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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林君榮(Chun-Jung Lin) | |
| dc.contributor.author | Chia-Hao Chen | en |
| dc.contributor.author | 陳佳壕 | zh_TW |
| dc.date.accessioned | 2021-06-16T05:43:29Z | - |
| dc.date.available | 2019-10-20 | |
| dc.date.copyright | 2014-10-20 | |
| dc.date.issued | 2014 | |
| dc.date.submitted | 2014-08-11 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/56708 | - |
| dc.description.abstract | 第一部分: CYP2C19與CYP3A4在氫離子幫浦抑制劑與抗凝血藥物 (clopidogrel與prasugrel) 之藥物交互作用上所扮演角色之探討
本研究是探討氫離子幫浦抑制劑與抗凝血藥物 (clopidogrel與prasugrel) 之間的藥物交互作用。首先先利用人類肝臟微粒體系統，測量各種氫離子幫浦抑制劑 (包含omeprazole、esomeprazole、lansoprazole、pantoprazole與rabeprazole) 抑制百分之五十clopidogrel生成2-oxo-clopidogrel，2-oxo-clopidogrel生成clopidogrel活性代謝物與prasugrel thiolactone生成prasugrel活性代謝物之濃度 (IC50)。接著進一步評估clopidogrel與prasugrel之抗凝血功能是否會受到氫離子幫浦抑制劑的影響。結果顯示，大多數的氫離子幫浦抑制劑 (除了pantoprazole以外) 都會抑制2-oxo-clopidogrel與clopidogrel活性代謝物的生成，其IC50的濃度分別為22-32 μM與6-16 μM之間。氫離子幫浦抑制劑也會抑制prasugrel活性代謝物的生成，而IC50的濃度則為9-25 μM之間。在所有氫離子幫浦抑制劑之中，omeprazole對於clopidogrel活性代謝物的生成具有最強的抑制效果。而omeprazole、esomeprazole與rabeprazole對於prasugrel活性代謝物的生成具有著較強的抑制效果，在血小板凝集方面，omeprazole與lansoprazole對於抑制clopidogrel的抗血小板凝集的功能具有較強的作用。另一方面，omeprazole、esomeprazole與rabeprazole則對於抑制prasugrel的抗血小板凝集的功能具有較強的作用。這些結果顯示，不同的氫離子幫浦抑制劑對於clopidogrel與prasugrel在肝臟代謝與抗血小板凝集的功能上具有著不同程度的抑制效果。 第二部分: P-glycoprotein與CYP450酵素對於紅麴中lovastatin之生體可用率影響之探討 紅麴 (red yeast rice; RYR) 主要用來降低血中膽固醇的活性成分為lovastatin。本研究針對紅麴產品 (包含LipoCol Forte、Cholestin與Xuezhikang) 與二種市售lovastatin錠劑 (Mevacor與Lovasta) 中lovastatin之臨床藥物動力學與可能發生之交互作用進行探討。體外試驗中發現，在不同的溶離液中，三種紅麴產品中lovastatin均比lovastatin錠劑具有著較快的溶離速率與較高的溶解度。同時在粉末X光繞射與熱差分析儀的結果顯示紅麴產品中lovastatin具有較低的結晶性。