臺灣博碩士論文加值系統

中草藥-藥物交互作用（herbal-drug interaction）近年來陸續被發現，許多中草藥與處方藥物會產生藥物交互作用，目前也有許多研究指出中草藥-藥物交互作用與細胞色素P450有關，本研究目的為探討中草藥影響細胞色素P450而可能發生的中草藥-西藥藥物交互作用。
本研究參考中央健保局之中藥用量排行榜及中醫藥委員會所提供之中醫醫院及藥廠使用量排名，所選出的二十四種常用複方濃縮中藥，經由本研究室之前於體外人肝CYP3A活性篩選結果，所選出的十種於體外試驗中具有顯著抑制人肝CYP3A活性的複方濃縮中藥製劑進一步做體內動物實驗，評估其可能之實際影響。體內動物實驗第一階段為大鼠口服給予短期（一天三次，共七天）複方濃縮中藥製劑後，於第八天口服給予CYP3A受質midazolam進行藥物動力學之研究，以觀察該模式藥物之藥動學性質(如AUC, Cmax)是否顯著地受到中藥的影響而存在中西藥交互作用之可能性，同時在完成藥動試驗的抽血後，取其肝及腸以testosterone進行在肝及腸的CYP3A活性試驗。第二階段為口服給予七天複方濃縮中藥後，具有影響大鼠CYP3A活性的五種複方濃縮中藥，進一步做大鼠口服給予長期（一天三次，共十四天）複方濃縮中藥製劑後，於第十五天口服給予CYP3A受質midazolam進行藥物動力學之研究，以觀察該模式藥物之藥動學性質(如AUC, Cmax)是否顯著地受到中藥的影響而存在中西藥交互作用之可能性。
口服給予短期（一天三次，共七天）複方濃縮中藥實驗結果，短期使用蒼耳散和龍膽瀉肝湯會使Midazolam最高血中濃度及血中濃度曲線下面積顯著上升（P＜0.01），知柏地黃丸會使Midazolam生體清除率顯著增加（P＜0.05）。口服長期（一天三次，共十四天）複方濃縮中藥實驗結果，
長期使用加味逍遙散和知柏地黃丸會誘導CYP3A使Midazolam最高血中濃度（P＜0.05）及血中濃度曲線下面積（P＜0.01）顯著降低；半夏瀉心湯也會誘導CYP3A使Midazolam最高血中濃度和血中濃度曲線下面積（P＜0.01）。
最後將口服給予短期複方濃縮中藥後，所得到之Midazolam最高血中濃度、血中濃度曲線下面積和生體清除率與肝及腸的活性分析結果做比較，結果顯示肝的CYP3A活性與Midazolam最高血中濃度、血中濃度曲線下面積均有顯著的負相關（P＜0.01）；與Midazolam生體清除率呈現顯著的正相關（P＜0.01）。1'-OH-midazolam血中濃度曲線下面積/midazolam血中濃度曲線下面積與肝的CYP3A活性具有顯著的正相關（P＜0.001）。

The increased public interest of coadministration of Chinese herbal medicine with Western medicine has raised an important issue of drug interaction. Drug-drug interactions may result a loss in therapeutic efficacy or may induce the toxic effects. Many Chinese herbal medicine and prescription drugs have been found to have interactions. Recently, many studies have indicated that herbal drug interaction is related to Cytochrome P450 (CYP450), the most abundant enzyme in human liver and is highly expressed in the intestinal tract. The purpose of this study is to determine the effects of Chinese herbal medicine on CYP450 and to investigate the possible interactions of Chinese herbal medicine and Western medicine.
The 24 concentrated compound Chinese herbal medicines used in this study were referring to the order list of National Social Health Care System and Customs of Medicine use in Taiwan. These 24 concentrated compound Chinese herbal medicines were screened for the activity of CYP3A using human liver microsomes for in vitro study. 10 Chinese herbal medicines were selected for the in vivo test due to their inhibition effects on CYP3A. There were 2 groups for the in vivo study, short term and long term study. The in vivo study was performed by using the Sprague – Dawley (SD) rats. The short term study was carried out by orally administered concentrated compound Chinese herbal medicine to SD rats 3 times daily for 7 days followed by orally administered midazolam, a CYP3A substrate, on the 8th day. Pharmacokinetic parameters (i.e. AUC, Cmax) were observed to determine whether the metabolism of midazolam was affected by the Chinese herbal medicines or had the possible herbal – drug interaction. The SD rats were sacrificed and the livers and intestines were taken for the determination of CYP3A activity using testosterone as a model drug. 5 concentrated compound Chinese herbal medicines were selected for the long term in vivo study. The long term study was performed by giving the 5 concentrated compound Chinese herbal medicines orally to SD rats 3 times daily for 14 days followed by midazolam on the 15th day.
