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 C_max of diclofenac in the treated group was 1287.82 ± 454.16 μg/L, which was about 5-fold of that in the control group . The C_max 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 . The V_d of warfarin in the treated group was obviously increased, which was about 1.4-fold of that in the control group .

中文翻译：

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通过 UPLC-MS/MS 对大鼠血浆中典型 CYP2C9 底物的双氯芬酸、甲苯磺丁脲和华法林进行定量及其在评估林德烷介导的草药-药物相互作用中的应用

Linderane (LDR) 是L. 聚合体的主要活性和独特成分，是一种基于机制的体外CYP2C9 灭活剂，表明存在草药-药物相互作用。然而，临床常用药物作为CYP2C9底物与LDR合用后药代动力学性质的变化知之甚少。本研究开发了一种选择性快速超高效液相色谱-串联质谱 (UPLC-MS-MS) 方法，用于测定大鼠血浆中作为 CYP2C9 底物的双氯芬酸、甲苯磺丁脲和华法林。氯唑沙宗用作内标（IS），蛋白质沉淀用于样品制备。_{在 UPLC BEH-C 18}上实现色谱分离(2.1 × 50 mm, 1.7 µm)，使用 0.1% (v:v) 甲酸水溶液 ( A ) 和乙腈 (B) 作为流动相，进行梯度洗脱。总运行时间仅为 3.8 分钟。MS 分析在多重反应监测 (MRM) 下进行，电子喷雾电离 (ESI) 以负模式操作。生物分析方法经过验证，选择性、残留效应、线性、精密度、准确度、基质效应、萃取回收率和稳定性均可接受。当 LDR 分别与双氯芬酸、甲苯磺丁脲和华法林一起使用时，该验证方法成功地用于评估潜在的药代动力学相互作用。结果显示，治疗组双氯芬酸的C _max为1287.82 ± 454.16  μg/L，约为对照组的5倍. 治疗组_{甲苯磺丁脲Cmax为60.70±10.70 mg/} L，与对照组相比显着降低约25%. 治疗组华法林V _d明显升高，约为对照组的1.4倍.