除此之外，三種紅麴產品的萃取物比起lovastatin的標準品對於肝臟代謝酵素 (CYP450 enzymes) 與P-glycoprotin的活性有更強的抑制效果。紅麴產品的萃取物抑制CYP1A2與CYP2C19的效果則與這些酵素的特異性抑制劑的抑制效果相當。在臨床試驗部分，在健康受試者服用紅麴產品或是紅麴粉末後所得到的lovastatin或是其代謝物lovastatin acid之血液與時間作圖之曲線下面積 (AUC) 與最高血液中濃度 (Cmax) 均比起這些受試者服用lovastatin錠劑或是lovastatin錠劑磨碎後所得到的粉末來的高。同時服用紅麴產品或是紅麴粉末後到達最高血液中濃度的時間 (Tmax) 也比起服用lovastatin錠劑或是lovastatin錠劑磨碎後所得到的粉末來得較快且同時具有較小的變異性。在健康受試者單劑量口服1至4顆紅麴膠囊後，lovastatin與lovastatin acid的藥物動力學特性會呈現線性，同時在多劑量服用紅麴膠囊後，lovastatin與lovastatin acid也不會明顯的蓄積於體內。在藥物交互作用方面，同時服用紅麴產品與nifedipine後，紅麴產品並不會改變nifedipine的藥物動力學性質。然而，同時服用gemifbrozil與紅麴產品後，gemfibrozil會顯著的增加lovastatin acid的血中濃度。綜合上述結果顯示，在紅麴產品中，lovastatin具有較低的結晶性、較快的溶離速率與較高的溶解度使得lovastatin口服後的生體可用率顯著的增加。此外，雖然紅麴產品在體外會抑制肝臟代謝酵素與P-gp的活性，可是在人體內並不會有明顯之抑制效果而產生交互作用。不過仍須注意併用gemfibrozil與紅麴產品會使得lovastatin acid的血中濃度明顯增加。 第三部分: 關節炎對於轉運蛋白與CYP450酵素之表現與對於leflunomide、simvastatin與rosuvastatin藥動性質影響之探討 本篇研究的目的在探討肝臟與小腸上CYP450酵素與轉運蛋白在第二型膠原蛋白誘發的關節炎 (CIA) 大鼠mRNA之表現，以及leflunomide、simvastatin與rosuvastatin在CIA大鼠身上藥物動力學之性質。結果顯示，和健康老鼠相比較，關節炎會降低小腸中的CYP450酵素 (Cyp3a1) 之mRNA表現量。另一方面，關節炎則會降低肝臟中的Cyp酵素 (Cyp1a2、Cyp2c6、Cyp2c7與Cyp3a1) 與轉運蛋白 (Oatp1a1、Oatp1b2、Oatp1a4與Mrp2)，可是卻不影響Cyp2c12酵素與轉運蛋白 (Bcrp與Mdr1a) 的mRNA表現量。在藥物動力學實驗中發現，當關節炎大鼠分別服用leflunomide與simvastatin，所測得leflunomide與simvastatin/simvastatin acid的血中濃度與全身性的暴露量均顯著的高於健康老鼠。可是當關節炎大鼠服用rosuvastatin，所測得rosuvastatin的血中濃度則與健康老鼠無太大差異。另外，在關節炎大鼠服用leflunomide與simvastatin後，血漿中肝臟毒性指標 (天門冬胺酸轉胺酶 (AST)、丙胺酸轉胺酶 (ALT)) 或肌肉毒性指標(肌酸激酶 (CK)) 的濃度均顯著的高於健康老鼠。可是於關節炎大鼠服用rosuvastatin後，這些毒性指標的濃度則與健康老鼠無太大差異。根據這些發現，風溼性關節炎會造成代謝酵素與轉運蛋白的表現量改變，並進而影響leflunomide或是simvastatin之藥動性質及毒性反應。 | zh_TW |
| dc.description.abstract | Part I: CYP2C19 and CYP3A4-mediated drug-drug interaction between PPIs and anticoagulant agents (clopidogrel and prasugrel).
