Validated LC--MS/MS method for determination of YH-8, a novel PKnB inhibitor, in rat plasma and its application to pharmacokinetic study

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• 作者：Qianqian Zhai^a ; ^b ; Jing Pang^a ; Guoqing Li^a ; Congran Li^a ; Xinyi Yang^a ; Liyan Yu^a ; Yucheng Wang^a ; Jian Li^b ; Xuefu You^a ; ^{xuefuyou84@163.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：YH-8 ; LC&ndash ; MS/MS ; Pharmacokinetics ; Rat plasma ; Method validation
• 刊名：Acta Pharmaceutica Sinica B
• 出版年：2015
• 出版时间：September 2015
• 年：2015
• 卷：5
• 期：5
• 页码：467-472
• 全文大小：561 K

文摘

(E)-Methyl-4-aryl-4-oxabut-2-enoate (YH-8) is a novel PKnB protein kinase inhibitor with good anti-tuberculosis activity. To evaluate its pharmacokinetics in rats, a sensitive and selective high performance liquid chromatography–tandem mass spectrometric (LC--MS/MS) method has been developed and validated for the quantification of YH-8 in rat plasma for the first time. Samples were pre-treated using a liquid--liquid extraction with ethyl acetate and the chromatographic separation was performed on a C18 column by gradient elution with methanol--water as the mobile phase. YH-8 was detected using a tandem mass spectrometer in positive selected reaction monitoring (SRM) mode. Method validation revealed good linearity over the range of 1–500 ng/mL for YH-8 with a lower limit of quantification (LLOQ) of 1 ng/mL. Intra- and inter-day precision of YH-8 assay in rat plasma samples were 2.0%–6.8%, with accuracy of the method being 100.69%–106.18%. Stability test showed that when spiked into rat plasma, YH-8 was stable for 12 h at room temperature, for up to 15 days at −70 °C, and after three freeze-thaw cycles. Extracted samples were found to be stable over 12 h in an auto-sampler. The method was successfully applied to the pharmacokinetic study of YH-8 in rats after oral administration at 100 mg/kg and 200 mg/kg.