簡介
Cytochrome P450 是人類重要的代謝酵素之ㄧ，其中又以CYP3A 的含量最多。CYP3A的活性在不同個體間可以有很大的差異，因此對於許多經由CYP3A代謝的藥品其臨床表現可能會不同。利用體內探針性試藥可以評估個體間酵素活性的差異，其結果也比較具有臨床意義。Mosapride為新一代的胃腸蠕動促進劑，主要經由n-dealkylation的方式代謝成des-4-fluoro-benzyl metabolite（M-1）。根據許多體內藥品交互作用與體外酵素的研究發現，mosapride應該是主要經由CYP3A所代謝，因此mosapride應該可以發展成為體內CYP3A探針性試藥。
研究目的
本研究主要目的在利用大白鼠動物實驗模式來探討以mosapride 作為體內CYP3A活性探針性試藥的可行性。而為了研究mosapride在大白鼠體內動態，本研究也將開發新的分析方法以同時從血漿檢品中定量mosapride及其代謝物。
研究方法
在控制組實驗中，以靜脈注射方式投予1、5、10 or 15 mg/kg的mosapride至大白鼠以研究其藥物動態。另外，大白鼠事先以ketoconazole（抑制劑）或dexamethasone（誘導劑）進行CYP3A的活性調節後，再投予5 mg/kg的mosapride。Mosapride的血液檢體採樣收集至360分鐘，以二室模式估算其藥動參數。肝臟微粒體中CYP3A2含量表現則是以西方點墨法定量。
研究結果
Mosapride在大白鼠體內的清除率與肝臟微粒體中CYP3A2含量之相關性可利用well-stirred model與parallel tube model來加以描述，兩者呈現高度相關（分別為r = 0.824，p < 0.0001與r = 0.5412，p < 0.01），因此mosapride的清除率可以代表CYP3A的活性；另外，根據控制組與實驗組的數據，發展以有限採樣法（limited sampling strategy）的方式並經由確效評估證實，只要利用少量的血液檢品就可以對mosapride的AUC有準確的預測。
研究結論
以靜脈注射方式投予mosapride後，只要利用1至4個時間點的血中濃度就可以對mosapride的AUC有準確的預測，亦即對清除率有好的預測，因此對於mosapride作為大白鼠體內CYP3A活性探針性試藥的應用而言，提供了一個更方便並節省時間的評估方式。

Introduction
Cytochrome P450 3A is one of the most important CYP450 subfamilies because of its large number of xenobiotics and endogeneous substrates. Interindividual variability in the expression and activity of CYP3A is considerable, and may be responsible for variability in drug response. By administration of probe drug, it can permit measurement of real-time enzyme activity and provides more clinically relevant information. Mosapride, a new prokinetic agent, undergoes N-dealkylation metabolism to form des-4-fluoro-benzyl metabolite (M-1). According to the results of many drug-drug interaction studies and in vitro enzymatic studies, it seems that CYP3A family is the major enzyme which is responsible for the metabolism of mosapride. Therefore, mosapride could be a potential compound of CYP3A in vivo probe.
Purpose
The main objective of this study was to evaluate the feasibility of mosapride as an in vivo probe of CYP3A activity using the SD rat as an animal model. In order to study the kinetics of mosapride, a new HPLC method for simultaneous determination of mosapride and M-1 in rat plasma was developed.
Methods
Rats received mosapride（1、5、10 or 15 mg/kg）intravenously in the dose-linearity control groups. And in the CYP3A modulation groups, rats received 5 mg/kg mosapride after pretreatment with ketoconazole（inhibition）or dexamethasone ( induction ). The plasma concentrations of mosapride were followed for 360 min, and the kinetics parameters were estimated by two-compartmental analysis. The contents of CYP3A2 in hepatic microsomes of rats were measured by western blotting analysis.
Results
Based on the two hepatic clearance models, well-stirred model and parallel tube model, the hepatic CYP3A2 contents showed strongly correlation with mosapride clearance（r = 0.824，p < 0.0001 and r = 0.5412，p < 0.01 respectively）. Therefore, mosapride clearance can be used to reflect the in vivo CYP3A activity. Based on the data of control and CYP3A modulation group, limited sampling strategies were derived, validated, and evaluated for its applicability. Mosapride AUC can be well predicted by using one to four time points of plasma concentrations.
Conclusion
One to four time points of plasma concentrations following intravenous administration of mosapride can precisely predict its AUC and hence clearance in rats. Therefore, this approach represents an effective metbod for assessing in vivo CYP3A activity.

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