臺灣博碩士論文加值系統

簡介：
Rivaroxaban為一新型口服抗凝血劑，其藥理作用機轉為直接抑制凝血因子Xa，藉此達到抑制凝血、避免靜脈栓塞之功效。Rivaroxaban約有三分之二是藉由代謝排除，而CYP3A為其主要的代謝酵素，因此會誘導或抑制CYP3A的藥物皆有可能影響rivaroxaban的清除。有鑒於CYP3A參與了許多藥品的代謝且酵素本身在個體間變異性大，因此以CYP3A探針來評估不同個體內代謝酵素的活性具有其臨床的重要意義。Mosapride為選擇性5-HT4受體致效劑，為新ㄧ代的胃腸蠕動促進劑，主要經由CYP3A所代謝。先前的相關研究中發現，在大白鼠動物模式以靜脈注射及口服給予mosapride，分別可觀察到肝臟及腸道中CYP3A酵素含量和清除率成高度相關性，反應出mosapride可作為一CYP3A體內探針性試藥的可行性。
研究目的：
本研究主要目的是利用大白鼠動物模式，以mosapride當作CYP3A活性探針來實際應用於rivaroxaban清除率的評估，以強化mosapride作為CYP3A活性探針的應用性。而為了研究rivaroxaban在大白鼠體內的藥品動態，本研究也將開發一個能夠從生物檢品中準確定量rivaroxaban的分析方法，來定量血漿檢品中的rivaroxaban以進行其藥動參數的評估。
研究方法：
先以靜脈注射給予不同劑量的rivaroxaban，以觀察其在大白鼠的線性藥品動態學。在探討應用mosapride預測rivaroxaban動力學的實驗中，大白鼠控制組不加處置，或事先以誘導劑dexamethasone、抑制劑ketoconazole或者進行體內賀爾蒙的調節，來使CYP3A的含量及活性有所改變，再同時由靜脈給予mosapride和rivaroxaban，以研究mosapride在此些條件下對於rivaroxaban清除率評估的應用性。動物實驗的血液檢體採樣收集至480分鐘，以二室模式估算其藥動參數。
研究結果：
本實驗已成功開發一個靈敏的高效液相層析分析方法，並應用在定量小體積大鼠血漿中的rivaroxaban。Rivaroxaban在給藥劑量下呈線性動力學。給予CYP3A誘導劑dexamethasone後，rivaroxaban在大鼠體內之清除率增加，然而公鼠mosapride之清除率則與控制組並無顯著差異。當給予CYP3A抑制劑ketoconazole後，rivaroxaban及mosapride在大鼠體內之清除率皆顯著減低。在去勢後的公鼠體內rivaroxaban和mosapride血中濃度明顯上升。母鼠投予testosterone後，其mosapride血中濃度有明顯下降。而本實驗也證實了透過有限採樣法，mosapride的單點血中濃度能夠有效地評估其本身的清除率以及rivaroxaban清除率，進一步確認了mosapride在大白鼠體內作為肝臟CYP3A活性探針的可行性。
研究結論：
以靜脈注射投與mosapride後，只需要利用單點、少量的血液檢品就可對mosapride的清除率有準確的預測，並進一步利用於rivaroxaban清除率的預測。以上結果證實了mosapride能有效地作為體內CYP3A活性探針性試藥，而這也提供了未來在CYP3A相關藥物交互作用研究，或者在個體間CYP3A活性差異研究中，一個更方便並節省時間的評估方式。

