Simple Liquid Chromatography-Tandem Mass Spectrometry Method for Quantitation of Total and Free Aprepitant and Its Active N-Dealkylated Metabolites in Human Plasma
Simple Liquid Chromatography-Tandem Mass Spectrometry Method for Quantitation of Total and Free Aprepitant and Its Active N-Dealkylated Metabolites in Human Plasma
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DOI：
10.1097/ftd.0000000000000815
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发表时间：
2021-06-01
影响因子：
2.5
通讯作者：
Kawakami，Junichi
中科院分区：
文献类型：
--
作者：
Naito，Takafumi;Suzuki，Yusuke;Kawakami，Junichi
背景：阿瑞匹坦是一种止吐选择性神经激肽-1受体拮抗剂，在人体内主要代谢为活性N-脱烷基化形式（ND-AP），然后转化为羰基形式（ND-CAP）。本研究开发了一种简单的液相色谱-串联质谱法，采用电喷雾电离定量血浆总和游离阿瑞匹坦及其N-脱烷基代谢产物，并使用它们来分析患者plasma.Methods：游离阿瑞匹坦和ND-AP在血浆中采用离心超滤分馏。结果：总阿瑞匹坦、ND-AP和ND-CAP的标准曲线分别在50-2500、20-1000和5-250 ng/mL范围内，游离阿瑞匹坦和ND-AP的标准曲线在2-150 ng/mL范围内。批内和批间精密度分别为93.5%~ 107.7%和94.6%~ 103.3%;批内和批间精密度分别为2.1%~ 7.5%和1.0%~ 8.9%。阿瑞匹坦及其代谢产物在血浆样本中未表现出任何基质效应或不稳定性。在接受口服阿瑞匹坦的癌症患者中，总阿瑞匹坦、ND-AP和ND-CAP以及游离阿瑞匹坦和ND-AP的血浆浓度范围分别为137-2170、104-928、22.4-97.6、8.11-60.0和3.53-56.0 ng/mL。阿瑞匹坦和ND-AP的血浆游离分数比例中位数分别为4.14%和4.90%，respectively.Conclusions：本方法具有可接受的分析性能，可用于评价患者血浆中的总阿瑞匹坦和游离阿瑞匹坦及其N-脱烷基代谢产物。
Background:Aprepitant, an antiemetic selective neurokinin-1 receptor antagonist, is primarily metabolized to the active N-dealkylated form (ND-AP) and then converted to its carbonyl form (ND-CAP) in humans. This study developed a simple liquid chromatography–tandem mass spectrometry method using electrospray ionization for the quantitation of plasma total and free aprepitant and its N-dealkylated metabolites and used them to analyze patient plasma.Methods:Free aprepitant and ND-AP in plasma were fractionated using centrifugal ultrafiltration. The analytes in plasma or their ultrafiltered specimens treated with triethylamine/acetonitrile were isocratically separated using a 3-μm octadecylsilyl column with a total run time of 10 minutes and scanned using positive ion electrospray ionization.Results:The calibration curves of total aprepitant, ND-AP, and ND-CAP were prepared at concentration ranges of 50–2500, 20–1000, and 5–250 ng/mL, respectively, whereas that of free aprepitant and ND-AP were at a concentration range of 2–150 ng/mL. The intraassay and interassay accuracy and imprecision values were 93.5%–107.7% and 94.6%–103.3%, and 2.1%–7.5% and 1.0%–8.9%, respectively. Aprepitant and its metabolites did not exhibit any matrix effects or instabilities in the plasma specimens. In cancer patients receiving oral aprepitant, the plasma concentration ranges of total aprepitant, ND-AP, and ND-CAP, and free aprepitant and ND-AP were 137–2170, 104–928, 22.4–97.6, 8.11–60.0, and 3.53–56.0 ng/mL, respectively. The median plasma free fraction proportion of aprepitant and ND-AP was 4.14% and 4.90%, respectively.Conclusions:The present developed method showed an acceptable analytical performance and can be used to evaluate total and free aprepitant and its N-dealkylated metabolites in patient plasma.