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J October, L979 THE UNTVERSITY OF MANITOBA , A STUDY OF THE ¡TYÐROLYSTS IN V]TRO AI{Ð CERTAIN BIOTOGTCA¡ EFT'ECTS OF SOME ECGONINE A],KA],OTDS FOUND TN ERYTHROXYLON COCA by RICHARÐ ROSCOE A TTIESIS SUBMITTED 1O TITE FACT]LTY OF GRADUATE STUÐIES IN PARTTA], FULFTT,¡@NT OF TIIE REQUTRET,ENTS FOR THE DEGREE OE DOCTOR OF PHTLOSOPHY DEPART14ENT OF CHEMISTRY WINNIPEG, M.ANITOBA .",, r' 11 ,o¡!ìa '.., . fj- Ji'i,.- -; _rr.1¿. i : .. i.- I.i . i:, .l{ __,....,,.,,. {; j October, L979 ì, ..1. :' 1.tl .j a'ì1..,. i:. j,. ¡ . A STUDY OF THI HYDROLYSIS IN VITRO AND CERTAIN BIOLOGICAL EFFTCTS OF SOIVIE ECGONINE ALKALOIDS FOUND IN ERYTHROXYLON COCA BY RICHARD MAURICE HENRY ROSCOE A thesis submitted to the Faculty of Graduate Studies of the University of Manitoba in partial fulfillment of the requirements of the degree of DOCTOR OF PHILOSOPHY ool980 Permission has been granted to the LIBRARY OF THE UNIVER- SITY OF MANITOBA to lend or sell copies of this thesis, to the NATIONAL LIBRARY OF CANADA to rnicrofilnr this thesis and to lend or sell copies of the film, and UNIVERSITY MICROFILMS to publish an abstract of this thesis. The author reserves other publication rights, and neither the thesis nor extensive extracts from it may be printed or other- wise reproduced without the author's writteu pernrission. 'li.a:i-:¡?i: ï':: i 1:::! t:f ;.+', al r: : ft i7 ! ABSTRACT Investigations were completed concernj-ng the hydrolysis of cocaine and certain biological effects of selected ecgonine alkaloids derived from coca leaf. The alkaloid,s were cocaine, ecgonine methylester, benzoylecAonine, and ecgonine. Analyti-cal and hydrolysis procedures were developed to evaluate the hydrolysis of cocaine in a variety of alkaline media. In non-enzymatic systems of pH greater Èhan 11 ecgonine methylester v/as found to be the major inÈermediate in thre hydrolysis of cocaine to ecAonine. Cocaine was shown to rapidly hydrolyze in these systems, including those of the alkaline materiaLs used in the chewing of coca l-eaf, i.e., ishku. The rapid hydrotysis of cocaine to ecgonine proceeds via two parallel path- ways, one involving benzoyJ-ecgonine as an intermediate and the other, greatly favored at pH values greater than 11, ecaonine methylester. Measurements of the energy netabolism of rats indicated that signi- ficant depression of respiratory quotients occurred in raÈs fed a low protej-n-high carbohydrate diet containing cocaine, ecgonine methylester, or benzoylecaonine. Ecgonine was without effect. SÍnce avaiJable data showed that cocaine did not change the urinary nitrogen output of rats maintained on the low protein dieÈ, the changes in respiratory quotient point to changes in the relaÈive utilization of fat and carbohyd.rate íor energy metabolism. The depressed respiratory quotients would therefore indicate an increased relative utilízation of fat in the rats. The results of the metabolic sËr:dies involving ecgonine methylester in rats receiving low protein-high carbohydrate diets were confirmed by results of whole body analysis'studies in mice similarly treated. The increased -1- relative ut'ilization of fats found in rats was consistent with the reduced whole body triglyceride level-s found in the mice. When administered con- currently with oraL xylose test sol-utions, cocaine increased the absorp- tion of xylose while ecgonine. decreased xylose a,Jcsorption. A