Introduction
Rivaroxaban, an oral, direct, specific inhibitor of factor Xa, is indicated for the prophylaxis of deep vein thrombosis. About two-thirds of the administered dose of rivaroxaban undergoes metabolic degradation. CYP3A isozymes, one of the most important and abundant CYP450 subfamilies in the liver, are the major enzymes that responsible for the metabolism of rivaroxaban, thus drugs that induce or inhibit the CYP3A would change the clearance of rivaroxaban. The use of selected drugs as in vivio CYP3A probes in drug therapy is of great importance. Mosapride, a new prokinetic agent, is metabolism mainly by CYP3A enzymes. Previous studies have demonstrated that mosapride correlated well with hepatic and intestinal CYP3A contents and reflected the in vivo CYP3A activity. Therefore mosapride could be a potential in vivo CYP3A probe.
Purpose
The objectives of this study were to use the in vivo CYP3A probe - mospride for measuring hepatic CYP3A activity and evaluating the rivaroxaban clearance in rats to support the application of mosapride. A new HPLC method for determination of rivaroxaban in rat plasma was also developed and applied to explore its kinetics.
Methods
Rats received different dose of rivaroxaban intravenously in the dose-linearity experiment. To investigate the applicability of mosapride as a CYP3A probe, each rat was first introduced mosapride intravenously followed by the administration of rivaroxaban in the control groups. CYP3A activities of rats were modulated by the pretreatment with dexamethasone (induction), ketoconazole (inhibition) or through hormone regulation. The plasma concentrations of mosapride and rivaroxaban were followed for 480 min, and the kinetics parameters were estimated by two-compartmental analysis.
Results
A sensitive HPLC assay was developed and applied to quantify rivaroxaban in small volume of rat plasma. Rivaroxaban displayed linear kinetics in the dose range studied. Induction with dexamethasone significantly altered the clearance of rivaroxaban, whereas that of mosapride remained unchanged in male rats. In the presence of ketoconazole, clearance of rivaroxaban and mosapride decreased significantly. The plasma concentration of rivaroxaban and mosapride in male rats increased dramatically after surgical castration. The supplemental testosterone significantly decreased the systemic exposure of mosapride in female rats. Clearance of mosapride and rivaroxaban can be well predicted by using a single point (90 min) of plasma concentration of mosapride.
Conclusion
The pharmacokinetics of rivaroxaban in rats following intravenous administration was linear. Clearance of rivaroxaban could be well evaluated by single time point of plasma concentration of mosapride. These results provide more evidences on the applicability of mosapride as an in vivo hepatic CYP3A probe, and it provided a useful, simple and time-saved method to assess the CYP3A activity and CYP3A related drug interactions in drug development and in clinical application.

摘要 I
Abstract III
誌謝 V
目錄 VII
表目錄 X
圖目錄 XI
第壹章 緒論 1
第一節 肝臟細胞色素(Cytochrome P450) 2
一、 命名方式 2
二、 分布及特性 3
三、 不同物種間CYP450差異 5
第二節 代謝酵素CYP3A 7
一、 種類 7
二、 CYP3A的種族以及性別差異 8
三、 CYP3A酵素的調控 10
第三節 體內CYP3A探針性試藥 11
一、 CYP3A探針性試藥定義 12
二、 理想探針性試藥條件 12
三、 現行已知的CYP3A體內探針性試藥介紹 13
第四節 Mosapride簡介 16
一、 物化性質 16
二、 作用機轉 17
三、 藥動特性 17
四、 藥物交互作用 23
五、 Mosapride作為探針性試藥的相關研究 23
第五節 Rivaroxaban 簡介 26
一、 物化性質 26
二、 作用機轉 26
三、 藥動特性 27
四、 藥物交互作用 33
五、 分析方法整理 34
第貳章 研究目的 35
第一節 Rivaroxaban定量分析方法之開發 35
第二節 Rivaroxaban在大白鼠體內之藥動學研究 36
第三節 CYP3A活性探針 – mosapride於rivaroxaban藥動學之應用 36
第參章 實驗材料、儀器與方法 37
第一節 實驗材料 37
一、 實驗動物 37
二、 藥品與試劑 37
第二節 實驗儀器 38
一、 紫外光/可見光分光光度計 38
二、 高效液相層析系統 38
三、 動物實驗手術及檢品處理 39
四、 繪圖及藥動分析軟體 40
第三節 實驗方法 41
一、 Rivaroxaban 紫外光全光譜 41
二、 藥品配製與定量分析 41
三、 大白鼠靜脈注射給藥實驗 44
四、 實驗設計 47
五、 數據解析 50
第肆章 實驗結果 52
第一節 Rivaroxaban定量分析方法之開發 52
一、 分析條件開發 52
二、 校正曲線 56
三、 確效評估 58
第二節 Rivaroxaban在大白鼠體內之藥動學研究 60
一、 靜脈注射rivaroxaban之劑量依存性 60
二、 Mosapride與rivaroxaban之藥品動態研究 64
第三節 CYP3A活性探針 – mosapride於rivaroxaban藥物動力學之應用 82
一、 Mosapride單點血中濃度與mosapride AUC之相關性 82
二、 Mosapride單點血中濃度與mosapride清除率之相關性 84
三、 Mosapride清除率與rivaroxaban清除率之相關性 86
四、 Mosapride單點血中濃度與rivaroxaban清除率之相關性 88
第伍章 討論 90
第一節 Rivaroxaban定量分析方法之開發 90
第二節 Rivaroxaban在大白鼠體內之藥動學研究 90
一、 靜脈注射rivaroxaban之劑量依存性 90
二、 Mosapride與rivaroxaban之藥品動態研究 91
第三節 CYP3A活性探針 – mosapride於rivaroxaban藥物動力學之應用 93
一、 Mosapride單點血中濃度與mosapride AUC之相關性 93
二、 Mosapride單點血中濃度與mosapride清除率之相關性 93
三、 Mosapride清除率與rivaroxaban清除率之相關性 94
四、 Mosapride單點血中濃度與rivaroxaban清除率之相關性 94
第陸章 結論 95
參考文獻 96

