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Simultaneous quantitative LC-MS method of ketamine, midazolam and their metabolites (dehydronorketamine, norketamine and 1hydroxymidazolam) for its application in patients on extracorporeal membrane oxygenation (ECMO) therapy.

氯胺酮、咪达唑仑及其代谢产物 (去氢氯胺酮、去甲氯胺酮和 1 羟基咪达唑仑) 的同时定量 LC-MS 方法,用于体外膜肺氧合 (ECMO) 治疗患者。

  • 影响因子:3.15
  • DOI:10.1016/j.jpba.2019.112947
  • 作者列表:"Rochani A","Lam E","Tanjuakio J","Hirose H","Kraft WK","Kaushal G
  • 发表时间:2020-01-30
Abstract

:Ketamine (Ket) and midazolam (MDZ) are commonly administered drugs in the intensive care setting for analgesia and sedation. Ket and MDZ are metabolized to dehydro-norketamine (DHNK), nor-ketamine (NK) and 1-hydroxy midazolam (1HMDZ). Limited studies evaluating their pharmacokinetics exists in patients on extracorporeal membrane oxygenation (ECMO) therapy. Therefore, we developed a quantitative, high-performance liquid chromatography-mass spectrometry (with single ion monitoring) method to simultaneously detect Ket, MDZ and their (DHNK, NK and 1HMDZ) metabolites in human plasma. Considerable sensitivity was obtained for the analytes using a C18 HILIC column operated by a high-performance liquid chromatography system coupled with a Thermo Exactive Orbitrap mass spectrometer. Calibration curves were developed for analyte molecules (n = 5) in the presence of carbamazepine (CBZ) as an internal standard. The lower limits of quantitation (LLOQ) for Ket and MDZ were 20 and 10 ng/mL, respectively with the LLOQ for DHNK, NK and 1HMDZ at 470, 320 and 150 ng/ml. Moreover, the percent coefficient of variance and precision for inter- and intra-day runs were within the standards set forth by the ICH and FDA guidelines. This method is sensitive and has been successfully applied to an ongoing pharmacokinetic study in patients on ECMO therapy.

摘要

: 氯胺酮 (Ket) 和咪达唑仑 (MDZ) 是重症监护环境中常用的镇痛和镇静药物。Ket 和 MDZ 代谢为去氢去甲氯胺酮 (DHNK) 、 nor-氯胺酮 (NK) 和 1-羟基咪达唑仑 (1HMDZ)。在体外膜肺氧合 (ECMO) 治疗的患者中存在评价其药代动力学的有限研究。因此,我们开发了一种定量、高效液相色谱-质谱 (单离子监测) 方法,同时检测 Ket 、 MDZ 及其 (DHNK 、 NK 和 1HMDZ) 人血浆中的代谢物。使用 C18 HILIC 柱,通过高效液相色谱系统与热外露 Orbitrap 质谱仪联用,获得了相当高的分析物灵敏度。在卡马西平 (CBZ) 作为内标物存在下,对分析物分子 (n = 5) 建立校准曲线。Ket 和 MDZ 的定量下限 (LLOQ) 分别为 20 和 10 ng/mL,DHNK 、 NK 和 1HMDZ 的 LLOQ 分别为 470 、 320 和 150 ng/ml。此外,日间和日内运行的变异百分比系数和精密度均在 ICH 和 FDA 指南规定的标准范围内。该方法灵敏,已成功应用于 ECMO 治疗患者的药代动力学研究。

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