The result of short term study showed that the Cmax and AUC of midazolam increased significantly when orally administered Cang Er Zi San and Long-Daan-Shiah-Gan-Tang. The clearance was also increased significantly when orally administered Zhi-Bai-Di-Huang-Wan. On the other hand, the result for the long term study showed that the Cmax and AUC of midazolam decreased significantly when orally administered Jia-Wei-Xiao-Yao-San, Zhi-Bai-Di-Huang-Wan and Ban-Xia-Xie-Xin-Tang. According to the results of short term study, Cmax, AUC, and the activity of CYP3A of liver and intestine showed negative correlations, but the clearance of midazolam showed a positive correlation. Moreover, the ratio of AUC for 1’-OH-midazolam and midazolam and the activity of CYP3A showed significant positive correlation.

正文目錄 I
表目錄 V
圖目錄 VII
中文摘要 XIV
英文摘要 XVI
第一章 緒論 1
第一節、 前言 1
第二節、 藥物交互作用 2
一、 分布與含量 11
第四節、 複方濃縮中藥簡介 17
一、 方劑的組成 17
二、 複方濃縮中藥 18
第五節、 Midazolam簡介 28
第六節、 Testosterone簡介 32
第七節、 研究目的 35
第二章 試劑與儀器 36
第一節、 藥品與試劑 36
第二節、 儀器 38
一、 一般儀器 38
二、 液相層析串聯式質譜儀分析系統(LC/MS/MS) 38
第三章 實驗方法 39
第一節、 體內動物實驗方法 39
一、 動物 39
二、 動物實驗 39
三、 Midazolam分析方法： 44
1. Midazolam在液相層析儀分析條件： 44
3. 檢品處理 48
4. 校正曲線製作 50
5. 數據處理及統計方法 51
第二節、 CYP3A活性分析實驗 52
一、 實驗方法 52
三、 蛋白質含量測定： 55
四、 6β-hydroxytestosterone分析方法 57
1. 6β-hydroxytestosterone液相層析儀分析條件： 57
4. 校正曲線製作 60
5. 數據處理及統計方法 61
第四章 結果與討論 62
第一節、 體內藥物動力學實驗 62
一、 Midazolam分析方法之確效 62
二、 1'-OH-midazolam分析方法之確效 62
三、 大鼠口服給予複方濃縮中藥一週後，口服給予Midazolam 20mg/kg與控制組之比較 64
四、 大鼠口服給予複方濃縮中藥十四天後，口服給予Midazolam 20mg/kg與控制組之比較 75
第二節、 體內CYP3A活性分析實驗 107
一、 大白鼠肝臟酵素的蛋白質濃度之測定 107
二、 6β-hydroxytestosterone分析方法之確效 107
三、 大鼠口服給予複方濃縮中藥七天後，肝及腸CYP3A活性與控制組之比較 108
四、 大鼠口服給予複方濃縮中藥七天後，肝及腸CYP3A活性與midazolam之AUC0→∞、Cmax、Cl/F相關性比較 112
五、 大鼠口服給予複方濃縮中藥七天後，肝及腸CYP3A活性與1'-OH-midazolam之AUC0→∞、Cmax相關性比較 113
第五章 結論 126
第六章 參考文獻 127

表目錄
【表1- 1】已下市藥品－因CYP相關之藥物-藥物交互作用 6
【表1- 2】中草藥-藥物交互作用案例 7
【表1- 3】可經Cytochrome P450代謝之物質 15
【表1- 4】人類與大白鼠CYP3A胺基酸序列相似百分比 16
【表1- 5】常用複方濃縮中藥 25
【表1- 6】複方濃縮中藥於體外人肝CYP3A篩選抑制排行前十名 26
【表1- 7】複方常用濃縮中藥所含之單方濃縮中藥 27
【表1- 8】建議使用於CYP3A4體內試驗之受質 31
【表1- 9】建議使用於CYP3A4體外試驗之受質 34
【表3- 1】十種複方濃縮中藥製劑所使用之劑量 42
【表3- 2】Midazolam與1’-OH-midazolam於LC-MS/MS分析條件 46
【表3- 3】6β-hydroxytestosterone於LC-MS/MS分析條件 59
【表4- 1】Midazolam於大鼠血漿中異日間之標準曲線數據(n=6) 84
【表4- 2】Midazolam於大鼠血漿中同日間之品管檢品(QC sample) 在LC-MS-MS分析確效驗證結果（n=6） 85