The interaction between proton pump inhibitors (PPIs) and clopidogrel/prasugrel was investigated. The IC50 values of omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on the metabolic ratios of 2-oxo-clopidogrel/clopidogrel, active metabolite of clopidogrel/2-oxo-clopidogrel, and active metabolite of prasugrel/prasugrel thiolactone in human liver microsomes were determined. The antiplatelet aggregation activities of clopidogrel and prasugrel were measured with or without PPIs. As a result, most PPIs (except for pantoprazole) inhibited the formation of 2-oxo-clopidogrel with IC50 values of 22–32 μM and inhibited the formation of active metabolite of clopidogrel with IC50 values of 6–16 μM. PPIs inhibited the formation of active metabolite of prasugrel with IC50 values of 9–25 μM. Among the tested PPIs, omeprazole exhibited the highest inhibitory potency on the formation of active metabolite of clopidogrel. Omeprazole, esomeprazole, and rabeprazole exhibited higher inhibitory potencies on the formation of active metabolite of prasugrel. Omeprazole and lansoprazole show higher inhibitory effects on the activity of antiplatelet aggregation activity of clopidogrel. On the other hand, omeprazole, esomeprazole and rabeprazole significantly decreased the antiplatelet aggregation activity of prasugrel thiolactone. These data indicate that PPIs differ in their effects to inhibit the metabolism and antiplatelet aggregation activities of clopidogrel and prasugrel. Part II: Roles of P-glycoprotein and CYP450 enzymes on the bioavailability of lovastatin in red yeast rice. Red yeast rice (RYR) can reduce cholesterol through its active component, lovastatin. To investigate the pharmacokinetic properties of lovastatin in RYR products and potential RYR-drug interactions, three RYR products (LipoCol Forte, Cholestin, or Xuezhikang) and two lovastatin tablets (Mevacor or Lovasta) were included. The dissolution rate of lovastatin in various dissolution media in the RYR products was faster and higher than that of lovastatin in lovastatin tablets. Powder X-ray diffraction and differential scanning calorimetry patterns showed that the crystallinity of lovastatin was reduced in RYR products. Furthermore, extracts of three RYR products were more effective than pure lovastatin in inhibiting the activities of cytochrome P450 enzymes and P-glycoprotein. Among CYP450 enzymes, RYR showed the highest inhibition on CYP1A2 and CYP2C19, with comparable inhibitory potencies to the corresponding typical inhibitors. In human studies, the AUC and Cmax values for both lovastatin and its active metabolite, lovastatin acid, were