prelimínary sj-ngle-rat experjment showed Èhat ecgonine methylester is excreted in the urine of the rat in larger amounts tha¡¡ benzoylecgonj-ne following the oral administration of cocaj-ne white benzoylecgonine is the major urinary metabolite following subcutaneous cocaine administration. The results of the presenÈ research provide good evidence that, i: :::- cocaine alone is not responsible for the biological effects associated with coca chewing. The hydrolysis products of cocaine / in particular ecAonine methylester, must play a greater biologicaL role than previously realized in coca chewing. Í*Ì!ti.in'a: gå:¿.t14|*,æ¡{t4Ír$L''åïiËi::¡i¡l'::j ACK\TOWLEÐ@¡,ENTS At this time I wish to thank Dr. Trieste G. Vitti for his thoughtful and. expert direction, supervision and. assistance d.uring my period of stud,ies at the FaculÈy of Pharmacy. The recej-pt of a Medical Research Council Studentsïrip Award, a Teaching Assistantship from the Eaculty of Pharmacy, and a Geigy Pha:::nacy Scholarship was greaÈJ-y appreci-ated. I thank the members of Èhe Faculty, Support Staff, and Student Body of the .:.:r :.; Faculty of Pharmacy, Ðepartment of Chemistry, and the Health Sciences :: l Centre for the advice, counsel, and. techni-cal- assistance afforded i::l''' -:.:r... ': : "hey t-..1 me duri.ng my program The results presented in îable 19, page 101, are based on data graciously provid.ed by R. Boni and F. Burczynski who performed the nitrogen balance study. This acknowledgement is made eomplete when I express my deepest gratitude to my wife Barbara and my children, Robyn, Jodi, arld Jarnis for all of their laughter and, al-L of their tears. Thank-you. I..1 r-t_ '...' -f,ar- ÎABIE OF CONTENTS Page AbsÈract i Acknowledgements iii Table of Contents iv List of Figures vii List of Tables ix Chapter tr Introduction A. ErythroxyLon coca 1. Pharmacognosy 2. Coca Chewing I B. Cocaine and Related Ecgonine Alkal-oids 3 1. Chemistry 3 2. Pharmacology 3. Hydrolysis and Meta.bolism Chaptêr II Research Objectives A. General 15 B. Ecgonine Alkal-oids Hydrolysis 18 C. Ecgonine Alkaloids Biological Effects 19 1.. Energy Metabolism 19 2. Intestinal Carbohydrate. Absorption 20 3. }{ouse lfhole Body Composition . 20 Chapter.III Experimental A. Ecgonine AlkaLoid Assay 23 l. Materials and Equipment 23 2. Methods 23 i: l.:r-.- ': .IV- Page B. Ecgonine Al-kaloid Hydrolysis 29 I. Materials and Equipment 29 2. Methods 29 c. Ecgonine Alkaloid Urinary Excretion 31 l. Materials and Equipment 31 2. Methods 31 D. Rat Energy Metabolism '1,) l. Materials and Equipment 5¿ 2. Methods 34 E. Xylose Absorption in Rats 38 l. Materials and Equipment 38 2. Methods 38 F. Mouse lfho1e Body Composition 4L : l 1. Materials and Equipment 4L 2. Methods 42 46 Chqpter IV Results A. Ecgonine Alkaloid Assay 4A B. EcAonine Alkaloid Hlzdrolysis 52 : : C. Ecgonine Alkal-oid Urinary Excretion 83 Ð. Rat .Energy Metabolism 92 E. Xylose Absorption in Rats ro2 F. Mouse !'Ihol-e Body ComposiÈion L07 Chapter V Discussion A. Ecgonine Alkal-oid Assay 115 -v- page B. Ecaonine Alkaloid Hydrolysis llg C. Ecgonine Atkaloid Urinary Excretion L2l- D. Rat Energy Metabolism 1)) E. Xlzlose Absorption in RaÈs L25 F. Mouse Whole Body Composition L27 Chapter. IV Summary and Conclusions 130 References . 134 -vl_- LIST OF FIGURES page 1. The ecgonine alkal-oids 4 2. Cocaine hydrolysis pathways . 