【表4- 3】Midazolam於大鼠血漿中異日間之品管檢品在LC-MS-MS分析確效驗證結果（n=6） 85
【表4- 4】1'-OH-midazolam於大鼠血漿中異日間(Inter-day)之標準曲線數據（n=6） 86
【表4- 5】1'-OH-midazolam於大鼠血漿中同日間之品管檢品(QC sample) 在LC-MS-MS分析確效驗證結果（n=6） 87
【表4- 6】1'-OH-midazolam於大鼠血漿中異日間之品管檢品在LC-MS-MS分析確效驗證結果（n=6） 87
【表4- 7】大白鼠口服給予複方濃縮中藥製劑一週後，口服給予midazolam 20mg/kg與控制組之midazolam藥物動力學參數之比較 98
【表4- 8】大白鼠口服給予複方濃縮中藥製劑一週後，口服給予midazolam 20mg/kg與控制組之1'-OH-midazolam藥物動力學參數之比較 99
【表4- 9】大白鼠口服給予複方濃縮中藥製劑兩週後，口服給予midazolam 20mg/kg與控制組之midazolam藥物動力學參數之比較 105
【表4- 10】大白鼠口服給予複方濃縮中藥製劑兩週後，口服給予midazolam 20mg/kg與控制組之1'-OH-midazolam藥物動力學參數之比較 106
【表4- 11】蛋白質測定標準曲線數據（n=3） 115
【表4- 12】6β-hydroxytestosterone於大白鼠微粒酵素懸浮液異日間(Inter-day) 標準曲線數據(n=6) 116
【表4- 13】6β-hydroxytestosterone於大白鼠微粒酵素懸浮液異日間之品管檢品在LC-MS-MS分析確效驗證結果（n=6） 117

圖目錄
【圖1- 1】主要與藥物代謝有關之肝臟CYP450。圖中所表示的百分比為該酵素於肝中之含量 13
【圖1- 2】人類腸道中各型細胞色素之含量比例 14
【圖1- 3】臨床常用前200種處方藥物受各型細胞色素P-450代謝之比例 14
【圖1- 4】Midazolam代謝途徑 30
【圖1- 5】Testosterone和6β-hydroxytestosterone結構式 33
【圖3- 1】動物實驗流程簡略圖 43
【圖3- 2】Midazolam、1’-OH-midazolam、4-OH-midazolam與內部標準品Flunitrazepam於老鼠血漿之LC-MS/MS圖譜。 47
【圖3- 3】Midazolam血液檢品處理方法 49
【圖3- 4】微粒體酵素製備流程簡略說明圖 54
【圖3- 5】微粒體酵素蛋白質含量測定說明圖 56
【圖4- 1】Midazolam於大鼠血漿中異日間之標準曲線(n=6) 84
【圖4- 2】1'-OH-midazolam於大鼠血漿中異日間(Inter-day)之標準曲線（n=6） 86
【圖4- 3】口服給予辛夷清肺湯（n=6）一週後，口服給予 Midazolam 20mg/kg與控制組（n=23）Midazolam血中濃度之比較圖（Mean±SE）。 88
【圖4- 4】口服給予辛夷清肺湯（n=6）一週後，口服給予 Midazolam 20mg/kg與控制組（n=23）1'-OH-midazolam血中濃度之比較圖（Mean±SE）。 88
【圖4- 5】口服給予甘露飲（n=6）一週後，口服給予 Midazolam 20mg/kg與控制組（n=23）Midazolam血中濃度之比較圖（Mean±SE）。 89
【圖4- 6】口服給予甘露飲（n=6）一週後，口服給予 Midazolam 20mg/kg與控制組（n=23）1'-OH-midazolam血中濃度之比較圖（Mean±SE）。 89
【圖4- 7】口服給予川芎茶調散（n=7）一週後，口服給予 Midazolam 20mg/kg與控制組（n=23）Midazolam血中濃度之比較圖（Mean±SE）。 90
【圖4- 8】口服給予川芎茶調散（n=7）一週後，口服給予 Midazolam 20mg/kg與控制組（n=23）1'-OH-midazolam血中濃度之比較圖（Mean±SE）。 90
【圖4- 9】口服給予正骨紫金丹（n=8）一週後，口服給予 Midazolam 20mg/kg與控制組（n=23）Midazolam血中濃度之比較圖（Mean±SE）。 91
【圖4- 10】口服給予正骨紫金丹（n=8）一週後，口服給予 Midazolam 20mg/kg與控制組（n=23）1'-OH-midazolam血中濃度之比較圖（Mean±SE）。 91
【圖4- 11】口服給予小柴胡湯（n=8）一週後，口服給予 Midazolam 20mg/kg與控制組（n=23）Midazolam血中濃度之比較圖（Mean±SE）。 92
【圖4- 12】口服給予小柴胡湯（n=8）一週後，口服給予 Midazolam 20mg/kg與控制組（n=23）1'-OH-midazolam血中濃度之比較圖（Mean±SE）。 92
【圖4- 13】口服給予加味逍遙散（n=7）一週後，口服給予 Midazolam 20mg/kg與控制組（n=23）Midazolam血中濃度之比較圖（Mean±SE）。 93
