Simultaneous quantification of vincristine and its major M1 metabolite from dried blood spot samples of Kenyan pediatric cancer patients by UPLC-MS/MS.
Simultaneous quantification of vincristine and its major M1 metabolite from dried blood spot samples of Kenyan pediatric cancer patients by UPLC-MS/MS.
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DOI：
10.1016/j.jpba.2021.114143
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发表时间：
2021-09-05
影响因子：
3.4
通讯作者：
Chow, Diana S-L
中科院分区：
文献类型：
--
作者：
Agu, Lorita;Skiles, Jodi L.;Masters, Andrea R.;Renbarger, Jamie L.;Chow, Diana S-L
长春新碱（VCR）是美国和发展中国家化疗方案的组成部分。关于其处置和最佳治疗剂量的信息很少。VCR通过多态性CYP 3A 5酶优先代谢为其主要代谢产物M1，这可能具有临床意义，因为不同人群的CYP 3A 5表达不同。因此，监测VCR和M1并表征其处置非常重要。先前开发的用于VCR定量的HPLC-MS/MS方法不够灵敏，无法定量VCR给药后1小时后的M1代谢产物（未发表）。建立一种高灵敏度的检测方法是同时定量和监测VCR和M1的先决条件，这将能够表征儿科癌症人群中两种分析物的药物暴露和处置。在浸提过程中加入甲酸可增强DBS样品中的M1浸提。开发并验证了用于同时定量人干血斑（DBS）中VCR和M1的灵敏度、准确度和精密度的UPLC-MS/MS分析方法。在Inertsil ODS-3 C18柱（5 μm，3.0 x 150 mm）上进行色谱分离。使用移动的相A（甲醇-0.2%甲酸水溶液，20：80 v/v）和移动的相B（甲醇-0.2%甲酸水溶液，80：20 v/v）的梯度洗脱，流速为0.4 mL/min，总运行时间为5 min。分析物通过正离子模式下的电喷雾电离进行电离。DBS中两种分析物的线性范围分别为0.6-100 ng/ml（VCR）和0.4-100 ng/ml（M1）。VCR和M1的日内和日间准确度分别为93.10-117.17%和95.88- 111.21%。日内和日间精密度分别为1.05 ~ 10.11%和5.78 ~ 8.91%。DBS纸中VCR的提取回收率为35.3 - 39.4%，M1为10.4 - 13.4%，两种分析物均未观察到残留。这是第一种报告同时定量人DBS中VCR和M1的分析方法。首次在VCR给药后1小时后获得DBS患者样本中的M1浓度。所开发的方法成功地用于监测这两种化合物，并在肯尼亚儿科癌症患者人群中进行药代动力学分析。
Vincristine (VCR) is an integral part of chemotherapy regimens in the US and in developing countries. There is a paucity of information about its disposition and optimal therapeutic dosing. VCR is preferentially metabolized to its major M1 metabolite by the polymorphic CYP3A5 enzyme, which may be clinically significant as CYP3A5 expression varies across populations. Thus, it is important to monitor both VCR and M1 and characterize their dispositions. A previously developed HPLC-MS/MS method for VCR quantification was not sensitive enough to quantify the M1 metabolite beyond 1 hr. post VCR dose (not published). Establishing a highly sensitive assay is a pre-requisite to simultaneously quantify and monitor VCR and M1, which will enable characterization of drug exposure and dispositions of both analytes in a pediatric cancer population. The addition of formic acid during the extraction process enhanced M1 extraction from DBS samples. A sensitive, accurate, and precise UPLC-MS/MS assay method for the simultaneous quantification of VCR and M1 from human dried blood spots (DBS) was developed and validated. Chromatographic separation was performed on Inertsil ODS-3 C18 column (5 μm, 3.0 x 150 mm). A gradient elution of mobile phase A (methanol-0.2% formic acid in water, 20:80 v/v) and mobile phase B (methanol-0.2% formic acid in water, 80:20 v/v) was used with a flow rate of 0.4 mL/min and a total run time of 5 min. The analytes were ionized by electrospray ionization in the positive ion mode. The linearity range for both analytes in DBS were 0.6-100 ng/ml for VCR and 0.4-100 ng/ml for M1. The intra- and inter-day accuracies for VCR and M1 were 93.10-117.17% and 95.88-111.21%, respectively. While their intra- and inter-day precisions were 1.05 to 10.11% and 5.78 to 8.91%, respectively. The extraction recovery of VCR from DBS paper was 35.3 – 39.4% and 10.4 – 13.4% for M1, with no carryover observed for both analytes. This is the first analytical method to report the simultaneous quantification of VCR and M1 from human DBS. For the first time, concentrations of M1 from DBS patient samples were obtained beyond 1-hour post VCR dose. The developed method was successfully employed to monitor both compounds and perform pharmacokinetic analysis in a population of Kenyan pediatric cancer patients.
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影响因子：
8.2
作者：
Yan, Zhao;Zhu, Zhong-ling;Cheng, Guang
通讯作者：
Cheng, Guang
影响因子：
7.4
作者：
Spooner, Neil;Lad, Rakesh;Barfield, Matt
通讯作者：
Barfield, Matt
影响因子：
3.9
作者：
Dennison, Jennifer B.;Kulanthaivel, Palaniappan;Hall, Stephen D.
通讯作者：
Hall, Stephen D.
影响因子：
2.7
作者：
Hewawasam, Erandi;Liu, Ge;Muhlhausler, Beverly S.
通讯作者：
Muhlhausler, Beverly S.
DOI：
10.1124/jpet.106.118471
发表时间：
2007-05-01
影响因子：
3.5
作者：
Dennison, Jennifer B.;Jones, David R.;Hall, Stephen D.
通讯作者：
Hall, Stephen D.