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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 郭錦樺(Ching-Hua Kuo) | |
dc.contributor.author | Ting-Yu Wei | en |
dc.contributor.author | 魏廷宇 | zh_TW |
dc.date.accessioned | 2021-06-16T04:02:20Z | - |
dc.date.available | 2020-03-12 | |
dc.date.copyright | 2015-03-12 | |
dc.date.issued | 2014 | |
dc.date.submitted | 2014-10-17 | |
dc.identifier.citation | 1. Keady, S. and M. Thacker, Voriconazole in the treatment of invasive fungal infections. Intensive Crit Care Nurs, 2005. 21(6): p. 370-3.
2. Walsh, T.J., et al., Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group. N Engl J Med, 1999. 340(10): p. 764-71. 3. Le Guennec, R., et al., Fluconazole- and itraconazole-resistant Candida albicans strains from AIDS patients: multilocus enzyme electrophoresis analysis and antifungal susceptibilities. J Clin Microbiol, 1995. 33(10): p. 2732-7. 4. Martin, M.V., The use of fluconazole and itraconazole in the treatment of Candida albicans infections: a review. Journal of Antimicrobial Chemotherapy, 1999. 44(4): p. 429-437. 5. Somchit, N., et al., Hepatotoxicity induced by antifungal drugs itraconazole and fluconazole in rats: a comparative in vivo study. Human & Experimental Toxicology, 2004. 23(11): p. 519-525. 6. Park, I.S., E.M. Kang, and N. Kim, High-performance liquid chromatographic analysis of saponin compounds in Bupleurum falcatum. Journal of Chromatographic Science, 2000. 38(6): p. 229-233. 7. Dickinson, R.P., et al., Novel antifungal 2-aryl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol derivatives with high activity against Aspergillus fumigatus. Bioorganic & Medicinal Chemistry Letters, 1996. 6(16): p. 2031-2036. 8. Sanati, H., et al., A new triazole, voriconazole (UK-109,496), blocks sterol biosynthesis in Candida albicans and Candida krusei. Antimicrobial Agents and Chemotherapy, 1997. 41(11): p. 2492-2496. 9. Denning, D.W., et al., Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis. Clinical Infectious Diseases, 2002. 34(5): p. 563-571. 10. Herbrecht, R., et al., Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. New England Journal of Medicine, 2002. 347(6): p. 408-415. 11. Singh, N., et al., Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: A prospective, multicenter, observational study. Transplantation, 2006. 81(3): p. 320-326. 12. Imhof, A., et al., Breakthrough fungal infections in stem cell transplant recipients receiving voriconazole. Clinical Infectious Diseases, 2004. 39(5): p. 743-746. 13. Trifilio, S., et al., Monitoring plasma voriconazole levels may be necessary to avoid subtherapeutic levels in hematopoietic stem cell transplant recipients. Cancer, 2007. 109(8): p. 1532-1535. 14. Lat, A. and G.R. Thompson III, Update on the optimal use of voriconazole for invasive fungal infections. Infection and drug resistance, 2011. 4: p. 43. 15. Walsh, T.J., et al., Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clinical infectious diseases, 2008. 46(3): p. 327-360. 16. Lazarus, H.M., et al., Safety and pharmacokinetics of oral voriconazole in patients at risk of fungal infection: A dose escalation study. Journal of Clinical Pharmacology, 2002. 42(4): p. 395-402. 17. den Hollander, J.G., et al., Incidence of voriconazole hepatotoxicity during intravenous and oral treatment for invasive fungal infections. Journal of Antimicrobial Chemotherapy, 2006. 57(6): p. 1248-1250. 18. Jeu, L., et al., Voriconazole. Clinical therapeutics, 2003. 25(5): p. 1321-1381. 