significant higher in healthy volunteers receiving LipoCol Forte capsules or powder than in those receiving lovastatin tablets or powder. In addition, shorter and less variable Tmax values were observed in volunteers taking LipoCol Forte than in those taking lovastatin tablets. In volunteers taking the RYR product LipoCol Forte, the pharmacokinetic properties of lovastatin and lovastatin acid were linear in the dose range of 1 to 4 capsules taken as a single dose and no significant accumulation was observed after multiple dosing. For drug-drug interactions, concomitant use of one LipoCol Forte capsule with nifedipine did not change the pharmacokinetics of nifedipine. Yet, concomitant use of gemfibrozil with LipoCol Forte resulted in a significant increase in the plasma concentration of lovastatin acid. These findings suggest that the oral bioavailability of lovastatin is significantly improved in RYR products as a result of a higher dissolution rate and reduced crystallinity. In addition, the use of RYR products may not have effects on the pharmacokinetics of concomitant co-medications despite their effects to inhibit the activities of CYP450 enzymes and P-gp, whereas gemfibrozil affects the pharmacokinetics of lovastatin acid when used concomitantly with RYR products. Part III: The Effect of arthritis on the expression of transporters and CYP450 enzymes and its implication to the pharmacokinetics of leflunomide, simvastatin, and rosuvastatin. The objective of the present study was to investigate the expressions of intestinal and hepatic CYP450 enzymes and transporters and the pharmacokinetic properties of leflunomide, simvastatin and rosuvastatin in collagen-induced arthritis (CIA) rats. Compared with control rats, the mRNA level of CYP450 enzyme (Cyp3a1) was significantly decrease in the intestine of CIA rats. On the other hands, the mRNA levels of CYP450 enzymes (Cyp1a2, Cyp2c6, Cyp2c7 and Cyp3a1) and transporters (Oatp1a1, Oatp1b2, Oatp1a4 and Mrp2) were reduced in the liver of CIA rats, wherase compared to control rats, the expressions of Cyp2c12, Bcrp and Mdr1a did not change in CIA rats. When leflunomide and simvastatin were given orally, the plasma levels and systemic expourses of leflunomide and simvastatin/simvastatin acid were significantly higher in CIA rats than in control rats. Yet, there was no difference in the plasma levels of rosuvastatin between CIA rats and control rats when rosuvastatin was given orally. The plasma levels of markers of hepatoxicities (aspartate aminotransferase; AST and alanine aminotransferase; ALT) and/or myotoxicity (creatine kinase; CK) were significantly higher in CIA rats than in control rats after leflunomide and simvastatin was given. CIA rats change the expression of CYP450 enzymes and transporters, leading to the change in the pharmacokinetics and toxicities of leflunomide or simvastatin. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T05:43:29Z (GMT). No. of bitstreams: 1 ntu-103-D98423001-1.pdf: 4301984 bytes, checksum: b8742f723d01ab4bc811ae9b55534876 (MD5) Previous issue date: 2014 | en |
| dc.description.tableofcontents | 目錄
第一章 序論 1 1.1. 藥物動力學與藥物交互作用 1 1.2. BCS藥物分類系統與藥物吸收相關實驗模式 1 1.3. BDDCS藥物分類系統 3 1.4. 轉運蛋白對於藥物吸收與代謝的影響 5 1.5. 研究藥物代謝之相關實驗模式 6 第二章 研究目的 18 第三章 CYP2C19與CYP3A4在氫離子幫浦抑制劑與抗凝血藥物(clopidogrel與prasugrel)之藥物交互作用上所扮演角色之探討 20 3.1. 文獻回顧 20 3.2. 研究目的 25 3.3. 實驗材料 26 3.3.1. 試劑 26 3.3.2. 溶液配方 28 3.3.3. 材料與設備 28 3.4. 實驗方法 30 3.4.1. 人類肝臟微粒之CYP450酵素活性測定 30 3.4.1.1. CYP450酵素受質之代謝與時間依賴性試驗 30 3.4.1.2. CYP450酵素受質之代謝與濃度依賴性試驗 31 3.4.1.3. CYP450酵素抑制劑抑制50% CYP450酵素活性之濃度測定 31 3.4.2. 氫離子幫浦抑制劑抑制50% CYP450酵素活性之濃度測定 32 3.4.3. 抗凝血藥物 clopidogrel與prasugrel在人類肝臟微粒之代謝轉換測定 33 3.4.3.1. 抗凝血藥物之代謝轉換與時間依賴性試驗 33 3.4.3.2. 抗凝血藥物之代謝轉換與濃度依賴性試驗 35 3.4.4. 氫離子幫浦抑制劑抑制50%抗凝血藥物 clopidogrel與prasugrel代謝轉換之濃度測定 36 3.4.5. 液相層析串聯式質譜儀分析試驗 37 3.4.6. 氫離子幫浦抑制劑抑制抗凝血藥物 clopidogrel與prasugrel之抗血小板凝集之功能測定 38 3.4.7. 數據分析 39 3.5. 實驗結果 41 3.5.1. 人類肝臟微粒之CYP450酵素活性測定 41 3.5.1.1. CYP450酵素受質之代謝與時間依賴性試驗 41 3.5.1.2. CYP450酵素受質之代謝與濃度依賴性試驗 41 3.5.1.3. CYP450酵素抑制劑抑制50% CYP450酵素活性之濃度測定 41 3.5.2. 氫離子幫浦抑制劑抑制50% CYP450酵素活性之濃度測定 42 3.5.3. 抗凝血藥物 clopidogrel與prasugrel在人類肝臟微粒之代謝轉換測定 43 3.5.3.1. 抗凝血藥物之代謝轉換與時間依賴性試驗 43 3.5.3.2. 抗凝血藥物之代謝轉換與濃度依賴性試驗 43 3.5.4. 氫離子幫浦抑制劑抑制50%抗凝血藥物 clopidogrel與prasugrel代謝轉換之濃度測定 43 3.5.5. 氫離子幫浦抑制劑抑制抗凝血藥物clopidogrel與prasugrel之抗血小板凝集之功能測定 44 3.6. 結果討論 56 3.7. 結論 60 第四章P-glycoprotein與CYP450酵素對於紅麴中lovastatin之生體可用率影響之探討 61 4.1. 文獻回顧 61 4.2. 研究目的 64 4.3. 實驗材料 65 4.3.1. 試劑 65 4.3.2. 溶液配方 68 4.3.2. 材料與設備 71 4.4. 實驗方法 74 4.4.1. 紅麴產品中lovastatin之含量測定 74 4.4.2. 紅麴產品中lovastatin與lovastatin錠劑之體外溶離試驗 74 4.4.3. 紅麴產品中lovastatin之物理性質探討 75 4.4.4. 紅麴產品萃取物與肝臟CYP450酵素活性之探討 76 4.4.4.1. CYP450酵素受質之代謝與時間依賴性試驗 76 4.4.4.2. CYP450酵素抑制劑與紅麴萃取物抑制50%CYP450酵素活性之濃度測定 77 4.4.5. 紅麴產品萃取物與P-glycoprotein活性之探討 78 4.4.5.1. MDCK-MDR1細胞株培養 78 4.4.5.2. P-glycoprotein活性之探討 78 4.4.5.3. Lovastatin與紅麴產品萃取物抑制50% P-glycoprotein活性之濃度探討 79 4.4.6. 紅麴產品萃取物之細胞穿透試驗 79 4.4.6.1. Caco-2細胞株培養 79 4.4.6.2. lovastatin與紅麴產品中lovastatin之細胞穿透試驗 80 4.4.7. 紅麴產品之藥物動力學與藥物交互作用之臨床試驗 80 4.4.7.1. 紅麴膠囊與lovastatin錠劑在健康受試者身上之相對生體可用率探討 81 4.4.7.2. 紅麴膠囊之藥物動力學性質探討 83 4.4.7.3. 併用紅麴膠囊在健康受試者身上對於nifedipine在藥動學上影響之探討 84 4.4.7.4. 併用gemfibrozil在健康受試者身上對於紅麴膠囊中lovastatin在藥動學上影響之探討 85 4.4.8. 高效能液相層析試驗 86 4.4.9. 液相層析串聯式質譜儀分析試驗 86 4.4.10. 數據分析 88 4.5. 實驗結果 90 4.5.1. 