臺灣博碩士論文加值系統

中文摘要
根據文獻記載，葡萄柚汁與某些藥物共同服用時，會提高藥品的生體可用率，柚皮素是最有可能造成這種交互作用的成份之一。
本論文利用高效液相層析技術， 進行柚皮素在大白鼠體內的藥物動力學研究。 實驗共分為四部分: (1) 柚皮素在大白鼠體內之腦、 血分布 (2) 柚皮素在大白鼠體內的藥物動力學研究 (3) 利用配對老鼠動物模式， 探討柚皮素的腸肝循環特性 (4) 以微透析採樣技術，探討柚皮素膽汁排泄現象。
以柚皮素20 mg/kg靜脈注射大白鼠10分鐘後，對腦組織與血清進行含量分析。結果發現柚皮素不均勻分布於全腦，且腦中原型柚皮素的含量高於血中，但總合柚皮素(原型與被葡萄糖醛酸代謝之柚皮素總合)，則血中含量高於腦中。以柚皮素20或50 mg/kg靜脈注射大白鼠後，進行藥物動力學研究。其結果顯示當劑量增加，排除半衰期延長, 清除率下降。故推知柚皮素具非線性藥物動力學特性。配對之給藥鼠與接受鼠，膽汁相互導流至對方十二指腸。可同時在兩者的血中測得柚皮素，可證實柚皮素進行腸肝循環。靜脈注射大白鼠柚皮素，利用本實驗室自行改良的微透析探針植入大白鼠膽管, 以2 μl/min速度灌流生理食鹽水，自膽汁透析液可測得柚皮素，證實由膽汁排泄。
結論: 柚皮素不均勻分布於大白鼠腦部。由配對老鼠的實驗與微透析膽汁採樣技術，證實柚皮素可由膽汁排泄，進行腸肝循環，故呈現非線性藥物動力學特性。

Abstract
It has been reported that certain ingredients in grapefruit juice may affect the metabolism of certain drugs. The most probable causes of the interaction are naringenin.
In this study, high performance liquid chromatography (HPLC) was applied to study the pharmacokinetics of naringenin in the rat. The experiments consisted of four parts: (1) distribution of naringenin in the brain tissue and serum of the rat, (2) the pharmacokinetics of naringenin in the rat, (3) enterohepatic circulation of naringenin using paired rats, (4) using microdialysis sampling technique in biliary excretion of naringenin.
The results demonstrated that naringenin doesn't distribute evenly in the brain. Concentration of naringenin in brain tissue was higher than in the serum. Concentration of total naringenin (native and glucuronide) was higher in the serum than in the brain. When the I.V. bolus dose of naringenin was increased from 20 to 50 mg/kg, the apparent total body clearance (CL) decreased, and the elimination half-life (t1/2) increased. The results indicated that the pharmacokinetics of naringenin was non-linear. Naringenin could be detected in both serum of both donor and recipient rats connected by a bile duct-doudenum shunt, suggesting enterohepatic circulation . Naringenin could be detected in the dialysate of collected from a homemade probe inserted into the bile duct and perfused wuth saline at 2 μl/min , indicating biliary excretion.
In conclusion, the results indicated that naringenin was not evenly distribution in brain tissue. It was excreted in the bile and was subjected to enterohepatic circulation. The pharmacokinetics fitted best to nonlinear model.