19. Husain, S., et al., Voriconazole prophylaxis in lung transplant recipients. American Journal of Transplantation, 2006. 6(12): p. 3008-3016. 20. Luong, M.L., et al., Risk factors for voriconazole hepatotoxicity at 12 weeks in lung transplant recipients. American Journal of Transplantation, 2012. 12(7): p. 1929-1935. 21. Desta, Z., et al., Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet, 2002. 41(12): p. 913-58. 22. Pascual, A., et al., Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. Clin Infect Dis, 2008. 46(2): p. 201-11. 23. Smith, J., et al., Voriconazole therapeutic drug monitoring. Antimicrob Agents Chemother, 2006. 50(4): p. 1570-2. 24. Hussaini, T., et al., Therapeutic Drug Monitoring of Voriconazole and Posaconazole. Pharmacotherapy, 2011. 31(2): p. 214-225. 25. Park, W.B., et al., The Effect of Therapeutic Drug Monitoring on Safety and Efficacy of Voriconazole in Invasive Fungal Infections: A Randomized Controlled Trial. Clinical Infectious Diseases, 2012. 55(8): p. 1080-1087. 26. Koselke, E., et al., Evaluation of the effect of obesity on voriconazole serum concentrations. Journal of Antimicrobial Chemotherapy, 2012. 67(12): p. 2957-2962. 27. Lutsar, I., et al., Safety of voriconazole and dose individualization. Clinical Infectious Diseases, 2003. 36(8): p. 1087-1088. 28. Bruggemann, R.J.M., et al., Therapeutic drug monitoring of voriconazole. Therapeutic Drug Monitoring, 2008. 30(4): p. 403-411. 29. Chu, H.Y., et al., Voriconazole therapeutic drug monitoring: retrospective cohort study of the relationship to clinical outcomes and adverse events. Bmc Infectious Diseases, 2013. 13. 30. Cadena, J., et al., Antifungal prophylaxis with voriconazole or itraconazole in lung transplant recipients: hepatotoxicity and effectiveness. American Journal of Transplantation, 2009. 9(9): p. 2085-2091. 31. Pratt, D.S. and M.M. Kaplan, Primary care: Evaluation of abnormal liver-enzyme results in asymptomatic patients. New England Journal of Medicine, 2000. 342(17): p. 1266-1271. 32. Limdi, J. and G. Hyde, Evaluation of abnormal liver function tests. Postgraduate medical journal, 2003. 79(932): p. 307-312. 33. Rosolki, S.B., Gamma-glutamyl transpeptidase. Advances in clinical chemistry, 1975. 17: p. 53. 34. Courtay, C., et al., γ-Glutamyltransferase: nucleotide sequence of the human pancreatic cDNA: evidence for a ubiquitous γ-glutamyltransferase polypeptide in human tissues. Biochemical pharmacology, 1992. 43(12): p. 2527-2533. 35. Goldberg, D.M. and J.V. Martin, Role of gamma-glutamyl transpeptidase activity in the diagnosis of hepatobiliary disease. Digestion, 1975. 12(4-6): p. 232-46. 36. Giannini, E.G., R. Testa, and V. Savarino, Liver enzyme alteration: a guide for clinicians. Canadian medical association journal, 2005. 172(3): p. 367-379. 37. Wong, H.Y., J.Y.L. Tan, and C.C. Lim, Abnormal liver function tests in the symptomatic pregnant patient: The local experience in Singapore. Annals Academy of Medicine Singapore, 2004. 33(2): p. 204-208. 38. Knox, T.A. and L.B. Olans, Current concepts - Liver disease in pregnancy. New England Journal of Medicine, 1996. 335(8): p. 569-576. 39. Castro, M.A., et al., Reversible peripartum liver failure: A new perspective on the diagnosis, treatment, and cause of acute fatty liver of pregnancy, based on 28 consecutive cases. American Journal of Obstetrics and Gynecology, 1999. 181(2): p. 389-395. 40. Davidson, K.M., Intrahepatic cholestasis of pregnancy. Seminars in Perinatology, 1998. 22(2): p. 104-111. 41. Hunt, C.M. and A.I. Sharara, Liver disease in pregnancy. American Family Physician, 1999. 