【圖4- 14】口服給予加味逍遙散（n=7）一週後，口服給予 Midazolam 20mg/kg與控制組（n=23）1'-OH-midazolam血中濃度之比較圖（Mean±SE）。 93
【圖4- 15】口服給予半夏瀉心湯（n=6）一週後，口服給予 Midazolam 20mg/kg與控制組（n=23）Midazolam血中濃度之比較圖（Mean±SE）。 94
【圖4- 16】口服給予半夏瀉心湯（n=6）一週後，口服給予 Midazolam 20mg/kg與控制組（n=23）1'-OH-midazolam血中濃度之比較圖（Mean±SE）。 94
【圖4- 17】口服給予知柏地黃丸（n=4）一週後，口服給予 Midazolam 20mg/kg與控制組（n=23）Midazolam血中濃度之比較圖（Mean±SE）。 95
【圖4- 18】口服給予知柏地黃丸（n=4）一週後，口服給予 Midazolam 20mg/kg與控制組（n=23）1'-OH-midazolam血中濃度之比較圖（Mean±SE）。 95
【圖4- 19】口服給予龍膽瀉肝湯（n=6）一週後，口服給予 Midazolam 20mg/kg與控制組（n=23）Midazolam血中濃度之比較圖（Mean±SE）。 96
【圖4- 20】口服給予龍膽瀉肝湯（n=6）一週後，口服給予 Midazolam 20mg/kg與控制組（n=23）1'-OH-midazolam血中濃度之比較圖（Mean±SE）。 96
【圖4- 21】口服給予蒼耳散（n=5）一週後，口服給予 Midazolam 20mg/kg與控制組（n=23）Midazolam血中濃度之比較圖（Mean±SE）。 97
【圖4- 22】口服給予蒼耳散（n=5）一週後，口服給予 Midazolam 20mg/kg與控制組（n=23）1'-OH-midazolam血中濃度之比較圖（Mean±SE）。 97
【圖4- 23】口服給予龍膽瀉肝湯（n=6）兩週後，口服給予 Midazolam 20mg/kg與控制組（n=12）Midazolam血中濃度之比較圖（Mean±SE）。 100
【圖4- 24】口服給予龍膽瀉肝湯（n=6）兩週後，口服給予 Midazolam 20mg/kg與控制組（n=12）1'-OH-midazolam血中濃度之比較圖（Mean±SE）。 100
【圖4- 25】口服給予蒼耳散（n=11）兩週後，口服給予 Midazolam 20mg/kg與控制組（n=12）Midazolam血中濃度之比較圖（Mean±SE） 101
【圖4- 26】口服給予蒼耳散（n=11）兩週後，口服給予 Midazolam 20mg/kg與控制組（n=12）1'-OH-midazolam血中濃度之比較圖（Mean±SE）。 101
【圖4- 27】口服給予半夏瀉心湯（n=6）兩週後，口服給予 Midazolam 20mg/kg與控制組（n=12）Midazolam血中濃度之比較圖（Mean±SE）。 102
【圖4- 28】口服給予半夏瀉心湯（n=6）兩週後，口服給予 Midazolam 20mg/kg與控制組（n=12）1'-OH-midazolam血中濃度之比較圖（Mean±SE）。 102
【圖4- 29】口服給予知柏地黃丸（n=7）兩週後，口服給予 Midazolam 20mg/kg與控制組（n=12）Midazolam血中濃度之比較圖（Mean±SE）。 103
【圖4- 30】口服給予知柏地黃丸（n=7）兩週後，口服給予 Midazolam 20mg/kg與控制組（n=12）1'-OH-midazolam血中濃度之比較圖（Mean±SE）。 103
【圖4- 31】口服給予加味逍遙散（n=7）兩週後，口服給予 Midazolam 20mg/kg與控制組（n=12）Midazolam血中濃度之比較圖（Mean±SE）。 104
【圖4- 32】口服給予加味逍遙散（n=7）兩週後，口服給予 Midazolam 20mg/kg與控制組（n=12）1'-OH-midazolam血中濃度之比較圖（Mean±SE）。 104
【圖4- 33】蛋白質測定標準曲線（n=3） 115
【圖4- 34】6β-hydroxytestosterone於大白鼠微粒酵素懸浮液異日間(Inter-day) 標準曲線圖(n=6) 116
【圖4- 35】大白鼠餵食複方濃縮中藥一週後，肝CYP3A活性與控制組之比較（n=4~11） 118
【圖4- 36】大白鼠餵食複方濃縮中藥一週後，腸CYP3A活性與控制組之比較（n=4~8） 119
【圖4- 37】Midazolam血中濃度曲線下面積與肝CYP3A活性關係圖 120
【圖4- 38】Midazolam最高血中濃度與肝CYP3A活性關係圖 120
【圖4- 39】Midazolam生體清除率與肝CYP3A活性關係圖 121
【圖4- 40】Midazolam血中濃度曲線下面積與腸CYP3A活性關係圖 121
【圖4- 41】Midazolam最高血中濃度與腸CYP3A活性關係圖 122
【圖4- 42】Midazolam生體清除率與腸CYP3A活性關係圖 122
【圖4- 43】1’OH-midazolam血中濃度曲線下面積與肝CYP3A活性關係圖 123
【圖4- 44】1’OH-midazolam最高血中濃度與肝CYP3A活性關係圖 123
【圖4- 45】1’-OH-midazolam血中濃度曲線下面積與腸CYP3A活性關係圖 124