目錄
中文摘要 6
ABSTRACT 8
第一章 緒論 10
第一節 背景介紹 11
第二節 藥物動力學 15
2-1 定義 15
2-2 吸收分佈排除 15
2-3 非線性藥物動力學 16
2-4 腸肝循環 17
2-5 膽汁排泄 17
2-6 膽汁排泄的意義 18
第三節 微透析簡介 19
3-1 微透析理論基礎 19
3-2 微透析系統與分析系統 20
3-3 回收率及回收率的影響因素 20
3-4 影響回收率的因素 21
3-4.1 透析時間及灌注流速 21
3-4.2 微透析探針尖端的半透膜面積 21
3-4.3半透膜的材質 22
3-4.4溫度 22
3-5灌流液的組成 22
第四節 實驗動機 23
第二章 實驗器材與方法 24
第一節 實驗器材 25
1-1 試藥 25
1-2 儀器 26
1-2.1 高效液相層析儀系統 26
1-2.2 微透析採樣係統 26
1-2.3 其他 27
1-3 應用軟體 27
1-4 微透析探針 27
1-4.1 材料 27
1-4.2 微透析探針製作 28
1-5 動物的管理 28
第二節 實驗方法 29
2.1 柚皮素的大白鼠血腦分佈研究 29
2-1.1 空白樣品的製備 29
2-1.1a 血液樣品 29
2-1.1b 腦組織樣品 29
2-1.2 高效液相層析儀分析系統的設定 30
2-1.2a 分析系統 30
2-1.2b 積分儀的設定 30
2-1.3 試藥的製備 30
2-1.3a 柚皮素注射液的製備 30
2-1.3b 柚皮素標準品溶液的製備 31
2-1.3c 內標準品溶液的製備 31
2-1.4 柚皮素在大白鼠血清及腦組織中檢量線的製作 31
2-1.4a 血清部份 31
2-1.4b 腦組織部份 32
2-1.5 回收率的分析 32
2-1.6 精確度與準確度 32
2-1.7 實驗動物的製備 33
2-1.7a 血液樣品 33
2-1.7b 腦組織樣品 33
2-1.7c β-葡萄醣醛酸分解酵素的去共軛化作用 34
2-2 柚皮素的藥物動力學研究 34
2-2.1 實驗動物的製備 34
2-2.2 高效液相層析分析系統的設定 34
2-3 柚皮素的大白鼠腸肝循環研究 35
2-3.1 配對老鼠 35
2-3.2 手術方法 35
2-3.3 給藥及採樣 35
2-3.4高效液相層析分析系統的設定 36
2-4 柚皮素膽汁排泄的微透析應用 36
2-4.1 實驗動物的製備 36
2-4.2 微透析系統的設定 36
2-4.3 高效液相層析分析系統的設定 37
2-4.4 檢量線的製作 37
2-4.5 微透析探針的回收率 37
2-4.6 精確度及準確度 37
2-4.7 樣品的製備 38
第三章 結果 39
(一) 柚皮素在大白鼠的血、腦分佈研究 40
1-1 血清及腦組織樣品的分析 40
1-2 柚皮素在血清及腦組織均質液中之檢量線 40
1-3 柚皮素在血清及腦組織均質液中之回收率 40
1-4 精確度與準確度 41
1-5 柚皮素在血清及腦組織中之分佈 41
(二) 柚皮素的藥物動力學研究 43
2-1 柚皮素在大白鼠體內的濃度變化 43
2-2 藥物動力學參數 43
2-3 葡萄糖醛酸接合率 44
(三) 柚皮素在大白鼠的腸肝循環研究 46
3-1 給藥鼠及接受鼠血清中柚皮素的含量分析 46
3-2 給藥鼠及接受鼠血清中總合柚皮素的時間-濃度關係圖之曲線下面積 46
3-3 給藥鼠及接受鼠血清中總合柚皮素的濃度變化 46
(四) 利用微透析採樣技術進行柚皮素在大白鼠的膽汁排泄研究…………..49
4-1膽汁透析液中柚皮素分析 48
4-2 柚皮素之檢量線 48
4-3精確度與準確度 48
4-4 柚皮素於微透析探針體內回收率 49
4-5 總合與原型柚皮素在膽汁的時間-濃度關係圖之曲線下面積 49
第四章 討論 50
(一) 柚皮素的分析方法 51
(二) 微透析採樣與傳統採樣法的比較 53
(三) 葡萄糖醛酸接合代謝與腸肝循環 55
(四) 柚皮素在鼠腦及血中的分佈情形 58
(五)柚皮素在大白鼠體內的藥物動力學討論 60
5-1 非線性藥物動力學 60
5-2 腸肝循環與膽汁排泄 61
5-3 綜合討論 63
第五章 結論 65
參考文獻 68
圖表(一)
FIG.1 柚皮素與柚皮的結構式 79
FIG.2 微透析探針示意圖………………………………………………………….80
FIG.3 配對老鼠實驗模式示意圖 81
FIG.4 微透析探針植入膽管示意圖 82
FIG.5 血清樣品的層析圖 83
FIG.6 腦組織樣品的層析圖 84
FIG.7 PHOTODIODE-ARRAY DETECTOR 對柚皮素進行定性分析 85
FIG.8 原型柚皮素濃度變化半對數座標圖……………………………………….86
FIG.9 總合柚皮素濃度變化半對數座標圖 87
FIG.10血清樣品層析圖 88
FIG.11給藥鼠與接受鼠血清樣品層析圖 89