59(4): p. 829-836. 42. Shrestha, R., et al., Quantitative liver function tests define the functional severity of liver disease in early-stage cirrhosis. Liver Transplantation and Surgery, 1997. 3(2): p. 166-173. 43. Saravolatz, L.D., L.B. Johnson, and C.A. Kauffman, Voriconazole: a new triazole antifungal agent. Clinical Infectious Diseases, 2003. 36(5): p. 630-637. 44. Huang, Y.T., Shan, L. C., Lin, S. W., Therapeutic drug monitoring of voriconazole in patients with invasive fungal infections, in Graduate Institute of Clinical Pharmacy, College of Medicine. 2011, National Taiwan University. p. 63. 45. Nicholson, J.K., J.C. Lindon, and E. Holmes, 'Metabonomics': understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica, 1999. 29(11): p. 1181-1189. 46. Oliver, S.G., Functional genomics: lessons from yeast. Philos Trans R Soc Lond B Biol Sci, 2002. 357(1417): p. 17-23. 47. Ellis, D.I., et al., Metabolic fingerprinting as a diagnostic tool. Pharmacogenomics, 2007. 8(9): p. 1243-1266. 48. Dahlin, D.C., et al., N-Acetyl-Para-Benzoquinone Imine - a Cytochrome-P-450-Mediated Oxidation-Product of Acetaminophen. Proceedings of the National Academy of Sciences of the United States of America-Biological Sciences, 1984. 81(5): p. 1327-1331. 49. Vendemiale, G., et al., Effect of acetaminophen administration on hepatic glutathione compartmentation and mitochondrial energy metabolism in the rat. Biochemical Pharmacology, 1996. 52(8): p. 1147-1154. 50. Wallace, J.L., Acetaminophen hepatotoxicity: NO to the rescue. British Journal of Pharmacology, 2004. 143(1): p. 1-2. 51. Mitchell, J.R., et al., Acetaminophen-Induced Hepatic Necrosis .1. Role of Drug-Metabolism. Journal of Pharmacology and Experimental Therapeutics, 1973. 187(1): p. 185-194. 52. Hinson, J.A., et al., Acetaminophen-induced hepatotoxicity: Role of metabolic activation, reactive oxygen/nitrogen species, and mitochondrial permeability transition. Drug Metabolism Reviews, 2004. 36(3-4): p. 805-822. 53. Gibson, J.D., et al., Mechanism of acetaminophen-induced hepatotoxicity: Covalent binding versus oxidative stress. Chemical Research in Toxicology, 1996. 9(3): p. 580-585. 54. Soga, T., et al., Differential metabolomics reveals ophthalmic acid as an oxidative stress biomarker indicating hepatic glutathione consumption. Journal of Biological Chemistry, 2006. 281(24): p. 16768-16776. 55. Alnouti, Y., Bile Acid Sulfation: A Pathway of Bile Acid Elimination and Detoxification. Toxicological Sciences, 2009. 108(2): p. 225-246. 56. Summerfield, J.A., B.H. Billing, and C.H. Shackleton, Identification of bile acids in the serum and urine in cholestasis. Evidence for 6alpha-hydroxylation of bile acids in man. Biochem J, 1976. 154(2): p. 507-16. 57. Bobeldijk, I., et al., Quantitative profiling of bile acids in biofluids and tissues based on accurate mass high resolution LC-FT-MS: compound class targeting in a metabolomics workflow. J Chromatogr B Analyt Technol Biomed Life Sci, 2008. 871(2): p. 306-13. 58. Kumar, B.S., et al., Discovery of common urinary biomarkers for hepatotoxicity induced by carbon tetrachloride, acetaminophen and methotrexate by mass spectrometry-based metabolomics. Journal of Applied Toxicology, 2012. 32(7): p. 505-520. 59. Henshall, J., et al., Comparative analysis of CYP3A heteroactivation by steroid hormones and flavonoids in different in vitro systems and potential in vivo implications. Drug Metabolism and Disposition, 2008. 36(7): p. 1332-1340. 