Agrawal, A. K. and B. H. Shapiro (2003). Constitutive and inducible hepatic cytochrome P450 isoforms in senescent male and female rats and response to low-dose phenobarbital. Drug Metab Dispos 31(5): 612-619.

Anzenbacher, P. and E. Anzenbacherova (2001). Cytochromes P450 and metabolism of xenobiotics. Cell Mol Life Sci 58(5-6): 737-747.

Aoyama, T., S. Yamano, D. J. Waxman, D. P. Lapenson, U. A. Meyer, V. Fischer, R. Tyndale, T. Inaba, W. Kalow, H. V. Gelboin and et al. (1989). Cytochrome P-450 hPCN3, a novel cytochrome P-450 IIIA gene product that is differentially expressed in adult human liver. cDNA and deduced amino acid sequence and distinct specificities of cDNA-expressed hPCN1 and hPCN3 for the metabolism of steroid hormones and cyclosporine. J Biol Chem 264(18): 10388-10395.

Bjornsson, T. D., J. T. Callaghan, H. J. Einolf, V. Fischer, L. Gan, S. Grimm, J. Kao, S. P. King, G. Miwa, L. Ni, G. Kumar, J. McLeod, R. S. Obach, S. Roberts, A. Roe, A. Shah, F. Snikeris, J. T. Sullivan, D. Tweedie, J. M. Vega, J. Walsh and S. A. Wrighton (2003). The conduct of in vitro and in vivo drug-drug interaction studies: a Pharmaceutical Research and Manufacturers of America (PhRMA) perspective. Drug Metab Dispos 31(7): 815-832.

Boxenbaum, H. (1980). Interspecies variation in liver weight, hepatic blood flow, and antipyrine intrinsic clearance: extrapolation of data to benzodiazepines and phenytoin. J Pharmacokinet Biopharm 8(2): 165-176.

Dresser, G. K., J. D. Spence and D. G. Bailey (2000). Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet 38(1): 41-57.

Dubreuil, P., G. Pelletier, Y. Couture, H. Lapierre, D. Petitclerc, J. Morisset, P. Gaudreau and P. Brazeau (1989). Castration and testosterone effects on endogenous and somatocrinin-induced growth hormone release in intact and castrated male pigs. Domest Anim Endocrinol 6(1): 15-24.
Fuhr, U., A. Jetter and J. Kirchheiner (2007). Appropriate phenotyping procedures for drug metabolizing enzymes and transporters in humans and their simultaneous use in the cocktail approach. Clin Pharmacol Ther 81(2): 270-283.

Gandhi, M., F. Aweeka, R. M. Greenblatt and T. F. Blaschke (2004). Sex differences in pharmacokinetics and pharmacodynamics. Annu Rev Pharmacol Toxicol 44: 499-523.

