Zhang Tingting, Peng Ting, Rao Jinqiu, Wang Kai, Qiu Feng
School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
J Anal Methods Chem. 2022 Mar 10;2022:1900037. doi: 10.1155/2022/1900037. eCollection 2022.
Linderane (LDR), the main active and distinctive component of , is a mechanism-based inactivator of CYP2C9 , 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-C (2.1 × 50 mm, 1.7 µm) with 0.1% (v:v) formic acid in water () 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 of diclofenac in the treated group was 1287.82 ± 454.16 g/L, which was about 5-fold of that in the control group ( < 0.01). The 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 ( < 0.01). The of warfarin in the treated group was obviously increased, which was about 1.4-fold of that in the control group ( < 0.01).
林德内酯（LDR）是[具体物质]的主要活性和独特成分，是一种基于机制的CYP2C9失活剂，表明存在草药 - 药物相互作用。然而，对于与LDR合用时作为CYP2C9底物的常见临床药物的药代动力学性质变化知之甚少。在本研究中，已开发出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），采用蛋白沉淀法进行样品制备。在UPLC BEH-C（2.1×50 mm，1.7 µm）色谱柱上进行色谱分离，以0.1%（v:v）甲酸水溶液（A）和乙腈（B）为流动相进行梯度洗脱。总运行时间仅为3.8分钟。质谱分析在多反应监测（MRM）模式下进行，采用负模式操作的电喷雾电离（ESI）。对生物分析方法进行了验证，其选择性、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。经验证的方法随后成功应用于评估LDR分别与双氯芬酸、甲苯磺丁脲和华法林合用时的潜在药代动力学相互作用。结果表明，治疗组双氯芬酸的AUC为1287.82±454.16 μg/L，约为对照组的5倍（P<0.01）。治疗组甲苯磺丁脲的AUC为60.70±10.70 mg/L，与对照组相比显著降低约25%（P<0.01）。治疗组华法林的AUC明显升高，约为对照组的1.4倍（P<0.01）。