【圖4- 46】1’-OH-midazolam最高血中濃度與腸CYP3A活性關係 124
【圖4- 47】1’-OH-midazolam/Midazolam血中濃度曲線下面積比與肝CYP3A活性關係 125
【圖4- 48】1’-OH-midazolam/Midazolam血中濃度曲線下面積比與腸CYP3A活性關係 125

Aarons L., Mandema J. W. and Danhof M. A population analysis of the pharmacokinetics and pharmacodynamics of midazolam in the rat. J Pharmacokinet Biopharm. 19: 485-96, 1991.
Breidenbach T., Hoffmann M. W., Becker T., Schlitt H. and Klempnauer J. Drug interaction of St John's wort with cyclosporin. Lancet. 355: 1912, 2000.
Chao Lee Pei-Dawn. Survey of Concurrent Use of Chinese Medicine and Western Medicine in Cental Taiwan. Year book Chinese medicine and pharmacy 21: 413-459, 2003.
Cooper K. O., Reik L. M., Jayyosi Z., Bandiera S., Kelley M., Ryan D. E., Daniel R., Mccluskey S. A., Levin W. and Thomas P. E. Regulation of two members of the steroid-inducible cytochrome P450 subfamily (3A) in rats. Archives of Biochemistry & Biophysics. 301: 345-54, 1993.
Domanski T. L., Finta C., Halpert J. R. and Zaphiropoulos P. G. cDNA cloning and initial characterization of CYP3A43, a novel human cytochrome P450. Molecular Pharmacology. 59: 386-92, 2001.
Draper A. J., Madan A., Smith K. and Parkinson A. Development of a non-high pressure liquid chromatography assay to determine testosterone hydroxylase (CYP3A) activity in human liver microsomes. Drug Metab Dispos. 26: 299-304, 1998.
Dundee J. W., Halliday N. J., Harper K. W. and Brogden R. N. Midazolam. A review of its pharmacological properties and therapeutic use. Drugs. 28: 519-43, 1984.
Eisenberg D. M., Davis R. B., Ettner S. L., Appel S., Wilkey S., Van Rompay M. and Kessler R. C. Trends in alternative medicine use in the United States, 1990-1997: results of a follow-up national survey. Jama. 280: 1569-75, 1998.
Eisenberg D. M., Kessler R. C., Foster C., Norlock F. E., Calkins D. R. and Delbanco T. L. Unconventional medicine in the United States. Prevalence, costs, and patterns of use. N Engl J Med. 328: 246-52, 1993.
Gerecke M. Chemical structure and properties of midazolam compared with other benzodiazepines. Br J Clin Pharmacol. 16 Suppl 1: 11S-16S, 1983.
Gokhale M. S., Bunton T. E., Zurlo J. and Yager J. D. Cytochrome P450 isoenzyme activities in cultured rat and mouse liver slices. Xenobiotica. 27: 341-55, 1997.
