Wang Yu, Zhou Quan, Wang Huihui, Song Wei, Wang Jianfeng, Mamun Abdullah Al, Geng Peiwu, Zhou Yunfang, Wang Shuanghu
Key Laboratory of Joint Diagnosis and Treatment of Chronic Liver Disease and Liver Cancer of Lishui, Wenzhou Medical University Lishui Hospital, Lishui People's Hospital, Lishui, Zhejiang, China.
Front Pharmacol. 2024 Apr 8;15:1351882. doi: 10.3389/fphar.2024.1351882. eCollection 2024.
This work aimed to explore the mechanisms underlying the interaction of the active furanocoumarins on tofacitinib both and . The concentration of tofacitinib and its metabolite M8 was determined using UPLC-MS/MS. The peak area ratio of M8 to tofacitinib was calculated to compare the inhibitory ability of furanocoumarin contained in the traditional Chinese medicine in rat liver microsomes (RLMs), human liver microsomes (HLMs) and recombinant human CYP3A4 (rCYP3A4). We found that bergapten and isopsoralen exhibited more significant inhibitory activity in RLMs than other furanocoumarins. Bergapten and isopsoralen were selected to investigate tofacitinib drug interactions and . Thirty rats were randomly allocated into 5 groups ( = 6): control (0.5% CMC-Na), low-dose bergapten (20 mg/kg), high-dose bergapten (50 mg/kg), low-dose isopsoralen (20 mg/kg) and ketoconazole. 10 mg/kg of tofacitinib was orally intervented to each rat and the concentration level of tofacitinib in the rats were determined by UPLC-MS/MS. More imporrantly, the results showed that bergapten and isopsoralen significantly inhibited the metabolism of tofacitinib metabolism. The AUC, AUC, MRT, MRT and Cmax of tofacitinib increased in varying degrees compared with the control group (all < 0.05), but CLz/F decreased in varying degrees ( < 0.05) in the different dose bergapten group and isopsoralen group. Bergapten, isopsoralen and tofacitinib exhibit similar binding capacities with CYP3A4 by AutoDock 4.2 software, confirming that they compete for tofacitinib metabolism. may considerably impact the metabolism of tofacitinib, which can provide essential information for the accurate therapeutic application of tofacitinib.
这项工作旨在探究活性呋喃香豆素与托法替布相互作用的潜在机制。采用超高效液相色谱-串联质谱法（UPLC-MS/MS）测定托法替布及其代谢物M8的浓度。计算M8与托法替布的峰面积比，以比较中药中所含呋喃香豆素在大鼠肝微粒体（RLMs）、人肝微粒体（HLMs）和重组人CYP3A4（rCYP3A4）中的抑制能力。我们发现，补骨脂素和异补骨脂素在RLMs中比其他呋喃香豆素表现出更显著的抑制活性。选择补骨脂素和异补骨脂素研究托法替布的药物相互作用。30只大鼠随机分为5组（每组n = 6）：对照组（0.5%羧甲基纤维素钠）、低剂量补骨脂素组（20 mg/kg）、高剂量补骨脂素组（50 mg/kg）、低剂量异补骨脂素组（20 mg/kg）和酮康唑组。给每只大鼠口服10 mg/kg托法替布，并用UPLC-MS/MS测定大鼠体内托法替布的浓度水平。更重要的是，结果表明补骨脂素和异补骨脂素显著抑制托法替布的代谢。与对照组相比，托法替布的AUC、AUC、MRT、MRT和Cmax均有不同程度升高（均P < 0.05），但不同剂量补骨脂素组和异补骨脂素组的CLz/F均有不同程度降低（P < 0.05）。通过AutoDock 4.2软件，补骨脂素、异补骨脂素与托法替布对CYP3A4表现出相似的结合能力，证实它们竞争托法替布的代谢。这可能会对托法替布的代谢产生显著影响，可为托法替布的准确治疗应用提供重要信息。
