Quantitation of Diclofenac, Tolbutamide, and Warfarin as Typical CYP2C9 Substrates in Rat Plasma by UPLC-MS/MS and Its Application to Evaluate Linderane-Mediated Herb-Drug Interactions.
Quantitation of Diclofenac, Tolbutamide, and Warfarin as Typical CYP2C9 Substrates in Rat Plasma by UPLC-MS/MS and Its Application to Evaluate Linderane-Mediated Herb-Drug Interactions.
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DOI：
10.1155/2022/1900037
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发表时间：
2022
影响因子：
2.6
通讯作者：
Qiu F
中科院分区：
文献类型：
--
作者：
Zhang T;Peng T;Rao J;Wang K;Qiu F
Linderane（LDR）是L.聚集体，是体外CYP 2C 9的基于机制的灭活剂，表明草药-药物相互作用的发生。然而，临床常用药物作为CYP 2C 9底物与LDR联合给药后的药代动力学性质的变化却知之甚少。在这项研究中，一个选择性和快速的超高效液相色谱-串联质谱（UPLC-MS-MS）方法测定双氯芬酸，甲苯磺丁脲，华法林作为CYP 2C 9底物在大鼠血浆中已被开发。以氯唑沙宗为内标，蛋白质沉淀法制备样品。在UPLC BEH-C18（2.1 × 50 mm，1.7 µm）上进行色谱分离，以0.1%（v：v）甲酸水溶液（A）和乙腈（B）作为移动的相，采用梯度洗脱。总运行时间仅为3.8 min。MS分析在多反应监测（MRM）下进行，其中电子喷雾电离（ESI）以负模式操作。对生物分析方法进行了验证，选择性、残留效应、线性、精密度、准确度、基质效应、提取回收率和稳定性均符合要求。当LDR分别与双氯芬酸、甲苯磺丁脲和华法林沿着使用时，验证的方法成功用于评价潜在的药代动力学相互作用。结果表明，治疗组双氯芬酸的Cmax为1287.82 ± 454.16 μg/L，约为对照组的5倍（P < 0.01）。甲苯磺丁脲的Cmax为60.70 ± 10.70 mg/L，与对照组相比下降约25%（P < 0.01）。治疗组华法林的Vd明显增加，约为对照组的1.4倍（P < 0.01）。
Linderane (LDR), the main active and distinctive component of L. aggregate, is a mechanism-based inactivator of CYP2C9 in vitro, indicating the occurrence of herb-drug interactions. However, little is known about the changes of the pharmacokinetic properties of the common clinical drugs as CYP2C9 substrates after coadministration with LDR. In this study, a selective and rapid ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS-MS) method for the determination of diclofenac, tolbutamide, and warfarin as CYP2C9 substrates in rat plasma has been developed. Chlorzoxazone was employed as an internal standard (IS), and protein precipitation was used for sample preparation. Chromatographic separation was achieved on a UPLC BEH-C18 (2.1 × 50 mm, 1.7 µm) with 0.1% (v:v) formic acid in water (A) and acetonitrile (B) as the mobile phase with gradient elution. The total run time was only 3.8 min. MS analysis was performed under multiple reaction monitoring (MRM) with electron spray ionization (ESI) operated in the negative mode. The bioanalytical method was validated, and the selectivity, carryover effects, linearity, precision, accuracy, matrix effect, extraction recovery, and stability were acceptable. The validated method was then successfully applied for evaluating the potential pharmacokinetic interactions when LDR was used along with diclofenac, tolbutamide, and warfarin, respectively. Results showed that the Cmax of diclofenac in the treated group was 1287.82 ± 454.16 μg/L, which was about 5-fold of that in the control group (P < 0.01). The Cmax of tolbutamide in the treated group was 60.70 ± 10.70 mg/L, which was significantly decreased by about 25% when compared with the control group (P < 0.01). The Vd of warfarin in the treated group was obviously increased, which was about 1.4-fold of that in the control group (P < 0.01).
影响因子：
2.4
作者：
Noda Y;Mori A
通讯作者：
Mori A