紅麴產品中lovastatin之含量測定 90 4.5.2. 紅麴產品中lovastatin以及lovastatin標準品與錠劑之體外溶離試驗 90 4.5.3. 紅麴產品中lovastatin之物理性質探討 91 4.5.4. 紅麴產品萃取物與肝臟CYP450酵素活性之探討 92 4.5.4.1. CYP450酵素受質之代謝與時間依賴性試驗 92 4.5.4.2. CYP450酵素抑制劑與紅麴萃取物抑制CYP450酵素50%活性之濃度測定 92 4.5.5. 紅麴產品萃取物與P-glycoprotein活性之探討 93 4.5.6. Lovastatin與紅麴產品中lovastatin之細胞穿透試驗 93 4.5.7. 紅麴產品之藥物動力學與藥物交互作用之臨床試驗 94 4.5.7.1. 紅麴膠囊與lovastatin錠劑在健康受試者身上之相對生體可用率探討 94 4.5.7.2. 紅麴膠囊之藥物動力學性質探討 95 4.5.7.3. 併用紅麴膠囊在健康受試者身上對於nifedipine在藥動學上影響之探討 95 4.5.7.4. 併用gemfibrozil在健康受試者身上對於紅麴膠囊在藥動學上影響之探討 96 4.6. 結果討論 115 4.7. 結論 119 第五章 關節炎對於轉運蛋白與CYP450酵素之表現與對於leflunomide、simvastatin與rosuvastatin藥動性質影響之探討 120 5.1. 文獻回顧 120 5.2. 研究目的 124 5.3. 實驗材料 125 5.3.1. 試劑 125 5.3.2. 溶液配方 126 5.3.3. 材料與設備 127 5.4. 實驗方法 130 5.4.1. 膠原蛋白誘導之關節炎大鼠動物模式建立 130 5.4.2. 血漿中IL-1β、IL-6與TNF-α濃度的測量 130 5.4.3. Leflunomide與statins在CIA與control大鼠身上之藥物動力學與毒性試驗 131 5.4.4. Leflunomide與statins的血漿中濃度測定 131 5.4.5. Leflunomide與statins的毒性測定 132 5.4.6. 反轉錄及定量聚合酶連鎖反應 (Reverse transcription-quantitative polymerase chain reaction, RT-qPCR) 133 5.4.6.1. RNA抽取 133 5.4.6.2. RNA品質控制 133 5.4.6.3. 反轉錄反應 (RT; reverse transcription) 134 5.4.6.4. 定量即時聚合酶鏈鎖反應 134 5.4.7. 數據分析 135 5.5. 實驗結果 136 5.5.1. 評估膠原蛋白誘導之關節炎大鼠模式 136 5.5.2. Control與CIA大鼠在肝臟與小腸之Cyp代謝酵素與轉運蛋白的mRNA表現量 136 5.5.3. Leflunomide在CIA與control大鼠身上之藥物動力學與毒性試驗 137 5.5.4. Simvastatin在CIA與control大鼠身上之藥物動力學與毒性試驗 137 5.5.5. Rosuvastatin在CIA與control大鼠身上之藥物動力學與毒性試驗 138 5.6. 結果討論 144 5.7. 結論 148 第六章 結論與未來研究方向 149 第七章 參考文獻 151 圖目錄 圖1-1 生物藥劑學分類系統 (BCS) 9 圖1-2 生物藥劑學與藥物分佈分類系統 (BDDCS) 與藥物代謝影響之關係圖 9 圖1-3 生物藥劑學與藥物分佈分類系統 (BDDCS) 與轉運蛋白影響之關係圖 10 圖1-4 生物藥劑學與藥物分佈分類系統 (BDDCS) 與食物影響之關係圖 10 圖1-5 腸細胞轉運蛋白分布的示意圖 11 圖1-6 肝細胞進行藥物代謝與排除的示意圖 11 圖1-7 CYP1A2、CYP2B6、CYP2C9、CYP2C19、CYP2D6與CYP3A4酵素受質代謝轉換與抑制劑結構圖 12 圖3-1 Clopidogrel與prasugrel的代謝途徑示意圖 22 圖3-2 氫離子幫浦抑制劑的結構式 23 圖3-3 氫離子幫浦抑制劑的代謝途徑示意圖 24 圖3-4 CYP450酵素受質在人類肝臟微粒體代謝速率與時間之關係圖 45 圖3-5 CYP450酵素受質在人類肝臟微粒體代謝速率與受質濃度之關係圖 46 圖3-6 氫離子幫浦抑制劑抑制CYP450酵素受質在人類肝臟微粒體代謝速率之濃度關係圖 47 圖3-7 抗凝血藥物在人類肝臟微粒體代謝速率與時間之關係圖 48 圖3-8 抗凝血藥物在人類肝臟微粒體代謝轉換與其濃度之關係圖 49 圖3-9 氫離子幫浦抑制劑抑制抗凝血藥物在人類肝臟微粒體代謝轉換之濃度關係圖 50 圖3-10 氫離子幫浦抑制劑抑制抗凝血藥物之抗血小板凝集作用 51 圖4-1 Lovastatin的代謝轉換示意圖 63 圖4-2 紅麴產品中lovastatin以及lovastatin標準品與錠劑之體外溶離試驗結果 98 圖4-3 紅麴產品中lovastatin以及lovastatin錠劑在模擬空腹與餐後狀態腸液中之體外溶離試驗結果 99 圖4-4紅麴產品中lovastatin之物理性質探討 100 圖4-5 CYP代謝酵素受質在人類肝臟微粒體代謝轉換與時間之關係圖 101 圖4-6 各種不同濃度紅麴產品萃取物抑制各種CYP450酵素受質在人類肝臟微粒體代謝轉換之關係圖 102 圖4-7 Lovastatin與紅麴產品萃取物影響P-glycoprotein活性之探討 104 圖4-8 健康受試者單劑量口服Mevacor與LipoCol Forte所測得之lovastatin與lovastatin acid的血漿中濃度圖 105 圖4-9健康受試者單劑量口服Lovasta與LipoCol Forte所測得之lovastatin與lovastatin acid的血漿中濃度圖 107 圖4-10健康受試者單劑量與多劑量口服LipoCol Forte所測得之lovastatin與lovastatin acid的血漿中濃度圖 109 圖4-11健康受試者單劑量口服Adalat以及併服Adalat與LipoCol