FIG.12給藥鼠與接受鼠體內總合柚皮素的濃度變化……………………………90
FIG.13 膽汁透析液的層析圖 91
FIG.14 柚皮素的葡萄糖醛酸化作用 92
圖表 (二)
TABLE. 1 柚皮素在腦組織樣品及血清樣品中的回收率 94
TABLE. 2 柚皮素在血清樣品中同日分析及間日分析的結果…………………..95
TABLE. 3 柚皮素在腦組織樣品中同日分析及間日分析的結果 96
TABLE. 4 大白鼠腦部各區及血清中柚皮素的濃度 97
TABLE. 5原型柚皮素血中濃度變化 98
TABLE. 6原型柚皮素血中濃度變化……………………………..………………99
TABLE. 7 原型柚皮素的藥動參數 100
TABLE. 8 總合柚皮素的藥動參數………………………………………………..101
TABLE. 9-1 給予柚皮素(50 MG/KG, I.V.)後共軛結合率的變化 102
TABLE. 9-2 給予柚皮素 (20 MG/KG, I.V.)後共軛結合率的變化 102
TABLE. 10給藥鼠與接受鼠體內總合柚皮素的濃度變化……………………….103
TABLE.11 膽汁採樣微透析探針之體內回收率 104
TABLE. 12 柚皮素同日分析及間日分析的結果 105

參考文獻
1. Bailey, DG., Spence, JD., Munoz, C., Arnold, JM., Interaction of citrus juices with felodipine and nifedipine. Lancet. 337 : 268-9, 1991.
2. Abernethy, DR., Schwartz, JB., Pharmacokinetics of calcium antagonists under development. Clinical Pharmacokinetics. 15 : 1-14, 1988.
3. Bailey, DG., Arnold, JM., Strong, HA., Munoz, C., Spence, JD., Effect of grapefruit juice and naringin on nisoldipine pharmacokinetics. Clinical Pharmacology & Therapeutics. 54:589-94, 1993.
4. Bailey, DG., Arnold, JM., Munoz, C., Spence, JD., Grapefruit juice--felodipine interaction: mechanism, predictability, and effect of naringin. Clinical Pharmacology & Therapeutics. 53:637-42, 1993..
5. Rau, SE., Bend, JR., Arnold, MO., Tran, LT., Spence, JD., Bailey, DG., Grapefruit juice-terfenadine single-dose interaction: magnitude, mechanism, and relevance. Clinical Pharmacology & Therapeutics. 61:401-9, 1997.
6. Ducharme, MP., Warbasse, LH., Edwards, DJ., Disposition of intravenous and oral cyclosporine after administration with grapefruit juice. Clinical Pharmacology & Therapeutics. 57:485-91, 1995.
7. Fuhr, U., Klittich, K., Staib, AH., Inhibitory effect of grapefruit juice and its bitter principal, naringenin, on CYP1A2 dependent metabolism of caffeine in man. British Journal of Clinical Pharmacology. 35:431-6, 1993.
8. Guengerich, FP., Kim, DH., In vitro inhibition of dihydropyridine oxidation and aflatoxin B1 activation in human liver microsomes by naringenin and other flavonoids. Carcinogenesis. 11:2275-9, 1990 .
