簡介
細胞色素P450 3A 為目前所有亞型中涉及藥品代謝最重要之代謝酵素，在人體負責許多藥物之代謝。CYP3A的表現與活性在不同個體有很大的差異，且此變異造成個體對藥物反應之不同。利用探針性試藥評估個體之細胞色素P450活性已被廣泛的接受。Mosapride為新一代的腸胃蠕動促進劑，已被證實可作為大白鼠體內肝臟CYP3A活性探針性試藥。然而，口服投予mosapride牽涉腸道與肝臟中CYP3A活性之表現，因此mosapride在此種投藥方式下是否仍可做為CYP3A活性探針，仍待進一步研究。

研究目的
本研究主要目的在利用大白鼠動物實驗模式探討，以有限採樣法預測CYP3A探針藥物mosapride在口服投予後大鼠體內之血中濃度曲線下面積。

研究方法
控制組實驗中，以口服方式給予10、20、30、40、50 mg/kg的mosapride至大白鼠，並納入一組10 mg/kg mosapride的母鼠實驗以研究其藥物動態。另外，大白鼠事先給予ketoconazole (酵素抑制劑) 進行CYP3A的活性調節後，再投與10 mg/kg 的mosapride。Mosapride的血液檢體採樣收集至480分鐘(高劑量延長收集至720分鐘)，以非分室模式估算其藥動參數。肝臟及小腸微粒體中CYP3A2含量表現則是以西方點墨法定量之。

研究結果
利用well-stirred model描述mosapride在大白鼠體內之口服清除率與肝臟、小腸微粒體中CYP3A2含量之相關性，兩者呈現高度相關 (r=0.7635，p<0.0001) ，因此mosapride的清除率可代表體內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，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
以口服方式投與mosapride後，只要利用少數時間點的血中濃度就可以對mosapride的AUC有準確的預測，亦即對口服清除率有良好的預測；因此，對於mosapride作為大白鼠體內CYP3A活性碳針性試藥的應用而言，提供一個更方便並節省時間的評估方式。

Introduction
Cytochrome P450 3A (CYP3A) is an important subfamily of drug- metabolizing enzymes. In humans, it is responsible for metabolizing numerous drugs across several therapeutic classes. Interindividual variability in the expression and activity of CYP3A is considerable, and may be responsible for variability in drug response. The use of probe substrates is a widely accepted method for evaluating the activity of cytochrome P450 (CYP) enzymes in individuals. Mosapride, a new prokinetic agent, was evaluated as an in vivo probe for measuring hepatic CYP3A activity in rats. However, the metabolism of orally administrated mosapride involves the combination of gastrointestinal and hepatic CYP3A activity. Whether mosapride can be used as a CYP3A probe under such circumstance is of great interest.

Purpose
The objective of this study was to evaluate the suitability of limited sampling strategy to predict AUC of CYP3A phenotyping probe mosapride in rats following oral administration.

Methods
In control groups, male rats received mosapride（10、20、30、40、50 mg/kg）orally and a female control group (10mg/kg) was also included for studying its pharmacokinetics. And in the CYP3A- modulation group, male rats received 10 mg/kg mosapride after pretreatment with ketoconazole (inhibitor). The plasma concentrations of mosapride were followed for up to 480 or 720 min, and the kinetic parameters were estimated by non-compartment analysis. The contents of CYP 3A2 in hepatic and intestinal microsomes of rats were measured by western blotting analysis.

Results
Describing by well-stirred model, the hepatic and intestinal microsomes CYP3A2 contents showed strong correlation with mosapride oral clearance (r=0.7635，p<0.0001). Therefore, mosapride oral 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. It was demonstrated that the AUC of mosapride can be well predicted by the concentration of few time points.

Conclusion
Few time points of plasma concentrations after orally administrated mosapride was needed to precisely predict its AUC and hence clearance in rats. Therefore, this approach represents an effective method for assessing in vivo CYP3A activity.

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