研究背景：
Nemonoxacin 是一種無氟喹諾酮類(non-fluorinated quinolone) 抗生素，適應症為治療輕度到中度社區型肺炎，為台灣太景生物科技公司研發之新藥。其口服膠囊及靜脈輸液劑型先後在2014及2020於台灣取得藥品許可證。上市至今，關於nemonoxacin臨床前及人體之藥動學與藥物交互作用的研究仍屬有限。此藥品的血漿蛋白結合率的程度在不同文獻報告差異很大，而關於藥物轉運蛋白對nemonoxacin藥動學性質的影響亦不明確。這些都值得進一步的研究，以利其臨床的使用。
研究目的：
以大鼠為模式，探討nemonoxacin在體內之藥物動力學，並觀察藥物轉運蛋白對其藥動學之影響以及在藥物交互作用上的角色。為此同時開發一套靈敏的高效液相層析法，用於定量nemonoxacin於生物檢品的濃度，供藥動學試驗所需。
研究方法：
開發一套靈敏的高效液相層析(HPLC)方法來定量血漿、膽汁等檢品中的nemonoxacin，將分析方法最適化並進行確校。
使用超過濾(ultrafiltration)法以體外及離體試驗來探討nemonoxacin在不同基質、pH值及藥物濃度下的蛋白結合率情形。
以大白鼠動物模式投予nemonoxacin，觀察其在大白鼠體內的動態，再搭配合適的模式藥品觀察藥物轉運蛋白對其影響情形，探討臨床使用上可能產生的藥品交互作用情形。
研究結果：
已成功開發HPLC分析方法用來定量血漿、膽汁中的nemonoxacin，並將此分析方法實際應用於nemonoxacin在體外及體內的藥動學試驗。Nemonoxacin在人類跟大白鼠血漿蛋白質具有中等程度的結合，未結合率約為60%，在臨床濃度範圍內呈線性特徵。Nemonoxacin與人類及牛的血清白蛋白之未結合率在pH6~8之間會隨pH值下降而降低。在大白鼠體內動態部分，nemonoxacin具二室的分室模式特性，生體可用率約21%。Nemonoxacin在以不同給藥方式同時與典型P-gp抑制劑cyclosporine併服時，其血中濃度經時數據呈現AUC增加、半衰期延長、清除率下降趨勢，而膽汁路徑的排除顯著受到抑制。而在併服OCT受質藥品metformin時，nemonoxacin的血漿及膽汁中濃度變化趨勢與單獨給藥時相似。
結論：
Nemonoxacin在大鼠之口服生體可用率低，體內動態呈二室分室模式的特性，其血中蛋白未結合比率約60%；藥物轉運蛋白P-gp抑制劑cyclosporine對nemonoxacin的體內動態有影響，經由P-gp的抑制使得nemonoxacin在胃腸道的吸收增加，而膽汁排除下降。在臨床劑量下的OCT受質藥品metformin對於nemonoxacin體內動態影響則不明顯。

關鍵詞：nemonoxacin，血漿蛋白結合，超過濾法，cyclosporine，metformin

A simple and sensitive HPLC method with fluorescence and ultraviolet detection was developed and fully validated for the determination of nemonoxacin in small volumes of rat plasma and bile. The method was successfully applied to the in vitro and in vivo pharmacokinetic studies of nemonoxacin. Ultrafiltration was used to determine the unbound fraction of nemonoxacin in various matrices. The plasma protein binding of nemonoxacin is moderate and concentration-independent within the therapeutic range. Unbound fraction of nemonoxacin to albumin increased as the pH increased in the pH range of 6-8. The male Sprague-Dawley rats were given nemonoxacin intravenously and orally to explore the absorption and disposition kinetics of nemonoxacin. The oral bioavailability of nemonoxacin was low, and it displayed two-compartmental disposition kinetics. To investigate the effect of transporter-mediated drug-drug interactions on nemonoxacin, co-medication of cyclosporine or metformin with nemonoxacin via intravenous and oral routes were employed. Concomitant with the P-gp inhibitor cyclosporine increased the oral absorption and decreased and delayed the process of biliary excretion of nemonoxacin. And metformin in therapeutic concentration did not affect the kinetics of nemonoxacin significantly.

Key words: nemonoxacin, plasma protein binding, ultrafiltration, cyclosporine, metformin

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