Roflumilast (ROF), a nonsteroidal anti‐inflammatory drug, has successfully been used to treat systemic and pulmonary inflammation associated with chronic obstructive pulmonary disease. To evaluate its pharmacokinetics in monkeys, a sensitive, rapid and reliable liquid chromatography with tandem mass spectrometry (LC–MS/MS) method was developed for the simultaneous determination of ROF and its N‐oxide metabolite (RNO). The mobile phase contained 0.1% formic acid aqueous solution (A) and 0.1% formic acid acetonitrile solution (B). All monkey plasma samples were pretreated using protein precipitation with methanol–acetonitrile (50:50, v/v) in 50 μl plasma samples. Chromatographic separation was performed with mass spectral acquisition performed in positive electrospray ionization, utilizing multiple reaction monitoring. This method was successfully applied to a pharmacokinetic study in cynomolgus monkeys. Following administration of a single oral dose of 1 mg/kg ROF in monkeys, pharmacokinetic data for ROF and RNO was reported for the first time. After oral administration, ROF was rapidly absorbed and metabolized to its metabolite RNO. The mean area under the curve value of RNO was ~13 times larger than that of ROF, suggesting that most ROF was metabolized to RNO in cynomolgus monkeys.

中文翻译：

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LC-MS / MS法同时测定猕猴血浆中罗氟司特及其氮氧化物的定量和药代动力学

罗氟司特（ROF）是一种非甾体类抗炎药，已成功用于治疗与慢性阻塞性肺疾病相关的全身和肺部炎症。为了评估其在猴子中的药代动力学，开发了一种灵敏，快速，可靠的液相色谱-串联质谱（LC-MS / MS）方法，用于同时测定ROF及其N-氧化物代谢产物（RNO）。流动相包含0.1％的甲酸水溶液（A）和0.1％的甲酸乙腈溶液（B）。在50μl血浆样品中，使用甲醇-乙腈（50:50，v / v）进行蛋白质沉淀，对所有猴子血浆样品进行预处理。色谱分离是通过利用多反应监测在正电喷雾电离中进行质谱采集来进行的。该方法已成功应用于食蟹猴的药代动力学研究。在猴子中口服1 mg / kg ROF的单次口服剂量后，首次报道了ROF和RNO的药代动力学数据。口服后，ROF被迅速吸收并代谢成其代谢产物RNO。RNO曲线值下的平均面积约为ROF的13倍，这表明食蟹猴的大部分ROF都被代谢为RNO。