School of Basic Medical Sciences, Henan University of Science and Technology, Luoyang 471023, China.
Biomed Res Int. 2021 Feb 23;2021:6636266. doi: 10.1155/2021/6636266. eCollection 2021.
To develop and validate a sensitive and rapid ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the determination of enasidenib in rat plasma and to investigate the effect of Xiao-ai-ping injection (XAPI) on the pharmacokinetics of enasidenib in rats.
The rat plasma was precipitated with acetonitrile, enasidenib and internal standard (IS) were separated on an Acquity UPLC BEH C18 column, and acetonitrile and 0.1% formic acid were used as the mobile phase in gradient mode. Enasidenib and IS were monitored and detected by multiple reaction monitoring (MRM) using tandem mass spectrometry in positive ion mode. 12 Sprague-Dawley (SD) rats were randomly divided into control group (group A) and experimental group (group B), 6 rats in each group. Group B was intramuscularly injected with XAPI (0.3 mL/kg) every morning, 7 days in a row. Group A was intramuscularly injected with normal saline, 7 days in a row. On the seventh day, enasidenib (10 mg/kg) was given to both groups 30 min after injection of normal saline (group A) or XAPI (group B), and the blood was collected at different time points such as 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 9, 12, 24, and 48 h. The concentration of enasidenib was detected by UPLC-MS/MS, and the main parameters of pharmacokinetic of enasidenib were calculated using the DAS 2.0 software.
Under the current experimental conditions, this UPLC method showed good linearity in the detection of enasidenib. Interday and intraday precision did not exceed 10%, the range of accuracy values were from -1.43% to 2.76%. The results of matrix effect, extraction recovery, and stability met the requirements of FDA approval guidelines of bioanalytical method validation. The of enasidenib in the group A and the group B was (458.87 ± 136.02) ng/mL and (661.47 ± 107.32) ng/mL, was (7.74 ± 0.91) h and (8.64 ± 0.42) h, AUC was (4067.24 ± 1214.36) ng·h/mL and (5645.40 ± 1046.30) ng·h/mL, AUC was (4125.79 ± 1235.91) ng·h/mL and (5759.61 ± 1078.59) ng·h/mL, respectively. The of enasidenib in group B was 44.15% higher than that in group A, and the AUC and AUC of enasidenib in group B were 38.80% and 39.60% higher than that in group A, respectively, and the was prolonged from 7.74 h to 8.64 h.
An UPLC-MS/MS method for the determination of enasidenib in rat plasma was established. XAPI can inhibit the metabolism of enasidenib and increase the concentration of enasidenib in rats. It is suggested that when XAPI was combined with enasidenib, the herb-drug interaction and adverse reactions should be paid attention to, and the dosage should be adjusted if necessary.
建立一种灵敏、快速的超高效液相色谱-串联质谱法（UPLC-MS/MS），用于测定大鼠血浆中的enasidenib，并研究小艾平注射液（XAPI）对大鼠enasidenib药代动力学的影响。
采用乙腈沉淀法处理大鼠血浆，采用 Acquity UPLC BEH C18 柱分离，乙腈和 0.1%甲酸为流动相，梯度洗脱，在正离子模式下采用多反应监测（MRM）进行监测和检测。将 12 只 Sprague-Dawley（SD）大鼠随机分为对照组（A 组）和实验组（B 组），每组 6 只。B 组每天上午肌肉注射 XAPI（0.3mL/kg），连续 7 天。A 组每天上午肌肉注射生理盐水，连续 7 天。第 7 天，两组分别在注射生理盐水（A 组）或 XAPI（B 组）后 30min 给予enasidenib（10mg/kg），并在 0.33、0.67、1、1.5、2、3、4、6、9、12、24 和 48h 等不同时间点采集血液。采用 UPLC-MS/MS 检测 enasidenib 浓度，用 DAS 2.0 软件计算 enasidenib 的药代动力学主要参数。
在当前实验条件下，该 UPLC 方法对 enasidenib 的检测具有良好的线性。日内和日间精密度不超过 10%，准确度值范围为-1.43%至 2.76%。基质效应、提取回收率和稳定性的结果符合 FDA 批准的生物分析方法验证指南的要求。A 组和 B 组的 enasidenib 分别为（458.87±136.02）ng/mL 和（661.47±107.32）ng/mL，分别为（7.74±0.91）h 和（8.64±0.42）h，AUC 分别为（4067.24±1214.36）ng·h/mL 和（5645.40±1046.30）ng·h/mL，AUC 分别为（4125.79±1235.91）ng·h/mL 和（5759.61±1078.59）ng·h/mL。B 组的 enasidenib 分别比 A 组高 44.15%，B 组的 AUC 和 AUC 分别比 A 组高 38.80%和 39.60%，分别延长至 8.64h。
建立了一种用于测定大鼠血浆中 enasidenib 的 UPLC-MS/MS 方法。XAPI 可抑制 enasidenib 的代谢，增加大鼠 enasidenib 的浓度。建议在 XAPI 与 enasidenib 联合使用时，应注意草药-药物相互作用和不良反应，并根据需要调整剂量。