60. Josephson, F., et al., CYP3A induction and inhibition by different antiretroviral regimens reflected by changes in plasma 4beta-hydroxycholesterol levels. Eur J Clin Pharmacol, 2008. 64(8): p. 775-81. 61. Kanebratt, K.P., et al., Cytochrome P450 Induction by Rifampicin in Healthy Subjects: Determination Using the Karolinska Cocktail and the Endogenous CYP3A4 Marker 4 beta-Hydroxycholesterol. Clinical Pharmacology & Therapeutics, 2008. 84(5): p. 589-594. 62. Kobayashi, K., et al., Role of human cytochrome p450 3A4 in metabolism of medroxyprogesterone acetate. Clinical Cancer Research, 2000. 6(8): p. 3297-3303. 63. Sugimoto, T., et al., Reye-Like Syndrome Associated with Valproic Acid. Brain & Development, 1983. 5(3): p. 334-337. 64. Murakami, K., et al., Abnormal-Metabolism of Carnitine and Valproate in a Case of Acute Encephalopathy during Chronic Valproate Therapy. Brain & Development, 1992. 14(3): p. 178-181. 65. Loscher, W., et al., Effects of valproate and E-2-en-valproate on functional and morphological parameters of rat liver. II. Influence of phenobarbital comedication. Epilepsy Res, 1993. 15(2): p. 113-31. 66. Gerber, N., et al., Reye-Like Syndrome Associated with Valproic Acid Therapy. Journal of Pediatrics, 1979. 95(1): p. 142-144. 67. Zimmerman, H.J. and K.G. Ishak, Valproate-Induced Hepatic-Injury - Analyses of 23 Fatal Cases. Hepatology, 1982. 2(5): p. 591-597. 68. Kassahun, K., K. Farrell, and F. Abbott, Identification and Characterization of the Glutathione and N-Acetylcysteine Conjugates of (E)-2-Propyl-2,4-Pentadienoic Acid, a Toxic Metabolite of Valproic Acid, in Rats and Humans. Drug Metabolism and Disposition, 1991. 19(2): p. 525-535. 69. Farkas, V., et al., Inhibition of carnitine biosynthesis by valproic acid in rats--the biochemical mechanism of inhibition. Biochem Pharmacol, 1996. 52(9): p. 1429-33. 70. Lee, M.S., et al., Metabolomics Study With Gas Chromatography-Mass Spectrometry for Predicting Valproic Acid-induced Hepatotoxicity and Discovery of Novel Biomarkers in Rat Urine. International Journal of Toxicology, 2009. 28(5): p. 392-404. 71. Cengiz, M., A. Yuksel, and M. Seven, The effects of carbamazepine and valproic acid on the erythrocyte glutathione, glutathione peroxidase, superoxide dismutase and serum lipid peroxidation in epileptic children. Pharmacological Research, 2000. 41(4): p. 423-425. 72. Tabatabaei, A.R., et al., A rapid in vitro assay for evaluation of metabolism-dependent cytotoxicity of antiepileptic drugs on isolated human lymphocytes. Fundamental and Applied Toxicology, 1997. 37(2): p. 181-189. 73. Beger, R.D., et al., Single valproic acid treatment inhibits glycogen and RNA ribose turnover while disrupting glucose-derived cholesterol synthesis in liver as revealed by the [U-C-13(6)]-d-glucose tracer in mice. Metabolomics, 2009. 5(3): p. 336-345. 74. Labbe, G., D. Pessayre, and B. Fromenty, Drug‐induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studies. Fundamental & clinical pharmacology, 2008. 22(4): p. 335-353. 75. Pessayre, D., et al., Hepatotoxicity due to mitochondrial injury. Drug-induced liver disease, 2002: p. 49-84. 76. Fromenty, B. and D. Pessayre, Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity. Pharmacology & therapeutics, 1995. 67(1): p. 101-154. 77. Pessayre, D., et al., Hepatotoxicity due to mitochondrial dysfunction. Cell biology and toxicology, 1999. 15(6): p. 367-373. 78. Beckwith-Hall, B.M., et al., Nuclear magnetic resonance spectroscopic and principal components analysis investigations into biochemical effects of three model hepatotoxins. Chemical Research in Toxicology, 1998. 