PDE5抑制劑在臨床上廣泛被用來治療男性勃起功能障礙及肺動脈高壓。PDE5抑制劑在結構上與cGMP相似且其代謝途徑主要是經由肝臟的CYP3A及CYP2C9這兩個酵素，並有活性代謝物的產生。目前對PDE5抑制劑的交互作用研究著重在代謝酵素方面，但在藥物運輸子的研究仍不多。然而，已有研究指出sildenafil對於MRP4、MRP5及OATP有抑制的作用，在臨床文獻指出PDE5抑制劑與ritonavir之交互作用可能與P-gp有關。在本實驗室研究發現，vardenafil在活體鼠膽汁有主動分泌的現象，推論其現象可能經由藥物運輸子調控。因此有關藥物運輸子在PDE5抑制劑於肝臟之動態學與交互作用上的角色值得加以研究。
本研究目的為使用離體肝臟灌流裝置來觀察PDE5抑制劑的肝臟藥品動態，再進一步藉由sildenafil與各藥品的交互作用討論藥物運輸子所扮演的角色。
研究結果發現在穩定灌流下sildenafil在離體老鼠肝臟的主動分泌現象遠大於tadalafil及vardenafil，顯示sildeanfil在膽汁排除的趨勢大於tadalafil及vardenafil。因此，使用sildenafil作為探討交互作用之PDE5抑制劑。於離體老鼠肝臟，若給予P-gp、MRP2及OATP抑制劑cyclosporine A（CsA），會顯著減少sildenafil之膽汁排除，而在灌流液的部分則沒有差異；代謝物部分則發現到灌流液隨CsA濃度增加而呈上升的趨勢，而膽汁則隨CsA濃度增加而減少。而在併用OATP、MRP2抑制劑rifampicin（RIF）時sildenafil膽汁排除量有明顯增加。代謝物部分則發現其在膽汁濃度有略微下降的趨勢。併用MRP抑制劑probenecid（PBED）則可發現到sildenafil的灌流液濃度曲線下面積與膽汁排除量是呈現上升的狀況；代謝物部分則發現灌流液代謝物濃度上升，而膽汁代謝物略為下降但不具統計差異。併用P-gp受質amisulpride（AMI）則發現在不論灌流液或膽汁sildenafil與其代謝物在肝臟的動態與灌流CsA者相近。
本研究之結果可知sildenafil、tadalafil與vardenafil皆有膽汁主動分泌的現象，而藉由交互作用推論sildenafil在體內的動態可能被許多藥物運輸子影響。其運輸似乎與P-gp調控有關，而OATP則影響不大。sildenafil在肝中的運輸似乎與竇狀隙的藥物運輸子有關，但與何種藥物運輸子有關仍須進一步探討。

Introduction： PDE5 inhibitors are used for the treatment of male erectile dysfunction and pulmonary arterial hypertension. The structures of PDE5 inhibitors are similar to cGMP and they are mainly metabolized by CYP3A and CYP2C9 isozymes in the liver. Currently, the interaction studies of PDE5 inhibitors are focused on the metabolic aspect and none of them has addressed on the transporter interactions. However, recent studies have demonstrated that sildenafil can inhibit the activity of MRP4, MRP5 and OATP. And it has beeen suggested that P-gp, in addition to CYP3A, was responsible for the increase of the concentration of PDE5 inhibitors when concomitant with ritonavir in clinical settings. In our previous study, we found that vardenafil underwent active biliary secretion in rats. Therefore, it is of great interest to investigate the role of drug transporters on the hepatobiliary disposition of PDE5 inhibitors.
Purpose：The aim of this study was to investigate the hepatic disposition of PDE5 inhibitors, and to explore the role of drug transporters on their hepatobiliary transport in the isolated perfused rat liver.
Results：All PDE5 inhibitors showed active biliary secretion during single-pass constant perfusion experiments. As the extent of secretion of sildenafil was greater than that of tadalafil and vardenafil, sildenafil was chosen as the model drug to further explore drug interactions of PDE5 inhibitors. Using the recirculated perfused rat liver preparation, the biliary secretion of sildenafil and its metabolite was found to decrease with increasing concentration of concomitant cyclosporine A, an inhibitor of OATP、MRP2、P-gp. When co-administered with rifampicin, an OATP and MRP2 inhibitor, the perfusate concentration of sildenafil increased slightly, yet the cumulative amount excreted in bile of sildenafil was increased appreciably. In the prescence of the MRPs inhibitor probenecid, both the perfusate concentration and the cumulative amount excreted in bile of sildenafil increased significantly. When concomitant with amisulpride, a P-gp substrate, the biliary secretion of sildenafil and its metabolite was found to decrease slightly.
Conclusion：In this study, we found that all three PDE5 inhibitors underwent active biliary secretion. This study also demonstrated that the disposition of sildenafil was influenced by various inhibitors of membeane transporters. Sildenafil appeared to be a substrate for P-gp, and the role of OATP was limited for hepatic transport of sildenafil. Whether the transporters in sinusolidar membrane are involved in the hepatic disposition of sildenafil or not remains unclear.

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