Fu Ran, Wang Xiao-Nan, Guo Cai-Hui, Li Ying, Ding Cong-Yang, Li Ya-Jing, Dong Zhan-Jun
Department of Pharmacy, Hebei General Hospital, Shijiazhuang, China.
Ann Transl Med. 2021 May;9(10):845. doi: 10.21037/atm-21-1303.
Methotrexate (MTX) is an important anticancer agent and immunosuppressant with a narrow therapeutic window. Wuzhi capsule (WZC) is an extract of Schisandra which is widely used to treat liver diseases. Co-administration of MTX and WZC is common in the clinical setting, but research on the interaction between WZC and MTX is limited. This study aimed to investigate the effects of WZC on the pharmacokinetics of MTX in rats and to explore the role of membrane transport proteins OAT1/3 and P-gp in the interaction of these drugs.
Plasma MTX concentration was detected by ultra-performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS), and the messenger RNA (mRNA) and protein expression of OAT1/3 and P-gp was evaluated by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting analyses, respectively.
The study results revealed that co-administration of WZC decreased the CL and V of MTX, increased the C and area under the curve [(AUC)] of MTX, and inhibited OAT1/3 expression in the kidney and P-gp expression in the small intestine.
The findings suggested that there is a drug interaction between WZC and MTX and that OAT1/3 in the kidney and P-gp in the small intestine may be the main targets mediating the drug interaction, and attention should be paid when they are used in combination.
甲氨蝶呤（MTX）是一种重要的抗癌药物和免疫抑制剂，治疗窗狭窄。五酯胶囊（WZC）是五味子提取物，广泛用于治疗肝脏疾病。MTX与WZC在临床中常联合使用，但关于WZC与MTX相互作用的研究有限。本研究旨在探讨WZC对大鼠体内MTX药代动力学的影响，并探究膜转运蛋白OAT1/3和P-糖蛋白（P-gp）在这些药物相互作用中的作用。
采用超高效液相色谱-串联质谱仪（UPLC-MS/MS）检测血浆MTX浓度，分别通过逆转录定量聚合酶链反应（RT-qPCR）和蛋白质免疫印迹分析评估OAT1/3和P-gp的信使核糖核酸（mRNA）和蛋白表达。
研究结果显示，联合使用WZC可降低MTX的清除率（CL）和表观分布容积（V），增加MTX的血药浓度（C）和曲线下面积（AUC），并抑制肾脏中OAT1/3的表达以及小肠中P-gp的表达。
研究结果表明，WZC与MTX之间存在药物相互作用，肾脏中的OAT1/3和小肠中的P-gp可能是介导药物相互作用的主要靶点，联合使用时应予以关注。