11(4): p. 260-272. 79. Heijne, W.H.M., et al., Profiles of metabolites and gene expression in rats with chemically induced hepatic necrosis. Toxicologic Pathology, 2005. 33(4): p. 425-433. 80. Waters, N.J., et al., Integrated metabonomic analysis of bromobenzene-induced hepatotoxicity: Novel induction of 5-oxoprolinosis. Journal of Proteome Research, 2006. 5(6): p. 1448-1459. 81. Spagou, K., et al., HILIC-UPLC-MS for Exploratory Urinary Metabolic Profiling in Toxicological Studies. Analytical Chemistry, 2011. 83(1): p. 382-390. 82. Yang, L., et al., Bile Acids Metabonomic Study on the CCl4-and α-Naphthylisothiocyanate-Induced Animal Models: Quantitative Analysis of 22 Bile Acids by Ultraperformance Liquid Chromatography− Mass Spectrometry. Chemical research in toxicology, 2008. 21(12): p. 2280-2288. 83. Geenen, S., et al., HPLC–MS/MS methods for the quantitative analysis of 5-oxoproline (pyroglutamate) in rat plasma and hepatic cell line culture medium. Journal of pharmaceutical and biomedical analysis, 2011. 56(3): p. 655-663. 84. Bando, K., et al., GC‐MS‐based metabolomics reveals mechanism of action for hydrazine induced hepatotoxicity in rats. Journal of Applied Toxicology, 2011. 31(6): p. 524-535. 85. Craig, A., et al., Systems toxicology: Integrated genomic, proteomic and metabonomic analysis of methapyrilene induced hepatotoxicity in the rat. Journal of Proteome Research, 2006. 5(7): p. 1586-1601. 86. Wishart, D.S., et al., HMDB: the human metabolome database. Nucleic acids research, 2007. 35(suppl 1): p. D521-D526. 87. Kind, T., et al., FiehnLib: Mass Spectral and Retention Index Libraries for Metabolomics Based on Quadrupole and Time-of-Flight Gas Chromatography/Mass Spectrometry. Analytical Chemistry, 2009. 81(24): p. 10038-10048. 88. Sreekumar, A., et al., Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature, 2009. 457(7231): p. 910-914. 89. Tian, J., et al., Phenotype differentiation of three< i> E. coli</i> strains by GC-FID and GC–MS based metabolomics. Journal of Chromatography B, 2008. 871(2): p. 220-226. 90. Kind, T., et al., A comprehensive urinary metabolomic approach for identifying kidney cancer. Analytical Biochemistry, 2007. 363(2): p. 185-195. 91. Abdi, H. and L.J. Williams, Principal component analysis. Wiley Interdisciplinary Reviews: Computational Statistics, 2010. 2(4): p. 433-459. 92. Wold, S., M. Sjöström, and L. Eriksson, PLS-regression: a basic tool of chemometrics. Chemometrics and intelligent laboratory systems, 2001. 58(2): p. 109-130. 93. McINTYRE, N., Plasma lipids and lipoproteins in liver disease. Gut, 1978. 19(6): p. 526-530. 94. Sun, J., et al., Metabonomics evaluation of urine from rats given acute and chronic doses of acetaminophen using NMR and UPLC/MS. Journal of Chromatography B, 2008. 871(2): p. 328-340. 95. Thompson, M.G., et al., Measurement of protein degradation by release of labelled 3‐methylhistidine from skeletal muscle and non‐muscle cells. Journal of cellular physiology, 1996. 166(3): p. 506-511. 96. Hinson, J.A., Reactive metabolites of phenacetin and acetaminophen: a review. Environmental health perspectives, 1983. 49: p. 71. 97. Ullrich, A., et al., Use of a standardised and validated long-term human hepatocyte culture system for repetitive analyses of drugs: repeated administrations of acetaminophen reduces albumin and urea secretion. Altex, 2006. 24(1): p. 35-40. 