Gervot, L., V. Carriere, P. Costet, P. H. Cugnenc, A. Berger, P. H. Beaune and I. de Waziers (1996). CYP3A5 is the major cytochrome P450 3A expressed in human colon and colonic cell lines. Environ Toxicol Pharmacol 2(4): 381-388.

Gnoth, M. J., U. Buetehorn, U. Muenster, T. Schwarz and S. Sandmann (2011). In vitro and in vivo P-glycoprotein transport characteristics of rivaroxaban. J Pharmacol Exp Ther 338(1): 372-380.

Guengerich, F. P. (2006). Cytochrome P450s and other enzymes in drug metabolism and toxicity. AAPS J 8(1): E101-111.

Guengerich, F. P. (2008). Cytochrome p450 and chemical toxicology. Chem Res Toxicol 21(1): 70-83.

He, P., M. H. Court, D. J. Greenblatt and L. L. von Moltke (2006). Factors influencing midazolam hydroxylation activity in human liver microsomes. Drug Metab Dispos 34(7): 1198-1207.

Ingelman-Sundberg, M. (2005). The human genome project and novel aspects of cytochrome P450 research. Toxicol Appl Pharmacol 207(2 Suppl): 52-56.

Kato, R. and K. Onoda (1970). Studies on the regulation of the activity of drug oxidation in rat liver microsomes by androgen and estrogen. Biochem Pharmacol 19(5): 1649-1660.

Katoh, T., H. Saitoh, N. Ohno, M. Tateno, T. Nakamura, I. Dendo, S. Kobayashi and K. Nagasawa (2003). Drug interaction between mosapride and erythromycin without electrocardiographic changes. Jpn Heart J 44(2): 225-234.

Kharasch, E. D., K. E. Thummel and P. B. Watkins (2005). CYP3A probes can quantitatively predict the in vivo kinetics of other CYP3A substrates and can accurately assess CYP3A induction and inhibition. Mol Interv 5(3): 151-153.

Kharasch, E. D., A. Walker, C. Hoffer and P. Sheffels (2004). Intravenous and oral alfentanil as in vivo probes for hepatic and first-pass cytochrome P450 3A activity: noninvasive assessment by use of pupillary miosis. Clin Pharmacol Ther 76(5): 452-466.

Kim, R. B., C. Wandel, B. Leake, M. Cvetkovic, M. F. Fromm, P. J. Dempsey, M. M. Roden, F. Belas, A. K. Chaudhary, D. M. Roden, A. J. Wood and G. R. Wilkinson (1999). Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein. Pharm Res 16(3): 408-414.

Kitada, M., T. Kamataki, K. Itahashi, T. Rikihisa, R. Kato and Y. Kanakubo (1985). Purification and properties of cytochrome P-450 from homogenates of human fetal livers. Arch Biochem Biophys 241(1): 275-280.

Klees, T. M., P. Sheffels, O. Dale and E. D. Kharasch (2005). Metabolism of alfentanil by cytochrome p4503a (cyp3a) enzymes. Drug Metab Dispos 33(3): 303-311.

Klees, T. M., P. Sheffels, K. E. Thummel and E. D. Kharasch (2005). Pharmacogenetic determinants of human liver microsomal alfentanil metabolism and the role of cytochrome P450 3A5. Anesthesiology 102(3): 550-556.

Kolars, J. C., K. S. Lown, P. Schmiedlin-Ren, M. Ghosh, C. Fang, S. A. Wrighton, R. M. Merion and P. B. Watkins (1994). CYP3A gene expression in human gut epithelium. Pharmacogenetics 4(5): 247-259.

Kramer, R. E., J. W. Greiner, R. C. Rumbaugh, T. D. Sweeney and H. D. Colby (1978). Relation of the gonadal hormones to growth hormone actions on hepatic drug metabolism in rats. J Pharmacol Exp Ther 204(2): 247-254.
Kreutz, R. (2012). Pharmacodynamic and pharmacokinetic basics of rivaroxaban. Fundam Clin Pharmacol 26(1): 27-32.

Kubitza, D., M. Becka, B. Voith, M. Zuehlsdorf and G. Wensing (2005). Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther 78(4): 412-421.