9. Ameer, B., Weintraub, RA., Johnson, JV., Yost, RA., Rouseff ,RL., Flavanone absorption after naringin, hesperidin, and citrus administration. Clinical Pharmacology & Therapeutics. 60:34-40, 1996.
10. Cheng, KJ., Krishnamurty, HG., Jones, GA., Simpson, FJ., Identification of products produced by the anaerobic degradation of naringin by Butyrivibrio sp. C3. Canadian Journal of Microbiology. 17:129-31, 1971.
11. 國家醫藥管理局中草藥情報中心站編，植物藥有效成分手冊，p.760-761
12. 黃美聲、沈玉剛，反相高效液相色譜法測定化橘紅中柚皮的含量，中草藥，21(5):75-8,1990.
13 朱正義，枳殼麩炒前後黃酮的分析比較，中藥材，17(6):30-2,1994.
14. Li, C., Homma, M., Oka, K., Chromatographic identification of phenolic compounds in human urine following oral administration of the herbal medicines Daisaiko-to and Shosaiko-to. Journal of Chromatography. B, Biomedical Sciences & Applications. 693:191-8, 1997.
15. Fuhr, U., Kummert, AL., The fate of naringin in humans: a key to grapefruit juice-drug interactions?. Clinical Pharmacology & Therapeutics. 58:365-73, 1995.
16. Green, MD., Oturu, EM., Tephly, TR., Stable expression of a human liver UDP-glucuronosyltransferase (UGT2B15) with activity toward steroid and xenobiotic substrates. Drug Metabolism & Disposition. 22:799-805, 1994.
17. Abe, K-I., Katayama, H., Suzuki, A., Yumioka, E., Biological fate of orally administered Naringin and Naringenin in rats. Japanese Journal of Pharmacognosy. 47 : 402-407, 1994.
18. So, FV., Guthrie, N., Chambers, AF., Carroll, KK., Inhibition of proliferation of estrogen receptor-positive MCF-7 human breast cancer cells by flavonoids in the presence and absence of excess estrogen]. Cancer Letters. 112:127-33, 1997.
19. So, FV., Guthrie, N., Chambers, AF., Moussa, M., Carroll, KK., Inhibition of human breast cancer cell proliferation and delay of mammary tumorigenesis by flavonoids and citrus juices. Nutrition & Cancer. 26 :167-81, 1996.
20. Rosenberg, RS., Grass, L., Jenkins, DJ., Kendall, CW., Diamandis, EP., Modulation of androgen and progesterone receptors by phytochemicals in breast cancer cell lines. Biochemical & Biophysical Research Communications. 248:935-9, 1998.
21. Ratty, AK., Das, NP, Effects of flavonoids on nonenzymatic lipid peroxidation: structure-activity relationship. Biochemical Medicine & Metabolic Biology. 39:69-79, 1988.
22. Tordera, M., Ferrandiz, ML., Alcaraz, MJ., Influence of anti-inflammatory flavonoids on degranulation and arachidonic acid release in rat neutrophils. Zeitschrift fur Naturforschung. Section C. Journal of Biosciences. 49:235-40, 1994.
23. Parmar, NS., The gastric anti-ulcer activity of naringenin, a specific histidine decarboxylase inhibitor. International Journal of Tissue Reactions. 5: 415-20, 1983.
24. Ishii, K., Furuta, T., Kasuya, Y., Determination of naringin and naringenin in human urine by high-performance liquid chromatography utilizing solid-phase extraction. Journal of Chromatography. B, Biomedical Sciences & Applications. 704:299-305, 1997.
25. Ishii, K., Furuta, T., Kasuya, Y., Determination of naringin and naringenin in human plasma by high-performance liquid chromatography. Journal of Chromatography B: Biomedical Applications. 683:225-9, 1996.
26. Baldi, A., Rosen, RT,. Fukuda, EK., Ho, C-T., Identification of nonvolatile components in lemon peel by high-performance liquid chromatography with confirmation by mass spectrometry and diode-array detection. Journal of Chromatography. 718 : 89-97, 1995.
