摘要
　　肝臟細胞酵素的功能與藥品的代謝情形有很大的關係，尤其在藥品交互作用上，可能涉及代謝酵素的誘導與抑制而改變了原藥品在體內代謝的模式，針對此情形發展了各種不同的探針性試藥來反應酵素的活性狀況。目前發展成為體外使用的探針性試藥主要midazolam，testosterone，nifedipine以及terfenadine，由於受質在代謝的型態上涉及結合位置(binding site)、多重代謝途徑(multiple metabolic pathway)以及與代謝酵素親和力等性質皆不相同，因此在動力學的表現也不盡相同。針對受質與酵素作用方式的不同，使用同時具有活化與抑制作用的物質可將受質作定性的評估。

　　本研究主要目的在評估cisapride與delavirdine作為CYP3A活性之體外探針性試藥的適用性。首先將建立各受質(midazolam、testosterone、delavirdine與cisapride)在微粒體的CYP3A代謝反應之培養條件以及確認其與文獻有一致性的代謝動力學參數，進而利用多種不同抑制強度的藥品對來評估受質代謝反應間的相關性。再以文獻中對於不同受質有不同影響的作用劑quinidine與haloperidol來針對cisapride、delavirdine與testosterone作定性上的討論及描述各別抑制模式，並且利用與CYP3A具有專一性抑制藥品，ketoconazole作用於cisapride與delavirdine，將抑制結果與文獻作對應。

　　研究結果顯示，有別於midazolam，delavirdine、cisapride與testosteorne三者間之CYP3A代謝反應具有高度的相關性，顯示cisapride與delavirdine在探針試藥的分類上，可能與testosterone在於同一類，尤其是cisapride最具有潛力與testosterone為同類的CYP3A受質；而在quinidine與haloperidol不同作用機制探討下，發現cisapride與testosterone皆會與haloperidol與quinidine產生抑制型的交互作用，而delavirdine則在quinidine的作用下呈現活化型的反應，因此cisapride作為探針性試藥的特質上與tesotosterone有機制上的相似性；而在ketoconazole的作用下，cisapride與delavirdine分別呈現mix-type 與competitive 的抑制模式，且在同一抑制濃度下cisapride具有較高的敏感性。

　　綜合以上與典型體外探針試藥比較的結果，本研究提出delavirdine與cisapride具有相當潛力成為CYP3A活性評估的探針性試藥品。

Abstract
　Introduction. CYP3A enzymes play potentially important role in the metabolism of drugs and metabolism-related the drug-drug interactions. With various in vitro incubation systems, there have been numerous compounds used as marker substrates of CYP3A function. The choice of one compound over another relies on findings that are consistent with the test for CYP3A activity being a quantitative and specific measure.

　Objectives. Cisapride and delavirdine are metabolized primarily through desalkylation catalyzed by CYP3A. In this study the potential application of cisapride and delavirdine as a CYP3A probe was investigated.

　Methods. Delavirdine and its metabolite dealkyl delavirdine, cisapride and its metabolite norcisapride were measured by reverse-phase HPLC methods using gradient elution mode. Metabolic kinetic studies of delavirdine, cisapride and typical probe substrates midazolam and testoste- rone were undertaken in rat liver microsomes to determine the in vitro CYP3A activity. The meta- bolite formation rates of these CYP3A substrates were estimated under various degree of inhibition, and their correlations were examined to investigate the applicability of delavirdine and cisapride as CYP3A probes. Furthermore, the metabolic characteristics of delavirdine and cisapride were explored by examining their interaction profiles with two different effec tors, quinidine and haloperidol, as reported. Also, the inhibition models on CYP3A of both substrates were identified by using the selective inhibitor ketokonazole.

　Results. The metabolic kinetic parameters for different substrates were similar to those reported in the literature. High correlation was observed between desalkylation of delavirdine and cisapride and hydroxylation of testosterone. Based on the interaction patterns, the desalkylation characteristics of cisapride were different from those of delavirdine, but similar with hydroxylation of testosterone. According to the inhibition features by ketoconazole, the CYP3A metabolism of cisapride and delavirdine was identified as mixed-type and competitive inhibition models, respectively. Also, the sensitivity of cisapride was better than that of delavirdine at the same concentration of ketoconazole.

　Conclusions. In summary, the present study demonstrates that the CYP3A-dependent metabolism of cisapride and delavirdine correlated significantly with those of typical CYP3A probes, suggesting the potential applicability of both drugs as in vitro probes for CYP3A.

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