98. Turnbull, D., et al., The effects of valproate on intermediary metabolism in isolated rat hepatocytes and intact rats. Biochemical pharmacology, 1983. 32(12): p. 1887-1892. 99. Turnbull, D., et al., Valproate causes metabolic disturbance in normal man. Journal of Neurology, Neurosurgery & Psychiatry, 1986. 49(4): p. 405-410. 100. Tong, V., et al., Valproic acid II: effects on oxidative stress, mitochondrial membrane potential, and cytotoxicity in glutathione-depleted rat hepatocytes. Toxicological Sciences, 2005. 86(2): p. 436-443. 101. Chang, T.K. and F.S. Abbott, Oxidative Stress as a Mechanism of Valproic Acid-Associated Hepatotoxicity*. Drug metabolism reviews, 2006. 38(4): p. 627-639. 102. Cotariu, D. and J. Zaidman, Valproic acid and the liver. Clinical chemistry, 1988. 34(5): p. 890-897. 103. Parks, D.J., et al., Bile acids: natural ligands for an orphan nuclear receptor. Science, 1999. 284(5418): p. 1365-8. 104. King, C.D. and J. Van Lancker, Molecular mechanisms of liver regeneration: VII. Conversion of cytidine to deoxycytidine in rat regenerating livers. Archives of biochemistry and biophysics, 1969. 129(2): p. 603-608. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/55435 | - |
dc.description.abstract | Voriconazole是治療真菌感染之重要藥物,而肝毒性是其主要副作用之一,嚴重肝毒性可能造成治療中止。目前臨床上使用肝功能指數(liver function index或liver function tests)作為評估依據,但肝功能指數可能會受到生理因素或其他組織的傷害與病變所影響,無法清楚歸因是否voriconazole所造成。為了專一地偵測voriconazole引發的肝毒性,急需發展準確有效的voriconazole肝毒性生物指標。
本論文採用標的代謝體學 (targeted metabolomics) 研究方法,開發了liquid chromatography - triple-quadrupole mass spectrometer (LC-QqQ MS) 與gas chromatography - mass spectrometer (GC-MS) 之分析方法,並以之尋找反映voriconazole引發肝毒性之代謝物生物指標 (metabolite biomarkers)。我們挑選文獻報導與藥物引發肝毒性有關之代謝物作為標的代謝物 (target metabolites),以之為基準在LC-QqQ MS調整了樣品回溶溶劑與體積、管柱選擇、移動相組成、離子源選擇、MRM離子選擇與層析梯度等參數;在GC-MS平台則探討了凍乾步驟之影響、SIM (selective ion monitoring) mode與scan mode之比較、衍生物穩定性與dwell time對訊號強度之影響。我們以調整後LC-QqQ MS與GC-MS分析條件,進行voriconazole肝毒性研究。 我們使用小鼠作為藥物引發肝毒性之模式生物 (model organism),分別給予三種藥物和兩種溶劑:acetaminophen、valproate、voriconazole、去離子水或poly ethylene glycol,於24小時後收集血漿,比較急性肝毒性小鼠與控制組血漿內選定的代謝物濃度之差異。 實驗結果顯示本研究所挑選之標的代謝物確實對acetaminophen、valproate與voriconazole三種藥物皆具有分辨實驗組與控制組之能力。在給予acetaminophen 24小時後,小鼠血漿中之threonine、aspartate、glutamate、serine、tryptophan、ornithine、cholesterol、ascorbate等八種代謝物之血中濃度顯著高於控制組;而trimethylamine-N-oxide (TMAO)、urea、urocanate、3-methylhistidine、1-methylhistidine則顯著較低;另一方面valproate造成實驗組之acetoacetate、inosine和ursodeoxycholate三種標的代謝物的血中濃度顯著低於控制組。此兩種已知引發肝毒性之模式藥物(model drugs)之結果證實本研究之研究策略確實可用於藥物引發肝毒性之研究。 在voriconazole的部分,給藥後24小時之小鼠其血中citrate、3-hydroxybutyrate、chenodeoxycholate與cytidine之濃度顯著高於poly ethylene glycol組,lysine、alanine、asparagine、glycine、5-hydroxylysine、methionine、serine、threonine與1-methylhistidine之血中濃度則顯著低於控制組。由此可以推測voriconazole可能影響了醣類之使用,使得脂質與蛋白質被作為替代能量。 在本研究所使用的兩種平台中,LC-QqQ MS平台之樣品前處理較簡單方便,分析時間亦較短。在本研究觀察到顯著變化之代謝物之中,有三個代謝物是在GC-MS平台分析,其餘23個代謝物皆於LC-QqQ MS平台分析。綜合而言,LC-QqQ MS平台較適用於本研究所挑選之標的代謝物。 本研究成功開發LC-QqQ MS之藥物肝毒性偵測平台應用於藥物引發肝毒性小鼠之血漿樣品,並以小鼠模式找到具有偵測voriconazole引發肝毒性生物指標潛力之代謝物,進一步的臨床研究將有助於確認這些代謝物對偵測voriconazole引發肝毒性之適用性。 | zh_TW |
dc.description.abstract | Voriconazole is an antifugal drug commonly used for the treatment of invasive fungal infections. Hepatotoxicity is one of its major side effects, which may limit its use. Liver function tests are clinically used to evaluate hepatotoxicity. Nevertheless, liver function tests may be influenced by other physiological or pathological factors and can not distinguish the causes of liver injuries. To detect voriconazole-induced liver injury specifically, it is necessary to investigate new hepatotoxicity biomarkers.
