)Preparation of tissues. 51 b)Incubation procedure. 51 c)Extraction of metabolic products. 52 6. Chromatography. 53 a)Paper chromatography. 53 b)Alumina column chromatography. 53 c)Thin—layer chromatography. 53 d)Gas—liquid chromatography. 54 i)Instrumentation and operating conditions 54 ii)Quantitation. 56 iii)Use of internal standard. 58 iv)Reliability data for gas—liquid chromatography. 58 a)characterisation of steroids. 58 b)precision. 58 c)accuracy. 60 d)sensitivity. 60 e)specificity. 62 7. Identification of incubation products. 62 11. 8. Derivative formation. 64 a)Preparation of trimethylsilyl ether derivatives. 64 b) Acetylation. 54 c)Reduction. 64 d)Oxidation. 64 9. Estimation of radioactivity. 65 10. Statistical treatment of data. 65 RESULTS. 66 1. Metabolism bf 19—nortestosterone and various synthetic 66 19—norprogestogens by rabbit hepatic tissue. a)Rate of metabolism. 66 b) Nature and formation of metabolites in hepatic 69 tissue. 2. Metabolism of 19—nortestosterone and various synthetic 75 19—norprogestogens by the hepatic and extrahepatic tissues. a)Hepatic tissue metabolism. 76 b)Kidney tissue metabolism. 80 c)Skeletal muscle tissue metabolism. 82 d)Lung tissue metabolism. 84 e)Spleen tissue metabolism. 86 f)Small intestine tissue metabolism. 86 g)Adipose tissue metabolism. 89 h)Heart tissue metabolism. 91 DISCUSSION. 94 12. CHAPTER 2. HYDROXYLATION OF 19—NORPROGESTOGENS. 107 INTRODUCTION 107 MATERIAL AND METHODS. 108 1. Animals. 108 2. Chemicals. 108 a)Steroids 108 b)Organic solvents. 108 c)Other chemicals. 108 d)Cofactors. 108 e)Gas—liquid chromatographic material.
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