用新開發之大鼠細胞色素3A活性探針試藥－Mosapride於相關藥品肝臟抑制作用之預測性評估:體外體內外推定量評估

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Title:	用新開發之大鼠細胞色素3A活性探針試藥－Mosapride於相關藥品肝臟抑制作用之預測性評估:體外體內外推定量評估 Using a Novel Hepatic Cyp3a Probe－Mosapride to Evaluate the Predictivity of Cyp3a Inhibition on Drug-Drug Interactions: in Vitro-In Vivo Extrapolation
Authors:	鄭靜玲
Contributors:	藥學系
Keywords:	mosapride CYP3A probe drug-drug interaction rat in vitro – in vivo extrapolation (IVIVE)
Date:	2011
Issue Date:	2012-01-03 13:57:27 (UTC+8)
Abstract:	本實驗室正在執行的國科會計畫結果顯示：莫沙普萊得於靜脈注射給藥於大鼠後，利用well-stirred model 證明CYP3A2 含量與清除率具高度相關性，體外試驗結果也顯示CYP3A2 為體內肝臟代謝的主要酵素，因此莫沙普萊得清除率可用來反應細胞色素3A 之體內活性。另外，本實驗室也成功開發有限採樣法，可有效利用少數血液樣本即可成功估算本藥之AUC (or CL)。可謂已開發出可反應大鼠體內肝臟細胞色素3A 活性之簡便易得及易分析的探針試藥。然細胞色素 3A 體內活性是否可利用其他探針預測，向來為爭辯話題，為進一步瞭解本探針試藥應用於其他探針試藥的清除率預測及細胞色素3A 相關藥品交互作用的預測應用，仍待進一步的探討。本三年期計畫，將進一步利用大鼠肝臟微粒體以其他體外CYP3A 探針（如midazolam）標定莫沙普來得之抑制酵素動力學，瞭解其酵素抑制機轉(reversible vs. time-dependent inactivation)，以進一步確立本藥對其他受質的影響。另外也將選用至少四種不同強弱之抑制劑 (分屬可逆reversible 及time-dependent inactivation inhibitors) 在大鼠體外的微粒體來得到體外抑制的基本參數，並利用近來研發的IVIVE 公式，來作體內抑制程度的預測。為確效應用此探針試藥預測此一作用的可行性，體內控制組與加各抑制劑後的mosapride 體內藥物動態也需進行評估。此計畫之研究成果，將有助於細胞色素 3A 相關藥品交互作用評估，對藥品研發，臨床使用，藥政管理等，都將能有所助益。 It has been shown that one to three time points of plasma concentrations following intravenous 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 been developed. In reality, whether in vivo CYP3A activity can be predicted by another CYP3A probes is still under debate. In order to explore the application of this developed in vivo CYP3A probe, we believe it is worthwhile to further evaluate the predictivity of mosapride on clearance of other CYP3A probes and that of drug-drug interactions. We propose this three-year proposal to further characterize the in vitro inhibition microsome kinetics of mosapride and other known CYP3A inhibitors. Reversible and time-dependent inactivation inhibition will be assessed for the selected probes and inhibitors. To evaluate the accuracy of the prediction via in vitro-in vivo extrapolation (IVIVE), in vivo pharmacokinetics of mosapride will also be determined in control and drug-drug interaction groups. At least 4 pair of mosapride-inhibitor reactions will be completed. Results from these studies will provide more inside mechanisms to provide evidence and to 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：100-2320-B-041-001 計畫年度：100；起迄日期：2011-08-01~2012-07-31 核定金額：800,000元
Appears in Collections:	[Dept. of Pharmacy] MOST Project

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