11 ? Cocaine metabolites 13 À Energy metabolism study apparatus 33 Ecgonine al-kaloids - synthesis 49 6. Ecaonine aLkal-oid thin layer chromatographic separation 50 Sample gas chromatograms - hydrolysis study 51 a Standard assay curves - hydrolysis study 55 o Sample gas chromaÈograms - urine excretion study 56 10. Standard assay curves - urine excretion study 58 11. Cocaine hydrolysis profile - distilled water . 59 L2. Cocaine hydrolysis profile - 0.I N HCl 60 13. Cocaine hydrolysis profife - simulated gastric fluid 61 L4. Cocaine hyd.rotysJ-s profile - pH 7.3 buffer 63 15. Cocaine hydrolysis profile - simulated intestinal fluid 64 16. Cocaine hydrolysis profile - pH IO buffer 65 L7. Cocaine hydrolysis profile - pH 11 buffer 66 18. Cocaine hydrolysis profile - 0.04 N NaOH 67 19. Cocaine hydrolysis profile - 0.04 N Ca (OH), 68 20. Cocaine hydrolysis - kinetic model 69 2L. Cocaine hydrolysís profile - 0.01 N NaOH 72 )2 Cocaine hydrolysis profiJ-e - 0.01 N Ca(OH), 73 23. Cocaj-ne hydrolysis prôfile - ishku suBernatant solution 74 )A Cocaine hydrolysis profile - llipta supernatant solution 78 - vl_l_ - Page 25 - Respiratory quotient and oxygen consumption ,orofiles - ecgonine/low protein triaL 85 26. Respiratory quotient and oxygen consumptio.n profiles - benzoylecgionine/Iow protein trial g6 27. Respiratory quotient and oxygen consumption .orofiles - ecgonine nethylester /Low protein trial 87 28. Respiratory quotient and. oxygen consump¡ie¡: profiles - cocaine,/low protein trial 88 29. Respiratory.quotient and oxygen consumption profiles - cocaj-ne/hj-gh protein trial 89 30. Respiratory quoti-ent profiles - all_ trials 90 3L. Oxygen consumption profiles - all trials 91 32. Sample xylose assay sÈandard curve IO3 . 108 34. Sample glucose assay standard, curve . lO9 35. Sample glycogen assay stand.ard curve l1O - vlII - LIST OF TABT,ES Page r. Semi-synthetic diet compositions 35 Gas chromatographj- c d.ata 53 ) Ecgonine alkaloid extracti-on recovery data - hydrolysis study. 54 4. Ecgoni-ne alkaloid extraction recovery data - urinary excretion study 57 q Cocalne hydrolysis kinetic modeL - equations 7L 6. Ishku solution characteristics 76 1 L-L j-pta soluÈj-on characteris tics 77 8. Cocaine disappearance rate constants 79 9. Cocaine hydrolysis rate constants 8l r0. RaÈios of cocaine hydrolysis rate constants 82 11. Urinary ecAonine alkaloid excretion 84 L2. Energy metabolism data - ecgonine/Iow protein trial 93 t3. Energy metabolism data - benzoylecgonine/low protein triaL 94 L4. Energy metabolism d.ata - ecAonine methylester,/Iow protein trial oà 15. Energy metabolism data - cocaj-ne /Lçw protej-n trial 96 1^ Energy metabolism d.ata - cocaine /nLqn protein trial 97 L7, Tank air composition 99 18. Sample energy metabolism calculation r00 19. Urinary nitrogen excretion data 101 ¿u- Xylose excretion data - trial l- I04 2L. Xylose excretion data - trial 2 105 22. Xyfose excretion data - triaf 3 106 -l-X- Page 23. Mouse whole body analysis - co¡runercial high protein diet 111 24. Mouse whol-e body analysis - ecaonine methylester,/Low protein diet 113 25. Mouse whol-e body analysis ratios - ecgonine methylesterr/low -x- CHAPTER I TNTRODUCTTON I-A Erythroxyloncoca l. Pharmacognosy Erythroxylon coca is a ha::dy shrub growing to a height of :bout I met'er in the mountainous uplands of South America, primarily in the Andes of Peru and Bolivia, and to a lesser extent ín the mountains of llexico, the lfest Indes and Java (I, 2).
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