液相色谱-串联质谱测定感染小鼠血浆中百纳培南: 方法学的建立、验证及其药物动力学研究应用

doi:10.5246/jcps.2019.11.076

中国药学(英文版) ›› 2019, Vol. 28 ›› Issue (11): 802-811.DOI: 10.5246/jcps.2019.11.076

液相色谱-串联质谱测定感染小鼠血浆中百纳培南: 方法学的建立、验证及其药物动力学研究应用

冀希炜¹, 康子胜¹, 李耘¹, 杨西平², 马西凤², 石崇铁², 吕媛^1*

1. 北京大学第一医院临床药理研究所, 北京 100191
2. 山东轩竹医药科技有限公司, 山东济南 250101

收稿日期:2019-07-29 修回日期:2019-09-13 出版日期:2019-12-01 发布日期:2019-10-11
通讯作者: Tel.: +86-10-82802542, E-mail: jxezz@sina.com
基金资助:
National Natural Science Foundation of China (Grant No. 81803614).

An established LC-MS/MS method and a developed PK model for the study of pharmacokinetic properties of benapenem in infected mice

Xiwei Ji1, Zisheng Kang1, Yun Li1, Xiping Yang2, Xifeng Ma², Chongtie Shi², Yuan Lv^1*

1. Institute of Clinical Pharmacology, Peking University First Hospital, Beijing 100191, China
2. XuanZhu Pharma Co., Ltd., Jinan 250101, Shandong, China

Received:2019-07-29 Revised:2019-09-13 Online:2019-12-01 Published:2019-10-11
Contact: Tel.: +86-10-82802542, E-mail: jxezz@sina.com
Supported by:
National Natural Science Foundation of China (Grant No. 81803614).

摘要/Abstract

摘要：

百纳培南是一类新型的广谱β-内酰胺类经肠外给药抗菌药物。本研究建立了一种简便、快速、灵敏的液质联用方法用于测定感染小鼠血浆中百纳培南的浓度。采用百纳培南氘代内标, 血浆样品经甲醇进行蛋白沉淀处理后, 采用乙腈(含0.2%甲酸)–10 mM乙酸铵溶液(含0.2%甲酸)作为流动相, 采用C₁₈反相色谱柱进行梯度洗脱分离。使用三重四级杆串联质谱, 电喷雾正离子模式、多反应监测技术进行检测。标准曲线在10~2000 ng/mL范围内线性良好(r>0.99), 定量下限为10 ng/mL, 批内及批间精密度分别<4.85%和<1.47%。百纳培南和内标的提取回收率分别为97.07%~107.09%和92.47%~111.59%。批内及批间准确度为–9.70%~–11.00%, 百纳培南和内标的基质效应分别为85.68%~92.04%和83.17%~92.04%。该方法已成功应用于百纳培南的临床前药代动力学研究。此外, 我们还建立了一个二室模型来描述百纳培南在感染小鼠体内的药物动力学行为, 以更好地了解其药动学特征。

关键词: 液质联用, 百纳培南, 感染小鼠, 药物动力学, 建模

Abstract:

Benapenem is a new parenteral beta-lactam antibacterial with a broad antibacterial spectrum. In the present study, we developed and validated a simple, rapid and sensitive assay method using D6-benapenem as internal standard (IS) after one-step precipitation with methanol to determine benapenem in the plasma of infected mice. Separation was achieved on a reverse phase C₁₈ column with a mobile phase composed of acetonitrile containing 0.2% formic acid–water (0.2% formic acid) and 10 mmol/L ammonium acetate in gradient elution mode. A triple quadrupole tandem mass spectrometer with electrospray ionization source was used as detector and operated by multiple reaction monitoring (MRM) in the positive ion mode. Calibration curves were linear (r>0.99) between 10 and 2000 ng/mL. The quantitative limit was 10 ng/mL, and the intra- and inter- precisions were <4.85% and <1.47%, respectively. The extraction recovery of benapenem and IS was 97.07%–107.09% and 92.47%–111.59%, respectively. The intra- and inter- accuracies were –9.70%– –11.00%, and the matrix effects of benapenem and IS were 85.68%–92.04% and 83.17%–92.04%, respectively. The method was successfully applied to the preclinical pharmacokinetic (PK) studies of benapenem. We also developed a two-compartment model to characterize the PK profiles of benapenem in infected mice, which could provide a better understanding of the PK properties of benapenem.

Key words: LC-MS/MS, Benapenem, Infected mice, Pharmacokinetics, Modeling

中图分类号:

R917

Supporting:

冀希炜, 康子胜, 李耘, 杨西平, 马西凤, 石崇铁, 吕媛. 液相色谱-串联质谱测定感染小鼠血浆中百纳培南: 方法学的建立、验证及其药物动力学研究应用[J]. 中国药学(英文版), 2019, 28(11): 802-811.

Xiwei Ji, Zisheng Kang, Yun Li, Xiping Yang, Xifeng Ma, Chongtie Shi, Yuan Lv. An established LC-MS/MS method and a developed PK model for the study of pharmacokinetic properties of benapenem in infected mice[J]. Journal of Chinese Pharmaceutical Sciences, 2019, 28(11): 802-811.

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液相色谱-串联质谱测定感染小鼠血浆中百纳培南: 方法学的建立、验证及其药物动力学研究应用

An established LC-MS/MS method and a developed PK model for the study of pharmacokinetic properties of benapenem in infected mice

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