Simultaneous determination of parecoxib and its main metabolites valdecoxib and hydroxylated valdecoxib in mouse plasma with a sensitive LC-MS/MS method to elucidate the decreased drug metabolism of tumor bearing mice.
Simultaneous determination of parecoxib and its main metabolites valdecoxib and hydroxylated valdecoxib in mouse plasma with a sensitive LC-MS/MS method to elucidate the decreased drug metabolism of tumor bearing mice.
复制标题
采用灵敏的 LC-MS/MS 方法同时测定小鼠血浆中帕瑞昔布及其主要代谢物伐地昔布和羟基化伐地昔布，以阐明荷瘤小鼠药物代谢的降低。
DOI：
10.1016/j.jpba.2018.05.034
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Zhang Jingwei
中科院分区：
文献类型：
--
作者：
Jin Xiaoliang;Zhou Fang;Liu Yan;Cheng Chen;Yao Lan;Jia Yuanwei;Wang Guangji;Zhang Jingwei
帕瑞昔布（Parecoxib，PX）是伐地昔布（valdecoxib，VX）的前体药物，是一种可注射的选择性考克斯-2抑制剂，被推荐用于治疗癌症疼痛。PX可迅速水解成其活性代谢物VX，VX进一步被细胞色素P450酶代谢成羟基化伐地昔布（OH-VX）。然而，据报道，癌症患者的药物代谢能力下降，这可能会导致药物过量积聚。这种过量的PX显著增加了肾脏安全性和心血管事件的风险。因此，有必要阐明PX及其代谢产物在癌症状态下的浓度分布。本研究建立了一种灵敏、快速、特异的LC-MS/MS法测定荷瘤小鼠血浆中PX、VX和OH-VX的方法。蛋白沉淀后，所有分析物在Agilent ZORBAX Extend-C18 HPLC柱（2.1 × 100 mm，3.5 μm）上进行梯度洗脱分离。分析物通过电喷雾负离子质谱在多反应监测模式下检测。用m/z369.0 → 119.0、m/z312.9 → 117.9、m/z329.0 → 196.0和m/z307.1 → 161.3的跃迁分别监测PX、VX、OH-VX和IS。PX和VX在3-3000 ng/mL范围内线性关系良好，OH-VX在3-1000 ng/mL范围内线性关系良好。批内、批间精密度（相对误差RE < 9.9%）和精密度（相对标准偏差RSD < 8.8%）均符合验证标准。基质效应、回收率和稳定性也在可接受标准范围内。将该方法成功应用于荷瘤小鼠体内PX的药代动力学研究，发现随着肿瘤体积的增大，PX和VX的浓度升高，可能增加药物过量的风险。
Parecoxib (PX), a prodrug of valdecoxib (VX), is an injectable selective COX-2 inhibitor, and is recommended for the treatment of cancer pain. PX can be rapidly hydrolyzed into its active metabolite VX, and VX is further metabolized into hydroxylated valdecoxib (OH-VX) by cytochrome P450 enzymes. However, cancer patients have been reported to possess reduced drug metabolism ability, which might cause excessive drug accumulation. Such overdose of PX significantly increased the risk of renal safety and cardiovascular events. Therefore, it is necessary to elucidate the concentration profiles of PX and its metabolites in cancer status. In this study, a sensitive, rapid and specific LC–MS/MS method for quantification of PX, VX and OH-VX in the plasma of tumor bearing mouse was developed and validated. After protein precipitation, all the analytes were separated on an Agilent ZORBAX Extend-C18 HPLC column (2.1 × 100 mm, 3.5 μm) with gradient elution. The analytes were detected by an electrospray negative ionization mass spectrometry in the multiple reaction monitoring mode. The transitionm/z369.0 → 119.0,m/z312.9 → 117.9,m/z329.0 → 196.0, andm/z307.1 → 161.3 were used for monitoring PX, VX, OH-VX and IS respectively. The calibration curves of the analytes showed good linearity over the concentration range of 3–3000 ng/mL for PX and VX, and 3–1000 ng/mL for OH-VX. Intra- and inter-batch accuracies (in terms of relative error, RE < 9.9%) and precisions (in terms of relative standard deviation, RSD < 8.8%) satisfied the standard of validation. The matrix effect, recovery and stability were also within acceptable criteria. The method was successfully applied to the pharmacokinetics study of PX in tumor bearing mice, and PX and VX levels were found elevated with the growth of tumor volume, which might increase the risk of drug overdose.