Kubitza, D., M. Becka, M. Zuehlsdorf and W. Mueck (2006). Effect of food, an antacid, and the H2 antagonist ranitidine on the absorption of BAY 59-7939 (rivaroxaban), an oral, direct factor Xa inhibitor, in healthy subjects. J Clin Pharmacol 46(5): 549-558.

Kubitza, D., M. Becka, M. Zuehlsdorf and W. Mueck (2007). Body weight has limited influence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY 59-7939) in healthy subjects. J Clin Pharmacol 47(2): 218-226.

Lacroix, D., M. Sonnier, A. Moncion, G. Cheron and T. Cresteil (1997). Expression of CYP3A in the human liver--evidence that the shift between CYP3A7 and CYP3A4 occurs immediately after birth. Eur J Biochem 247(2): 625-634.

Lang, D., C. Freudenberger and C. Weinz (2009). In vitro metabolism of rivaroxaban, an oral, direct factor Xa inhibitor, in liver microsomes and hepatocytes of rats, dogs, and humans. Drug Metab Dispos 37(5): 1046-1055.

LeCluyse, E. L. (2001). Pregnane X receptor: molecular basis for species differences in CYP3A induction by xenobiotics. Chem Biol Interact 134(3): 283-289.

Lowry, J. A., G. L. Kearns, S. M. Abdel-Rahman, A. N. Nafziger, I. S. Khan, A. D. Kashuba, E. G. Schuetz, J. S. Bertino, Jr., J. N. van den Anker and J. S. Leeder (2003). Cisapride: a potential model substrate to assess cytochrome P4503A4 activity in vivo. Clin Pharmacol Ther 73(3): 209-222.

Martignoni, M., G. M. Groothuis and R. de Kanter (2006). Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opin Drug Metab Toxicol 2(6): 875-894.

Matsumoto, S., K. Yoshida, A. Itogawa, M. Tagawa, T. Fujii, H. Miyazaki and Y. Sekine (1993). Metabolism of [carbonyl-14C]mosapride citrate after a single oral administration in rats, dogs and monkeys. Arzneimittelforschung 43(10): 1095-1102.

McGraw, J. and D. Waller (2012). Cytochrome P450 variations in different ethnic populations. Expert Opin Drug Metab Toxicol 8(3): 371-382.

Mode, A., P. Tollet, A. Strom, C. Legraverend, C. Liddle and J. A. Gustafsson (1992). Growth hormone regulation of hepatic cytochrome P450 expression in the rat. Adv Enzyme Regul 32: 255-263.

Mueck, W., D. Kubitza and M. Becka (2013). Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol.

Mushiroda, T., R. Douya, E. Takahara and O. Nagata (2000). The involvement of flavin-containing monooxygenase but not CYP3A4 in metabolism of itopride hydrochloride, a gastroprokinetic agent: comparison with cisapride and mosapride citrate. Drug Metab Dispos 28(10): 1231-1237.

Nakata, K., Y. Tanaka, T. Nakano, T. Adachi, H. Tanaka, T. Kaminuma and T. Ishikawa (2006). Nuclear receptor-mediated transcriptional regulation in Phase I, II, and III xenobiotic metabolizing systems. Drug Metab Pharmacokinet 21(6): 437-457.

Nebert, D. W. and D. W. Russell (2002). Clinical importance of the cytochromes P450. Lancet 360(9340): 1155-1162.

Nelson, D. R. (2006). Cytochrome P450 nomenclature, 2004. Methods Mol Biol 320: 1-10.

Nelson, D. R., D. C. Zeldin, S. M. Hoffman, L. J. Maltais, H. M. Wain and D. W. Nebert (2004). Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants. Pharmacogenetics 14(1): 1-18.

Pampori, N. A. and B. H. Shapiro (1999). Gender differences in the responsiveness of the sex-dependent isoforms of hepatic P450 to the feminine plasma growth hormone profile. Endocrinology 140(3): 1245-1254.

Pinto, N. and M. E. Dolan (2011). Clinically relevant genetic variations in drug metabolizing enzymes. Curr Drug Metab 12(5): 487-497.