27. Creaser, CS., Koupai-Abyazani, MR., Stephenson, GR., Gas chromatographic-mass spectrometric characterization of flavanones in citrus and grape juices. Analyst. 117 : 1105-1109, 1992.
28. Delgado, C., Tomas-Barberan, FA., Talou, T., Gaset, A., Capillary electrophoresis as an alternative to HPLC for determination of honey flavonoids. Chromatographia. 38: 71-78, 1994.
29. Payares, P., Diaz, D., Olivero, J., Vivas, R., Gomez, I., Prediction of the gas chromatographic relative retention times of flavonoids from molecular structure. Journal of Chromatography. Vol 771:213-219, 1997.
30.Tsai, T.H., Liao, J.F., Shum, Y.C., Chen, C.F., Pharmacokinetics of glycyrrhizin after intravenous administration to rats. Journal of Pharmaceutical Sciences. 819:961-963,1992.
31. Paintaud, G., Bechtel, Y., Brientini, MP., Miguet, JP., Bechtel, PR.,Effects of liver diseases on drug metabolism. Therapie. 51:384-9, 1996.
32. Matern, S., Bock, K.W., Gerok, W., Advances in glucuronide conjugation, West Germany : MTP Press Limited, 7-21, 329-330,1984.
33. Bito, L., Davson, H., Levin, E., Murray, M., Snider, N., The concentrations of free amino acids and other electrolytes in cerebrospinal fluid, in vivo dialysate of brain, and blood plasma of the dog. Journal of Neurochemistry. 13:1057-67, 1966.
34. Delgado, JM., DeFeudis, FV., Roth, RH., Ryugo, DK., Mitruka, BM., Dialytrode for long term intracerebral perfusion in awake monkeys. Archives Internationales de Pharmacodynamie et de Therapie. 198:9-21, 1972.
35. Zetterstrom, T., Sharp, T., Marsden, CA., Ungerstedt, U., In vivo measurement of dopamine and its metabolites by intracerebral dialysis: changes after d-amphetamine. Journal of Neurochemistry. 41(6):1769-73, 1983.
36. Scott, DO., Lunte, CE., In vivo microdialysis sampling in the bile, blood, and liver of rats to study the disposition of phenol. Pharmaceutical Research. 10:335-42, 1993.
37. Hansen, DK., Lunte, SM., Determination of kynurenic acid by capillary electrophoresis with laser-induced fluorescence detection. Journal of Chromatography A. 781:81-9, 1997.
38.Kostel, KL., Lunte, SM., Evaluation of capillary electrophoresis with post-column derivatization and laser-induced fluorescence detection for the determination of substance P and its metabolites. Journal of Chromatography. B, Biomedical Sciences & Applications. 695:27-38, 1997.
39.Telting-Diaz, M., Scott, DO., Lunte, CE.,Intravenous microdialysis sampling in awake, freely-moving rats. Analytical Chemistry. 64:806-10, 1992.
40.Nakashima, M., Takeuchi, N., Hamada, M., Matsuyama, K., Ichikawa, M., Goto, S., In vivo microdialysis for pharmacokinetic investigations: a plasma protein binding study of valproate in rabbits. Biological & Pharmaceutical Bulletin. 17:1630-4, 1994.
41.Hadwiger, ME., Telting-Diaz, M., Lunte, CE., Liquid chromatographic determination of tacrine and its metabolites in rat bile microdialysates. Journal of Chromatography B: Biomedical Applications. 655:235-41, 1994.
42. Nolting, A., Costa, TD., Vistelle, R., Rand, KH., Derendorf H. ,Determination of free extracellular concentrations of piperacillin by microdialysis. Journal of Pharmaceutical Sciences. 85:369-72, 1996.
43. Layton, ME., Wood, JG., Yan, ZY., Forster, J.,Ischemia/reperfusion alters uric acid and ascorbic acid levels in liver. Journal of Surgical Research. 64:1-5, 1996.