In this study, we used a mass based targeted metabolomics approach to identify metabolites associated with voriconazole induced liver injury. Sixty-five metabolites, which were reported to be associated with hepatotoxicity were selected as target metabolites. Both liquid chromatography - triple-quadrupole mass spectrometer (LC-QqQ MS) and gas chromatography - mass spectrometer (GC-MS) methods were developed to investigate hepatotoxicity biomarkers. The adjustment parameters of the LC-QqQ MS method included reconstitution solvent and volume, columns, mobile phase composition, ionization sources, elution gradient, and MS transition ions. In the GC-MS method, we investigated the influence of lyophilization, stability of the metabolite derivatives, and MS parameters. We used the adjusted LC-QqQ MS and GC-MS methods to investigate voriconazole-induced hepatotoxicity markers. Liver toxicity was induced in mice through the administration of two model drugs, acetaminophen and valproate, and our investigation drug, voriconazole. The results showed that the metabolite profile of mice plasma is able to discriminate treatment groups from the control groups. In the acetaminophen treatment group, plasma concentrations of threonine, aspartate, glutamate, serine, tryptophan, ornithine, cholesterol and ascorbate were significantly higher than the control group, and plasma concentrations of trimethylamine-N-oxide (TMAO), urea, urocanate, 3-methylhistidine and 1-methylhistidine were significantly lower than the control group. In the valproate treatment group, plasma concentrations of acetoacetate, inosine and ursodeoxycholate were significantly lower than the control group. The results of the two model drugs reveal that our developed MS based analytical platforms are feasible for the study of drug induced liver injury. In the voriconazole treatment group, plasma concentrations of citrate, 3-hydroxybutyrate, chenodeoxycholate and cytidine were significantly higher than the control group, and plasma concentrations of lysine, alanine, asparagine, glycine, 5-hydroxylysine, methionine, serine, threonine and 1-methylhistidine were significantly lower than the control group. This result suggests that voriconazole may affect the use of carbohydrate in the generation of energy, resulting in the compensatory consumption of amino acids and lipids. Comparing the two platforms used in this study, the sample preparation procedure of LC-QqQ MS method is simpler, and the analytical time of LC-QqQ MS method is shorter. Among the statistically significant metabolites, 3 metabolites are analyzed by the GC-MS platform, and the other 23 metabolites are analyzed by the LC-QqQ MS platform. In general, the developed LC-QqQ MS platform is more suitable for investigating hepatotoxicity markers. In conclusion, we successfully developed an LC-QqQ MS platform to detect drug-induced hepatotoxicity, and used mice models to elucidate the metabolic change that occurs after voriconazole-induced hepatotoxicity. We used the significant metabolites to propose possible mechanisms of voriconazole-induced hepatotoxicity. Further clinical study is required to improve our understaning on voriconazole induced hepatoxicity. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T04:02:20Z (GMT). No. of bitstreams: 1 ntu-103-R00423012-1.pdf: 5514237 bytes, checksum: 4f8dadee1c23d7bc9b48e96595faf998 (MD5) Previous issue date: 2014 | en |