Robertson, G. R., G. C. Farrell and C. Liddle (1998). Sexually dimorphic expression of rat CYP3A9 and CYP3A18 genes is regulated by growth hormone. Biochem Biophys Res Commun 242(1): 57-60.

Sakashita, M., Y. Mizuki, T. Hashizume, T. Yamaguchi, H. Miyazaki and Y. Sekine (1993). Pharmacokinetics of the gastrokinetic agent mosapride citrate after intravenous and oral administrations in rats. Arzneimittelforschung 43(8): 859-863.

Sakashita, M., T. Yamaguchi, H. Miyazaki, Y. Sekine, T. Nomiyama, S. Tanaka, T. Miwa and S. Harasawa (1993). Pharmacokinetics of the gastrokinetic agent mosapride citrate after single and multiple oral administrations in healthy subjects. Arzneimittelforschung 43(8): 867-872.

Salphati, L. and L. Z. Benet (1998). Modulation of P-glycoprotein expression by cytochrome P450 3A inducers in male and female rat livers. Biochem Pharmacol 55(4): 387-395.

Samama, M. M., G. Contant, T. E. Spiro, E. Perzborn, C. Guinet, Y. Gourmelin, L. Le Flem, G. Rohde and J. L. Martinoli (2012). Evaluation of the anti-factor Xa chromogenic assay for the measurement of rivaroxaban plasma concentrations using calibrators and controls. Thromb Haemost 107(2): 379-387.

Schuetz, E. G., J. D. Schuetz, S. C. Strom, M. T. Thompson, R. A. Fisher, D. T. Molowa, D. Li and P. S. Guzelian (1993). Regulation of human liver cytochromes P-450 in family 3A in primary and continuous culture of human hepatocytes. Hepatology 18(5): 1254-1262.

Schuetz, J. D., D. L. Beach and P. S. Guzelian (1994). Selective expression of cytochrome P450 CYP3A mRNAs in embryonic and adult human liver. Pharmacogenetics 4(1): 11-20.

Streetman, D. S., J. S. Bertino, Jr. and A. N. Nafziger (2000). Phenotyping of drug-metabolizing enzymes in adults: a review of in-vivo cytochrome P450 phenotyping probes. Pharmacogenetics 10(3): 187-216.

Sun, X., L. Niu, X. Li, X. Lu and F. Li (2009). Characterization of metabolic profile of mosapride citrate in rat and identification of two new metabolites: Mosapride N-oxide and morpholine ring-opened mosapride by UPLC-ESI-MS/MS. J Pharm Biomed Anal 50(1): 27-34.

Takano, M., R. Hasegawa, T. Fukuda, R. Yumoto, J. Nagai and T. Murakami (1998). Interaction with P-glycoprotein and transport of erythromycin, midazolam and ketoconazole in Caco-2 cells. Eur J Pharmacol 358(3): 289-294.

Tang, C. and T. Prueksaritanont (2010). Use of in vivo animal models to assess pharmacokinetic drug-drug interactions. Pharm Res 27(9): 1772-1787.

Tannenbaum, G. S., H. K. Choi, W. Gurd and D. J. Waxman (2001). Temporal relationship between the sexually dimorphic spontaneous GH secretory profiles and hepatic STAT5 activity. Endocrinology 142(11): 4599-4606.

Thangavel, C., E. Boopathi and B. H. Shapiro (2011). Intrinsic sexually dimorphic expression of the principal human CYP3A4 correlated with suboptimal activation of GH/glucocorticoid-dependent transcriptional pathways in men. Endocrinology 152(12): 4813-4824.

Thummel, K. E., D. D. Shen, T. D. Podoll, K. L. Kunze, W. F. Trager, P. S. Hartwell, V. A. Raisys, C. L. Marsh, J. P. McVicar, D. M. Barr and et al. (1994). Use of midazolam as a human cytochrome P450 3A probe: I. In vitro-in vivo correlations in liver transplant patients. J Pharmacol Exp Ther 271(1): 549-556.
Watkins, P. B. (1994). Noninvasive tests of CYP3A enzymes. Pharmacogenetics 4(4): 171-184.

Waxman, D. J. and M. G. Holloway (2009). Sex differences in the expression of hepatic drug metabolizing enzymes. Mol Pharmacol 76(2): 215-228.