44. Routledge, C., Marsden, CA., Adrenaline in the CNS: in vivo evidence for a functional pathway innervating the hypothalamus. Neuropharmacology. 26:823-30, 1987.
45. Benveniste, H., Drejer, J., Schousboe, A., Diemer, NH. ,Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. Journal of Neurochemistry. 43:1369-74, 1984.
46. Tossman, U., Wieloch, T., Ungerstedt, U., gamma-Aminobutyric acid and taurine release in the striatum of the rat during hypoglycemic coma, studied by microdialysis. Neuroscience Letters. 62:231-5, 1985.
47. Hallstrom, A., Carlsson, A., Hillered, L., Ungerstedt, U., Simultaneous determination of lactate, pyruvate, and ascorbate in microdialysis samples from rat brain, blood, fat, and muscle using high-performance liquid chromatography. Journal of Pharmacological Methods. 22:113-24, 1989.
48. Brodin, E., Lindefors, N., Ungerstedt, U., Potassium evoked in vivo release of substance P in rat caudate nucleus measured using a new technique of brain dialysis and an improved substance P-radioimmunoassay. Acta Physiologica Scandinavica. Supplementum. 515:17-20, 1983.
49. Ben-Nun, J., Cooper, RL., Cringle, SJ., Constable, IJ., Ocular dialysis. A new technique for in vivo intraocular pharmacokinetic measurements. Archives of Ophthalmology. 106:254-9, 1988.
50. Stahle, L., Segersvard, S., Ungerstedt, U., Theophylline concentration in the extracellular space of the rat brain: measurement by microdialysis and relation to behaviour. European Journal of Pharmacology. 185:187-93, 1990.
51. Amberg, G., Lindefors, N., Intracerebral microdialysis: II. Mathematical studies of diffusion kinetics. Journal of Pharmacological Methods. 22:157-83, 1989.
52. Benveniste, H., Hansen, AJ., Ottosen, NS., Determination of brain interstitial concentrations by microdialysis. Journal of Neurochemistry. 52:1741-50, 1989.
53. Menacherry, S., Hubert, W., Justice, JB., In vivo calibration of microdialysis probes for exogenous compounds. Analytical Chemistry. 64:577-83, 1992.
54. Tossman, U., Ungerstedt, U., Microdialysis in the study of extracellular levels of amino acids in the rat brain. Acta Physiologica Scandinavica. 128:9-14, 1986.
55. Tao, R., Hjorth, S., Differences in the in vitro and in vivo 5-hydroxytryptamine extraction performance among three common microdialysis membranes. Journal of Neurochemistry. 59:1778-85, 1992.
56. Lange, EC., Danhof, M., de Boer, AG., Breimer, DD., Critical factors of intracerebral microdialysis as a technique to determine the pharmacokinetics of drugs in rat brain. Brain Research. 666:1-8, 1994.
57 Ikeda, Y., Sunakawa, T., Tsuchiya, S., Toxicological studies on sophorlipid derives.(Ⅰ)Acute toxicity ,eye irritation, primary skin irritation, pototoxicity, photosensitization, mutagenicity of polyoxypropylene(12)[(2'-O-beta-D-glucopyranosyl)oxy-]fatty acid ester. J Toxicol Sic 11:197-211,1986
58.Boutin, JA., Meunier, F., Lambert, PH., Hennig, P., Bertin, D. ,Serkiz, B., Volland, JP., In vivo and in vitro glucuronidation of the flavonoid diosmetin in rats. Drug Metabolism & Disposition. 21:1157-66, 1993
59.Roger, Causon., Validation of chromatography methods in biomedical analysis viewpoin and dissusion. Journal of Chromatorgraphy B. 689:175-180 , 1997.
60. Francis, L.S., Tse. Frances, Ballard., James, M., Jaffe. A ,practical method for motoring drug excretion and enterohepatic circulation in the rat. Journal of Pharmacological Methods 7:139-144,1982
61. Behnia, K., Boroujerdi, M., Investigation of the enterohepatic recirculation of Adriamycin and its metabolites by a linked-rat model. Cancer Chemotherapy & Pharmacology. 41:370-6, 1998.