Goldman P. Herbal medicines today and the roots of modern pharmacology. Ann Intern Med. 135: 594-600, 2001.
Gonzalez F. J., Song B. J. and Hardwick J. P. Pregnenolone 16 alpha-carbonitrile-inducible P-450 gene family: gene conversion and differential regulation. Molecular & Cellular Biology. 6: 2969-76, 1986.
Guengerich F. P. Cytochrome P450s and other enzymes in drug metabolism and toxicity. AAPS Journal. 8: E101-11, 2006.
Guengerich F. P. Cytochromes P450, drugs, and diseases. Molecular Interventions. 3: 194-204, 2003.
Haehner B. D., Gorski J. C., Vandenbranden M., Wrighton S. A., Janardan S. K., Watkins P. B. and Hall S. D. Bimodal distribution of renal cytochrome P450 3A activity in humans. Molecular Pharmacology. 50: 52-9, 1996.
Heizmann P., Eckert M. and Ziegler W. H. Pharmacokinetics and bioavailability of midazolam in man. Br J Clin Pharmacol. 16 Suppl 1: 43S-49S, 1983.
Heizmann P. and Ziegler W. H. Excretion and metabolism of 14C-midazolam in humans following oral dosing. Arzneimittelforschung. 31: 2220-3, 1981.
Hu Z., Yang X., Ho P. C., Chan S. Y., Heng P. W., Chan E., Duan W., Koh H. L. and Zhou S. Herb-drug interactions: a literature review. Drugs. 65: 1239-82, 2005.
Inoue K., Inazawa J., Nakagawa H., Shimada T., Yamazaki H., Guengerich F. P. and Abe T. Assignment of the human cytochrome P-450 nifedipine oxidase gene (CYP3A4) to chromosome 7 at band q22.1 by fluorescence in situ hybridization. Japanese Journal of Human Genetics. 37: 133-8, 1992.
Johnson T. N., Tanner M. S. and Tucker G. T. A comparison of the ontogeny of enterocytic and hepatic cytochromes P450 3A in the rat. Biochem Pharmacol. 60: 1601-10, 2000.
Kageyama M., Namiki H., Fukushima H., Terasaka S., Togawa T., Tanaka A., Ito Y., Shibata N. and Takada K. Effect of chronic administration of ritonavir on function of cytochrome P450 3A and P-glycoprotein in rats. Biol Pharm Bull. 28: 130-7, 2005.
Kajosaari L. I., Jaakkola T., Neuvonen P. J. and Backman J. T. Pioglitazone, an in vitro inhibitor of CYP2C8 and CYP3A4, does not increase the plasma concentrations of the CYP2C8 and CYP3A4 substrate repaglinide. European Journal of Clinical Pharmacology. 62: 217-23, 2006.
Kitada M., Kamataki T., Itahashi K., Rikihisa T., Kato R. and Kanakubo Y. Purification and properties of cytochrome P-450 from homogenates of human fetal livers. Archives of Biochemistry & Biophysics. 241: 275-80, 1985.
Kolars J. C., Lown K. S., Schmiedlin-Ren P., Ghosh M., Fang C., Wrighton S. A., Merion R. M. and Watkins P. B. CYP3A gene expression in human gut epithelium. Pharmacogenetics. 4: 247-59, 1994.
Kupferschmidt H. H., Ha H. R., Ziegler W. H., Meier P. J. and Krahenbuhl S. Interaction between grapefruit juice and midazolam in humans. Clin Pharmacol Ther. 58: 20-8, 1995.
Lai M. Y., Hsiu S. L., Hou Y. C., Tsai S. Y. and Chao P. D. Significant decrease of cyclosporine bioavailability in rats caused by a decoction of the roots of Scutellaria baicalensis. Planta Med. 70: 132-7, 2004.
Lichtblau D., Berger J. M. and Nakanishi K. Efficient extraction of ginkgolides and bilobalide from Ginkgo biloba leaves. J Nat Prod. 65: 1501-4, 2002.
Lown K. S., Kolars J. C., Thummel K. E., Barnett J. L., Kunze K. L., Wrighton S. A. and Watkins P. B. Interpatient heterogeneity in expression of CYP3A4 and CYP3A5 in small bowel. Lack of prediction by the erythromycin breath test.[erratum appears in Drug Metab Dispos 1995 Mar;23(3):followi]. Drug Metabolism & Disposition. 22: 947-55, 1994.
Lowry O. H., Rosebrough N. J., Farr A. L. and Randall R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 193: 265-75, 1951.