Waxman, D. J., N. A. Pampori, P. A. Ram, A. K. Agrawal and B. H. Shapiro (1991). Interpulse interval in circulating growth hormone patterns regulates sexually dimorphic expression of hepatic cytochrome P450. Proc Natl Acad Sci U S A 88(15): 6868-6872.

Weinz, C., U. Buetehorn, H. P. Daehler, C. Kohlsdorfer, U. Pleiss, S. Sandmann, K. H. Schlemmer, T. Schwarz and W. Steinke (2005). Pharmacokinetics of BAY 59-7939--an oral, direct Factor Xa inhibitor--in rats and dogs. Xenobiotica 35(9): 891-910.

Weinz, C., T. Schwarz, D. Kubitza, W. Mueck and D. Lang (2009). Metabolism and excretion of rivaroxaban, an oral, direct factor Xa inhibitor, in rats, dogs, and humans. Drug Metab Dispos 37(5): 1056-1064.

Westlind, A., L. Lofberg, N. Tindberg, T. B. Andersson and M. Ingelman-Sundberg (1999). Interindividual differences in hepatic expression of CYP3A4: relationship to genetic polymorphism in the 5'-upstream regulatory region. Biochem Biophys Res Commun 259(1): 201-205.

Wiwi, C. A. and D. J. Waxman (2004). Role of hepatocyte nuclear factors in growth hormone-regulated, sexually dimorphic expression of liver cytochromes P450. Growth Factors 22(2): 79-88.

Wolbold, R., K. Klein, O. Burk, A. K. Nussler, P. Neuhaus, M. Eichelbaum, M. Schwab and U. M. Zanger (2003). Sex is a major determinant of CYP3A4 expression in human liver. Hepatology 38(4): 978-988.

Yamaori, S., H. Yamazaki, S. Iwano, K. Kiyotani, K. Matsumura, G. Honda, K. Nakagawa, T. Ishizaki and T. Kamataki (2004). CYP3A5 Contributes significantly to CYP3A-mediated drug oxidations in liver microsomes from Japanese subjects. Drug Metab Pharmacokinet 19(2): 120-129.
Yamazoe, Y., N. Murayama, M. Shimada, K. Yamauchi, K. Nagata, S. Imaoka, Y. Funae and R. Kato (1988). A sex-specific form of cytochrome P-450 catalyzing propoxycoumarin O-depropylation and its identity with testosterone 6 beta-hydroxylase in untreated rat livers: reconstitution of the activity with microsomal lipids. J Biochem 104(5): 785-790.

Yuan, R., S. Madani, X. X. Wei, K. Reynolds and S. M. Huang (2002). Evaluation of cytochrome P450 probe substrates commonly used by the pharmaceutical industry to study in vitro drug interactions. Drug Metab Dispos 30(12): 1311-1319.

Zhang, H., D. Zhang, W. Li, M. Yao, C. D'Arienzo, Y. X. Li, W. R. Ewing, Z. Gu, Y. Zhu, N. Murugesan, W. C. Shyu and W. G. Humphreys (2007). Reduction of site-specific CYP3A-mediated metabolism for dual angiotensin and endothelin receptor antagonists in various in vitro systems and in cynomolgus monkeys. Drug Metab Dispos 35(5): 795-805.

Zhou, S. F., J. P. Liu and B. Chowbay (2009). Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab Rev 41(2): 89-295.

Zuber, R., E. Anzenbacherova and P. Anzenbacher (2002). Cytochromes P450 and experimental models of drug metabolism. J Cell Mol Med 6(2): 189-198.

官玫仙 (2007). Cisapride作為大白鼠體內CYP3A活性探針性試藥之可行性. 國立成功大學.

張雅雯 (2008). Mosapride作為大白鼠體內CYP3A活性探針性試藥之可行性. 國立成功大學.

魏敬云 (2009). 有限採樣法預測 CYP3A 探針藥物mosapride 在大鼠體內之濃度曲線下面積. 國立成功大學.

陳慧瑾 (2012). 探討testosterone調控細胞色素3A1和3A2表現量之機制 國立成功大學.