dc.description.tableofcontents | 口試委員會審定書 i
致謝 ii 中文摘要 iii Abstract v 1. 序論: - 1 - 1.1. Voriconazole之臨床重要性與肝毒性 - 1 - 1.1.1. Voriconazole簡介 - 1 - 1.1.2. 目前肝毒性評估之方法與其缺點 - 2 - 1.1.3. 臨床上對於voriconazole肝毒性之偵測 - 3 - 1.2. 代謝體學之研究方法 - 3 - 2. 研究目的 - 5 - 3. 實驗部分 - 6 - 3.1. 實驗設計 - 6 - 3.2. 實驗材料與方法 - 7 - 3.2.1. 藥品與試劑 - 7 - 3.2.2. 標準品配製 - 7 - 3.2.3. 儀器 - 7 - 3.2.4. 分析條件 - 8 - 3.2.5. 數據處理 - 9 - 3.2.6. 動物實驗部分 - 9 - 3.2.7. 血漿樣品前處理 - 9 - 4. 結果與討論 - 12 - 4.1. 標的代謝物之選擇 - 12 - 4.2. LC-QqQ MS分析參數選擇 - 12 - 4.2.1. 管柱的選擇 - 12 - 4.2.2. 樣品萃取溶劑選擇 - 13 - 4.2.3. 樣品回溶溶劑與體積 - 13 - 4.2.4. 移動相組成 - 13 - 4.2.5. 離子源選擇 - 14 - 4.3. GC-MS分析參數選擇 - 15 - 4.3.1. 有無凍乾步驟之比較 - 16 - 4.3.2. 衍生物穩定性 - 16 - 4.3.3. 偵測模式 - 17 - 4.4. 藥物引發急性肝毒性所造成之肝臟外觀與組織學變化 - 17 - 4.5. 標的代謝物分辨肝毒性發生之能力 - 18 - 4.6. 藥物引發肝毒性所造成之代謝物血中濃度變化以及機轉探討 - 21 - 4.6.1. Acetaminophen所造成之代謝物血中濃度變化 - 21 - 4.6.2. Valproate所造成之代謝物血中濃度變化 - 22 - 4.6.3. Voriconazole所造成之代謝物血中濃度變化 - 23 - 4.7. LC-QqQ MS與GC-MS方法應用於藥物肝毒性研究之比較 - 25 - 5. 結論: - 27 - 附圖 Figure 1 藥物結構 - 36 - Figure 2 藥物引發肝毒性模式小鼠實驗設計 - 37 - Figure 3 Betaine 與fumarate於BEH HILIC管柱之MRM層析圖 - 38 - Figure 4 添加不同濃度threonine於血漿樣品之層析圖 - 39 - Figure 5 Adipate於scan mode與SIM mode之層析圖 - 40 - Figure 6 小鼠肝臟外觀 - 41 - Figure 7 小鼠肝組織病理切片圖 (H&E染色,10倍放大) - 42 - Figure 8 小鼠肝組織病理切片圖 (H&E染色,20倍放大) - 43 - Figure 9 LC-QqQ MS data 之PCA score plot (acetaminophen與其控制組) - 44 - Figure 10 GC-MS data 之PCA score plot (acetaminophen與其控制組) - 45 - Figure 11 GC-MS data 之PLS-DA之score plot (acetaminophen與其控制組) - 46 - Figure 12 LC-QqQ MS data之PCA score plot (valproate與其控制組) - 47 - Figure 13 LC-QqQ MS data之PLS-DA score plot (valproate與其控制組) - 48 - Figure 14 GC-MS data之PCA score plot (valproate與其控制組) - 49 - Figure 15 GC-MS data之PLS-DA score plot (valproate與其控制組) - 50 - Figure 16 LC-QqQ MS data之PCA score plot (voriconazole與其控制組) - 51 - Figure 17 GC-MS data之PCA score plot (voriconazole與其控制組) - 52 - Figure 18 GC-MS data之PLS-DA score plot (voriconazole與其控制組) - 53 - Figure 19 LC-QqQ MS data之PCA score plot (三種藥物與其控制組) - 54 - Figure 20 LC-QqQ MS data之PLS-DA score plot (三種藥物與其控制組) - 55 - Figure 21 GC-MS data之PCA score plot (三種藥物與其控制組) - 56 - Figure 22 GC-MS data之PLS-DA score plot (三種藥物與其控制組) - 57 - Figure 23十三個acetaminophen引發肝毒性顯著差異之代謝物之box plot - 58 - Figure 24 Acetaminophen引發肝毒性相關之代謝網絡 - 59 - Figure 25 三個valproate引發肝毒性顯著差異之代謝物之box plot - 60 - Figure 26 十三個voriconazole引發肝毒性顯著差異之代謝物之box plot - 61 - Figure 27 Voriconazole引發肝毒性相關之代謝網絡 - 62 - Figure 28 LC-QqQ MS data之PCA score plot - 63 - 附表 Table 1 正離子模式偵測代謝物之滯留時間、MRM transition與其質譜儀參數 - 64 - Table 2 負離子模式偵測代謝物之滯留時間、MRM transition與其質譜儀參數 - 67 - Table 3 GC-MS所偵測代謝物之滯留時間與分析離子 - 69 - Table 4 標的代謝物清單、其引用文獻與本研究所使用之分析平台 - 70 - Table 5 動物實驗設計 - 73 - Table 6 標的代謝物衍生物峰面積之相對標準差 (n=10) - 74 - | |
dc.language.iso | zh-TW | |
dc.title | 開發偵測voriconazole所引發肝毒性之分析平台 | zh_TW |
dc.title | Development of analytical platforms for the detection of voriconazole-induced liver injury | en |
dc.type | Thesis | |
dc.date.schoolyear | 103-1 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 蘇剛毅(Kang-Yi Su),陳家揚(Chia-Yang Chen),曾宇鳳(Yufeng J. Tseng) | |
dc.subject.keyword | voriconazole,肝毒性,代謝體,LC-MS/MS,GC-MS,小鼠, | zh_TW |
dc.subject.keyword | voriconazole,hepatotoxicity,metabolomics,LC-MS/MS,GC-MS,mice, | en |
dc.relation.page | 75 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2014-10-20 | |
dc.contributor.author-college | 藥學專業學院 | zh_TW |
dc.contributor.author-dept | 藥學研究所 | zh_TW |
顯示於系所單位: | 藥學系 |
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