Makino T., Inagaki T., Komatsu K. and Kano Y. Pharmacokinetic interactions between Japanese traditional Kampo medicine and modern medicine (IV). Effect of Kamisyoyosan and Tokisyakuyakusan on the pharmacokinetics of etizolam in rats. Biol Pharm Bull. 28: 280-4, 2005.
Mandema J. W., Tuk B., Van Steveninck A. L., Breimer D. D., Cohen A. F. and Danhof M. Pharmacokinetic-pharmacodynamic modeling of the central nervous system effects of midazolam and its main metabolite alpha-hydroxymidazolam in healthy volunteers. Clin Pharmacol Ther. 51: 715-28, 1992.
Mandema J. W., Tukker E. and Danhof M. Pharmacokinetic-pharmacodynamic modelling of the EEG effects of midazolam in individual rats: influence of rate and route of administration. Br J Pharmacol. 102: 663-8, 1991.
Matsubara T., Kim H. J., Miyata M., Shimada M., Nagata K. and Yamazoe Y. Isolation and characterization of a new major intestinal CYP3A form, CYP3A62, in the rat. Journal of Pharmacology & Experimental Therapeutics. 309: 1282-90, 2004.
Matsuda K., Nishimura Y., Kurata N., Iwase M. and Yasuhara H. Effects of continuous ingestion of herbal teas on intestinal CYP3A in the rat. J Pharmacol Sci. 103: 214-21, 2007.
Nagata K., Murayama N., Miyata M., Shimada M., Urahashi A., Yamazoe Y. and Kato R. Isolation and characterization of a new rat P450 (CYP3A18) cDNA encoding P450(6)beta-2 catalyzing testosterone 6 beta- and 16 alpha-hydroxylations. Pharmacogenetics. 6: 103-11, 1996.
Nebert D. W. and Russell D. W. Clinical importance of the cytochromes P450. Lancet. 360: 1155-62, 2002.
Nelson D. R., Koymans L., Kamataki T., Stegeman J. J., Feyereisen R., Waxman D. J., Waterman M. R., Gotoh O., Coon M. J., Estabrook R. W., Gunsalus I. C. and Nebert D. W. P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics. 6: 1-42, 1996.
Nishikawa M., Ariyoshi N., Kotani A., Ishii I., Nakamura H., Nakasa H., Ida M., Nakamura H., Kimura N., Kimura M., Hasegawa A., Kusu F., Ohmori S., Nakazawa K. and Kitada M. Effects of continuous ingestion of green tea or grape seed extracts on the pharmacokinetics of midazolam. Drug Metab Pharmacokinet. 19: 280-9, 2004.
Ohnishi N., Okada K., Yoshioka M., Kuroda K., Nagasawa K., Takara K. and Yokoyama T. Studies on interactions between traditional herbal and western medicines. V. effects of Sho-saiko-to (Xiao-Cai-hu-Tang) on the pharmacokinetics of carbamazepine in rats. Biol Pharm Bull. 25: 1461-6, 2002.
Page R. L., 2nd and Lawrence J. D. Potentiation of warfarin by dong quai. Pharmacotherapy. 19: 870-6, 1999.
Paine M. F., Hart H. L., Ludington S. S., Haining R. L., Rettie A. E. and Zeldin D. C. The human intestinal cytochrome P450 "pie". Drug Metabolism & Disposition. 34: 880-6, 2006.
Pal D. and Mitra A. K. MDR- and CYP3A4-mediated drug-herbal interactions. Life Sci. 78: 2131-45, 2006.
Qi J. W., Nakamura K., Hosokawa S., Okada Y., Horiuchi R. and Yamamoto K. Time-dependent induction of midazolam-1-hydroxylation enzymes in rats treated with St. John's wort. Biol Pharm Bull. 28: 1467-71, 2005.
Qi L., Zhou R., Wang Y. F. and Zhu Y. C. Study of major flavonoids in crude Scutellariae Radix by micellar electrokinetic capillary chromatography. J Capillary Electrophor. 5: 181-4, 1998.
Rafferty A. P., Mcgee H. B., Miller C. E. and Reyes M. Prevalence of complementary and alternative medicine use: state-specific estimates from the 2001 Behavioral Risk Factor Surveillance System. Am J Public Health. 92: 1598-600, 2002.
Rendic S. Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metabolism Reviews. 34: 83-448, 2002.
Rendic S. and Di Carlo F. J. Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors. Drug Metabolism Reviews. 29: 413-580, 1997.
Robertson G. R., Farrell G. C. and Liddle C. Sexually dimorphic expression of rat CYP3A9 and CYP3A18 genes is regulated by growth hormone. Biochemical & Biophysical Research Communications. 242: 57-60, 1998.