Forte所測得之nifedipine的血漿中濃度圖 111 圖4-12健康受試者單劑量口服LipoCol Forte以及併服Lopid與LipoCol Forte所測得之lovastatin與lovastatin acid的血漿中濃度圖 113 圖5-1 Leflunomide與其活性代謝物A771726、simvastatin與其活性代謝物simvastatin acid以及rosuvastatin的結構式 123 圖5-2 膠原蛋白誘導之關節炎大鼠動物模式建立 139 圖5-3 Cyp代謝酵素與轉運蛋白在關節炎與健康大鼠之小腸與肝臟之mRNA表現量 140 圖5-4 在關節炎與健康大鼠身上口服leflunomide之藥物動力學與毒性試驗 141 圖5-5 在關節炎與健康大鼠身上口服simvastatin之藥物動力學與毒性試驗 142 圖5-6 在關節炎與健康大鼠身上口服rosuvastatin之藥物動力學與毒性試驗 143 表目錄 表1-1 美國食品與藥物管理局列舉之穿透性試驗指標藥物 13 表1-2 藥物脂溶性與藥物穿透性之關係表 14 表1-3研究藥物代謝之體外模式整理表 15 表1-4 CYP450酵素受質整理表 16 表1-5 CYP450酵素抑制劑整理表 17 表3-1 CYP3A4、CYP2C19及CYP2C6之受質在人類肝臟微粒體代謝轉換之動力學參數 52 表3-2氫離子幫浦抑制劑與抑制50% CYP450酵素活性之濃度比較表 53 表3-3抗凝血藥物在人類肝臟微粒體代謝轉換之動力學參數 54 表3-4氫離子幫浦抑制劑抑制50%抗凝血藥物代謝轉換之濃度比較表 55 表4-1各種不同紅麴產品中lovastatin的含量比較表 97 表4-2各種紅麴產品萃取物、lovastatin標準品與CYP450酵素抑制劑抑制CYP450酵素50%活性之濃度比較表 103 表4-3健康受試者單劑量口服Mevacor與LipoCol Forte所測得之lovastatin與lovastatin acid的藥物動力學參數 106 表4-4健康受試者單劑量口服Lovasta與LipoCol Forte所測得之lovastatin與lovastatin acid的藥物動力學參數 108 表4-5健康受試者單劑量與多劑量口服LipoCol Forte所測得之lovastatin與lovastatin acid的藥物動力學參數 110 表4-6健康受試者單劑量口服Adalat以及併服Adalat與LipoCol Forte所測得之nifedipine的藥物動力學參數 112 表4-7健康受試者單劑量口服LipoCol Forte以及併服Lopid與LipoCol Forte所測得之lovastatin與lovastatin acid的藥物動力學參數 114 表5-1核酸引子序列 129 表5-2 關節炎動物模式以及對於小腸與肝臟中Cyp酵素與轉運蛋白影響之比較表 147 | |
| dc.language.iso | zh-TW | |
| dc.title | 轉運蛋白與CYP450酵素在藥物交互作用上所扮演角色之探討:
第一部分: CYP2C19與CYP3A4在氫離子幫浦抑制劑與抗凝血藥物(clopidogrel與prasugrel)之藥物交互作用上所扮演角色之探討 第二部分: P-glycoprotein與CYP450酵素對於紅麴中lovastatin之生體可用率影響之探討 第三部分: 關節炎對於轉運蛋白與CYP450酵素之表現與對於leflunomide、simvastatin與rosuvastatin藥動性質影響之探討 | zh_TW |
| dc.title | Roles of transporters and CYP450 enzymes on drug interaction:
Part I: CYP2C19 and CYP3A4-mediated drug-drug interaction between PPIs and anticoagulant agents (clopidogrel and prasugrel). Part II: Roles of P-glycoprotein and CYP450 enzymes on the bioavailability of lovastatin in red yeast rice. Part III: The Effect of arthritis on the expression of transporters and CYP450 enzymes and its implication to the pharmacokinetics of leflunomide, simvastatin, and rosuvastatin. | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 102-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 許光陽(Kuang-Yang Hsu),李水盛(Shoei-Sheng Lee),何蘊芳(Yunn-Fang Ho),周辰熹(Chen-Hsi Chou),林雲蓮(Yun-Lian Lin) | |
| dc.subject.keyword | CYP酵素,轉運蛋白,藥物交互作用,紅麴, | zh_TW |
| dc.subject.keyword | CYP450 enzymes,transporters,drug interaction,red yeast rice, | en |
| dc.relation.page | 173 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2014-08-11 | |
| dc.contributor.author-college | 醫學院 | 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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