開發Mosapride 為大屬細胞色素3A活性探針試藥之研究---以母鼠為動物模式應用於細胞色素3A酵素誘發作用之藥品交互作用預測性評估

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Title:	開發Mosapride 為大屬細胞色素3A活性探針試藥之研究---以母鼠為動物模式應用於細胞色素3A酵素誘發作用之藥品交互作用預測性評估 Investigation Mosapride as a CYP3A Probe---Using Female Rats as an Enzyme Inductive Evaluation Model to Predict CYP3A Related Drug-Drug Interactions
Authors:	鄭靜玲
Contributors:	嘉南藥理科技大學藥學系
Keywords:	莫沙普萊得細胞色素 3A 探針試藥藥品交互作用母鼠 mosapride CYP3A probe drug-drug interaction female rat
Date:	2012
Issue Date:	2014-10-20 21:48:35 (UTC+8)
Abstract:	本實驗室在執行完畢的NSC 97-2320-B-041 -001 -MY3國科會補助之研究計畫時，初步發現開發之大鼠CYP3A 探針試藥－mosapride，確如預期可依限量採點法(1-4 點血中濃度)，即可準確推估肝臟與口服清除率。利用 Well-stirred model 也證明CYP3A2 總含量的倒數與清除率倒數具高度相關性。唯過去之經驗發現應用大鼠(公鼠)為動物模式之前提下，給與誘導劑之後雖然能成功誘導體內CYP 之顯著生成，但後續的動力學參數卻無法呈現有效的統計差異。由藥動參數及公鼠之生理參數推論此現象可能是因本藥為高抽提率藥品所致。理論上來說，此現象在母鼠身上則因藥動參數不相同可能會不同。另外尚待解決問題為降低血漿樣本採樣方法的困難及提升樣本運送之便利。為進一步了解本探針試藥在母鼠的藥動及推廣本探針試藥在CYP3A 酵素誘導情況下之應用，並進一步評估其用於其他探針試藥的清除率預測及CYP3A 相關藥品交互作用的預測應用，本年度提出以母鼠作為動物測試模式之三年期計畫: 開發Mosapride 為大鼠細胞色素3A 活性探針試藥之研究:以母鼠為動物模式應用於細胞色素3A 酵素誘發作用之預測性評估。此三年期計劃各分年的目標如下：第一年：為方便開發方法之商業化與樣本運輸之方便性本次計畫將開發乾式全血點樣本大鼠血漿藥品濃度的確效方法。也將做新開發法與原方法之結果比對，確保過去結果單點法預測之適用度確效。第二年: 以靜脈注射方法給大鼠3 種不同劑量。又因CYP3A 表現量有性別差異，主要以母鼠研究對象，輔以公鼠劑量為控制對照組。再藉由血中濃度之藥動學解析，欲達成單點法(或二點法)的開發。為增大體內細胞色素3A 含量變化的範圍也需加入誘發劑 (預定母鼠三組+公鼠一組為對照)，並利用western blot 技術來測量肝臟中細胞色素CYP3A(1/2 & 9)的表現量，進而評估二者之關係。另外也需確定口服劑量範圍，達成下年度的預試驗。第三年: 與第二年方法類似，但欲改以口服方式給藥，評估是否亦能預測肝臟、腸道CYP3A 的表現量。我們相信合併 NSC 97-2320-B-041 -001 -MY3；NSC 100-2320-B-041 -001 驗證本探針試藥由體外到體內的預測性；及本次提出計畫之拓寬本探針試藥之應用範圍由細胞色素抑制性交互作用到誘導情況下的交互作用的研究成果，應能開發出具有商品價值之探針試藥並有助於細胞色素 3A 相關藥品交互作用評估，對藥品研發，臨床使用，藥政管理，及中草藥製劑開發及健康食品的使用等，都將能有所助益。 It has been shown that one to four time points of plasma concentrations following intravenous and oral administration of mosapride can precisely predict its AUC and hence clearance in rats in my current NSC grant (NSC97-2320-B-041 -001 -MY3). In addition, based on the well-stirred model, the reciprocal of hepatic CYP3A2 contents showed strongly correlation with reciprocal of mosapride clearance. Therefore, mosapride clearance can be used to reflect the in vivo CYP3A activity. A simple and convenient hepatic CYP3A probe was developed. On the other hand, the previous data showed that even though we successfully induced CYP3A enzyme level (based on western blot results), the corresponding mosapride PK parameters did not show statistically relevance to this change. This phenomenon could be resulted by using female rats as they should existing lower CYP3A2 levels and making mosapride possibly from high extraction drug in male rats to medium extraction drug in female rats. In addition to make this method easily to use, a more conveniently sampling and shipping method for analytical assay should be developed. We propose this three-year proposal to fulfill the following objectives. First, a dried blood spot (DBS) analytical assay will be developed, validated and correlated to the original assay method in the first year. Second, using female SD rats as an enzyme inductive animal model will be evaluated and validated for its usefulness in CYP3A-related drug-drug interactions after intravenous injection (second year) and oral administration (third year). Results from these studies will provide more inside mechanisms and will find the key to successful apply this newly developed CYP3A probe for related drug-drug, drug-herb, and drug-food interactions in drug development, clinical application, and drug regulatory
Relation:	計畫編號：NSC101-2320-B041-002 計畫年度：101；起迄日期：2012-08-01~2013-07-31
Appears in Collections:	[Dept. of Pharmacy] MOST Project

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