Saruwatari J., Nakagawa K., Shindo J., Nachi S., Echizen H. and Ishizaki T. The in-vivo effects of sho-saiko-to, a traditional Chinese herbal medicine, on two cytochrome P450 enzymes (1A2 and 3A) and xanthine oxidase in man. J Pharm Pharmacol. 55: 1553-9, 2003.
Tang Y., Lou F., Wang J., Li Y. and Zhuang S. Coumaroyl flavonol glycosides from the leaves of Ginkgo biloba. Phytochemistry. 58: 1251-6, 2001.
Tucker G. T., Houston J. B. and Huang S. M. EUFEPS conference report. Optimising drug development: strategies to assess drug metabolism/transporter interaction potential - towards a consensus. European Federation of Pharmaceutical Sciences. Eur J Pharm Sci. 13: 417-28, 2001.
Uchida S., Yamada H., Li X. D., Maruyama S., Ohmori Y., Oki T., Watanabe H., Umegaki K., Ohashi K. and Yamada S. Effects of Ginkgo biloba extract on pharmacokinetics and pharmacodynamics of tolbutamide and midazolam in healthy volunteers. J Clin Pharmacol. 46: 1290-8, 2006.
Wang H. and Strobel H. W. Regulation of CYP3A9 gene expression by estrogen and catalytic studies using cytochrome P450 3A9 expressed in Escherichia coli. Archives of Biochemistry & Biophysics. 344: 365-72, 1997.
Waxman D. J. P450-catalyzed steroid hydroxylation: assay and product identification by thin-layer chromatography. Methods Enzymol. 206: 462-76, 1991.
Waxman D. J., Attisano C., Guengerich F. P. and Lapenson D. P. Human liver microsomal steroid metabolism: identification of the major microsomal steroid hormone 6 beta-hydroxylase cytochrome P-450 enzyme. Arch Biochem Biophys. 263: 424-36, 1988.
Waxman D. J., Lapenson D. P., Aoyama T., Gelboin H. V., Gonzalez F. J. and Korzekwa K. Steroid hormone hydroxylase specificities of eleven cDNA-expressed human cytochrome P450s. Arch Biochem Biophys. 290: 160-6, 1991.
Westlind A., Malmebo S., Johansson I., Otter C., Andersson T. B., Ingelman-Sundberg M. and Oscarson M. Cloning and tissue distribution of a novel human cytochrome p450 of the CYP3A subfamily, CYP3A43. Biochemical & Biophysical Research Communications. 281: 1349-55, 2001.
Wienkers L. C. and Heath T. G. Predicting in vivo drug interactions from in vitro drug discovery data. Nat Rev Drug Discov. 4: 825-33, 2005.
Williams J. A., Hyland R., Jones B. C., Smith D. A., Hurst S., Goosen T. C., Peterkin V., Koup J. R. and Ball S. E. Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metabolism & Disposition. 32: 1201-8, 2004.
Wrighton S. A., Brian W. R., Sari M. A., Iwasaki M., Guengerich F. P., Raucy J. L., Molowa D. T. and Vandenbranden M. Studies on the expression and metabolic capabilities of human liver cytochrome P450IIIA5 (HLp3). Molecular Pharmacology. 38: 207-13, 1990.
Yang H. Y., Lee Q. P., Rettie A. E. and Juchau M. R. Functional cytochrome P4503A isoforms in human embryonic tissues: expression during organogenesis. Molecular Pharmacology. 46: 922-8, 1994.
Yin O. Q., Tomlinson B., Waye M. M., Chow A. H. and Chow M. S. Pharmacogenetics and herb-drug interactions: experience with Ginkgo biloba and omeprazole. Pharmacogenetics. 14: 841-50, 2004.
Yin Z. Z., Zhang L. Y. and Xu L. N. [The effect of Dang-Gui (Angelica sinensis) and its ingredient ferulic acid on rat platelet aggregation and release of 5-HT (author's transl)]. Yao Xue Xue Bao. 15: 321-6, 1980.
Zand R., Nelson S. D., Slattery J. T., Thummel K. E., Kalhorn T. F., Adams S. P. and Wright J. M. Inhibition and induction of cytochrome P4502E1-catalyzed oxidation by isoniazid in humans. Clin Pharmacol Ther. 54: 142-9, 1993.
王綿之，許濟群，方劑學，知音出版社，1998。
唐娜櫻，方劑學，中國醫藥大學，2004。
許劑群，方劑學，知音出版社，2002。
謝鳴，方劑學，文光出版社，2006。