研究背景：年齡會增加個體間差異性，並在藥物動力學扮演關鍵的角色，影響藥物的療效和安全性。CYP3A是肝臟和小腸中CYP450家族中最主要的代謝酵素，具有顯著的個體差異性。Mosapride為胃腸蠕動劑，主要經由CYP3A代謝，先前研究顯示，mosapride清除率與肝臟和腸道中CYP3A酵素含量具有高度相關性，反應出mosapride做為CYP3A體內探針性試藥的可行性。Rilpivirine在人體主要是經由CYP3A代謝來排除。
研究目的：探討年齡與CYP3A活性關聯對其受質藥物動力學之影響，並進一步研究mosapride與受質藥物由體內清除之相關性以評估其預測CYP3A活性的應用。
研究方法：本實驗使用6-48週的Sprague-Dawley大鼠，以靜脈注射同時投予mosapride和rilpivirine，並收集血液檢體至480分鐘後，以高效液相層析法分析血中濃度，再以分室模式估算其藥動參數。採樣後取出肝臟製備成microsome，以酵素免疫法分析CYP3A2總含量。
研究結果：Mosapride和rilpivirine在大鼠的藥物動力學展現了二室模式的特點，不論週齡組別，在同週齡比較上，母鼠的藥物血中濃度曲線下面積(AUC)都高於公鼠。Mosapride和rilpivirine於公鼠的清除率在青春期時週達到最高，之後隨年齡的增加而顯著減少;而兩藥品在母鼠的清除率並不會隨年齡的關係顯著改變。Mosapride清除率和rilpivirine清除率相關性0.77具良好的相關性，且Mosapride的AUC可應用單點採樣法精確得到。
研究結論：CYP3A受質藥物mosapride和rilpivirine在大鼠體內的清除率具性別差異。年齡對兩藥品在公鼠的清除率有顯著影響，但在母鼠CYP3A的活性並未隨年齡變化而改變。Mosapride清除率和肝臟CYP3A2含量之間的關係能以well-stirred clearance model描述。Mosapride清除率和rilpivirine的清除率具有良好的相關性，應證mosapride 作為大鼠體內CYP3A活性探針的可行性。

Age of subjects can play a key role in variability in pharmacokinetics and thus efficacy and safety of drugs. CYP3A is one of the most important CYP450 subfamilies with great variation. The use of CYP3A phenotyping probes in drug therapy is of great importance. In this study, the age-related changes in the pharmacokinetics of a putative CYP3A phenotyping probe mosapride and a CYP3A substrate rilpivirine in rats were investigated.

The disposition kinetics of mosapride and rilpivirine in rats displayed two-compartmental characteristics. Aging significantly affected the clearance of both drugs in male rats, but not in female rats. The clearance of CYP3A substrates mosapride and rilpivirine in rats was gender-dependent. The systemic exposure of both drugs in female rats was consistently greater than that in male rats. The clearance of mosapride and rilpivirine was maximal at 9-week-old in male rats and decreased after puberty. In female rats, the clearance of the drugs did not change significantly over the entire age range studied. The relationship between mosapride clearance and hepatic CYP3A2 content can be described by well-stirred clearance model. The correlation between mosapride clearance and rilpivirine clearance was relatively good with a correlation coefficient of 0.77. The systemic exposure of CYP3A probe mosapride in rats, in terms of AUC, can be precisely predicted using a single point plasma concentration.

The clearance of CYP3A substrates mosapride and rilpivirine in rats was gender-dependent. Aging significantly affected the clearance of both drugs in male rats, but not in female rats. The correlation between mosapride clearance and rilpivirine clearance was relatively good, supporting the applicability of mosapride as an in vivo CYP3A probe in rats.

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