62.Marika Pasternyk Di Marco., Guy Felix., Vincent Descorps. Murray P., Ducharme. ,Irving W., Wainer, On-line deconjugation of glucuronides using an immobilized enzyme reactor based upon base β-glucuronidase.Journal of Chromatography B. 715:379-386,1998
63 Howard, P., Hendrickson., Dennis, O., Scott Craig E., Lunte., Identification of 9- hydroxylamine-1,2,3,4-tetrahydroacridine as a hepatic microsomal metabolite of tacrine by high-performance liquid chromatography and electrochemistry. Journal of Chromatography B 487 :401-408,1989
64 Gigon, P.L., Biotransformation and biliary excretion of imipramine in rats under various experimental conitions. Pharmacodyn.216:315-327,1975.
65 K.W.Bock., B.S.Bock-Hennig Differential induction of human liver UDP-glucuronosyltansferase activities by penobarbital-tye inducer .Biochemical Pharmacology , 36(23):4137-4143,1987
66. Tsai, T.H., Hong, C.Y., Chen, C.F., Analysis of active ingredients in medicinal herbs with high-performance liquid chromatography and related technologies: a review. J. Food Drug Anal.5: 303-318, 1997
67.Dannette K.Hansen, MalonneI. Davies, Susan M. Lunte, Craig E.Lunte, Pharmacokinetic and metablism studies using microdialysis sampling, J. Pharmaceutical Sciences.88:14-27,1999.
68. Samuel N. Marcus, Claudio D. Scteingart, Margaret L. Marouez, Active absorption of conjugated bile acid in vivo, Gastroenterology 100:212-221, 1991.
69. Robert, RJ., Pharm, B., Plaa, GL., The effect of bile duct ligation bile duct cannulation and hypothermia on naphthylisothiocyanate-induced hyperbilirubinemia and cholestasis in rats, Gastroenterology 50:768-774, 1966.
70. Folkert, K., Tjalling, D., Rick, H., Wilma Van Asselt, Acute effect on pentobarbital-anaesthesia on bile seretion, Biochemcal Pharmacology, 34:1731-1736,1985.
71. Agamemnon, D., Stefan, S., Color Atlas of Physiology, New York: Thieme Medical Publishers.,194-201,1994.
72. Wingrad, Brody, Larner, Schwartz, Human Pharmacology, New York: Mosby - Year Book, 335, 1991.
73. Matern, S., Bock, K.W., Gerok, W., Advances in glucuronide conjugation, West Germany : MTP Press Limited, 7-21, 329-330,1984.
74. Elmquist, WF., Sawchuk, RJ., Application of microdialysis in pharmacokinetics studies, Pharmaceutical research 14:267-288, 1997.
75. Watt, JA., Dickinson, RG., The effct of diethyl ether, pentobarbitone and urethane anaesthesia on diflunisal conjugation and diposition in rats.,Xenobitica,20:289-301, 1991.
76. 侯鈺琪，徐素蘭，顏秀芳，陳忠川，李佩端，葡萄柚汁、枳殼與化橘紅煎劑中Naringin 於人體內吸收之比較，中國藥學會八十七年度藥學學術研討會。
77. Bradbury, M.W.B., The structure and function of blood-brain barrier., Fed. Proc., 43:186-190, 1984.
78. Bock, K.W., Burchell, B., Dutton, G. J., Hanninen, O., Mulder, G.J., Owen, I.S., Siest, G., and Tephly, T.R., UDP-glucuronidosyltransferase activities.Guidelines for consistnet interim terminology and assay conditions. Biochem. Pharmacol., 32: 953-975, 1983.
79. Bock, K.W., and White, I.N.H., UDP-glucuronosyltransferase in perfused rat liver and in microsomes: influence of phenobarital and 3-methylcholanthrene., Euro. J. Biochem., 46:451-459, 1974.