近年來造成藥物交互作用的原因除了考量代謝酵素外，藥物運輸載體的重要性也逐漸受到重視；目前臨床上用於治療男性勃起障礙的PDE5抑制劑有sildenafil、tadalafil與vardenafil三種。其中vardenafil因最晚上市且缺乏其在生物檢品的定量方法，故相關之藥動學與交互作用資料較少。Vardenafil與sildenafil及tadalafil皆為CYP3A受質且在結構上均與cGMP類似；由於cGMP進出細胞會受到藥物運輸蛋白MRP的調節，因此有關MRP等藥物運輸蛋白及CYP3A在vardenafil藥動學與交互作用上的角色是值得加以探討。
　　本研究目的首先在開發以螢光偵測器來定量vardenafil在生物體液中的高效能液相層析方法，且實際應用此方法來研究vardenafil在大白鼠體內的藥物動力學，並進一步探討vardenafil之藥物交互作用。
　　實驗結果已成功開發一個簡單又靈敏的液相層析方法，經確效後應用在vardenafil血漿與膽汁濃度之定量分析，並研究vardenafil在大白鼠體內的藥物動力學。由劑量依性試驗顯示在靜脈注射2-10 mg/kg下，vardenafil在血漿及膽汁的藥動學呈現線性，且其膽汁濃度遠高於血漿。當vardenafil以靜脈注射2 mg/kg於大白鼠時，若併用Pgp抑制劑cyclosporin A (10 mg/kg) 或verapamil (1 mg/kg) 時，皆會顯著降低vardenafil在血漿中的濃度，而cyclosporin A亦會使vardenafil代謝物之膽汁排除下降。而靜脈注射併用MRP2抑制劑probenecid (50mg/kg)對vardenafil在血漿及膽汁的動力學影響並不顯著。此外當vardenafil以口服20 mg/kg給予大白鼠時，若併服cyclosporin A (10 mg/kg)，則會顯著降低其最高血中濃度，而其口服清除率與分佈體積及排除半衰期均增加，顯示cyclosporin A對vardenafil之口服吸收、分佈與排除皆有影響。
　　本研究結論認為vardenafil的膽汁排除包含主動分泌並涉及運輸載體之調控；由活體動物實驗顯示Pgp抑制劑cyclosporin A及 verapamil會顯著影響vardenafil的藥動學，而vardenafil同時為一CYP3A受質，因此，造成交互作用的原因須再做進一步的探討。

Introduction. In addition to the metabolic enzymes, active transport systems have been described for their importance in drug-drug interactions. Currently there are three PDE5 inhibitors, sildenafil, tadalafil and vardenafil, available for the treatment of erectile dysfunction. Vardenafil was the last of the PDE5 inhibitors released into the market. Due to the lack of quantitation methods for vardenafil in biological fluids, the pharmacokinetics of vardenafil has not been studied extensively. Vardenafil and the other PDE5 inhibitors are all CYP3A substrates and they display structure similarity with cGMP. Recent studies suggest that members of the MRP family translocate cGMP across the cell membrane. Therefore, it is of great interest to investigate the role of drug transporters, such as MRP, and CYP3A on the pharmacokinetics of vardenafil.

Purpose. The aim of this study was to develop a high-performance liquid chromatography method with fluorescence detection to determine the concentration of vardenafil in biological samples, and to apply the method to investigate the pharmacokinetics and drug-drug interactions of vardenafil in rats.

Results. A simple and sensitive HPLC method for the quantitation of vardenafil in plasma and bile was developed and applied successfully to examine the pharmacokinetics of vardenafil in rats. Following bolus injection of 2-10 mg/kg to rats, the disposition of vardenafil in plasma and bile displayed linearity, and the concentration of vardenafil in bile was greater than that in the plasma. When Pgp inhibitors cyclosporin A (10 mg/kg) and verapamil (1 mg/kg) were given intravenously 10 min before bolus administration of vardenafil (2 mg/kg) to rats, the plasma concentrations of vardenafil were decreased significantly. The presence of cyclosporin A also resulted in a decrease in biliary secretion of a metabolite of vardenafil. On the other hand, the disposition kinetics of vardenafil in plasma and bile following intravenously administration were not altered when co-administered with MRP2 inhibitor probenecid (50 mg/kg). The effect of cyclosporin A (10 mg/kg) on the oral absorption of vardenafil (20 mg/kg) was also explored. Concomitant with cyclosporin A decreased the maximal plasma concentration of vardenafil and increased its oral clearance, volume of distribution and terminal elimination half-life, indicating that cyclosporin A altered the absorption, distribution and elimination of vardenafil.

Conclusion. In summary, active secretion was involved in the biliary excretion of vardenafil in rats, suggesting that biliary transport of vardenafil may be mediated by drug transporters. Co-administration with Pgp inhibitors cyclosporin A and verapamil changed the pharmacokinetics of vardenafil in rats to various degree, however, the exact mechanisms were not clear and further studies will be needed to fully elucidate the mechanisms of drug-drug interaction for vardenafil.

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