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中国临床药理学与治疗学 ›› 2022, Vol. 27 ›› Issue (5): 516-525.doi: 10.12092/j.issn.1009-2501.2022.05.004

• 基础研究 • 上一篇    下一篇

基于OAT3介导的MTX治疗佐剂诱导性关节炎大鼠的药动学研究

潘淑1,2，吴义金1,4，张洒洒1,2，王启海3，罗婷婷1，殷勤1,2   

  1. 1皖南医学院第二附属医院药剂科；2皖南医学院药学院；3安徽中医药高等专科学校药学系；4皖南医学院中西医结合研究中心，芜湖 241001，安徽
  • 收稿日期:2022-03-01 修回日期:2022-05-11 出版日期:2022-05-26 发布日期:2022-06-06
  • 通讯作者: 殷勤，男，硕导，副教授，主要研究方向：临床药学。 E-mail: yq0553@163.com
  • 作者简介:潘淑，女，在读硕士研究生，研究方向：药学。 E-mail: 2695566067@qq.com 吴义金，共同第一作者，男，硕士，主要研究方向：药理学。 E-mail: yijinwu1224@163.com
  • 基金资助:
    安徽省自然科学基金项目（2108085QH386）；安徽省高校自然科学研究项目（KJ2021A1276）；安徽省卫生健康委科研项目（AHWJ2021b038）；安徽省中医药传承创新科研项目（2020zcyb02）；皖南医学院大学生科研资助金项目（WK2021XS62）

Pharmacokinetics of methotrexate mediated by organic anion transporter 3 in adjuvant induced arthritis rats

PAN Shu1,2, WU Yijin1,4, ZHANG Sasa1,2, WANG Qihai3, LUO Tingting1, YIN Qin1,2   

  1. 1Department of Pharmacy, The Second Affiliated Hospital of Wannan Medical College; 2School of Pharmacy, Southern Anhui Medical College; 3Department of Pharmacy, Anhui College of Traditional Chinese Medicine; 4Research Center of Integrated Traditional Chinese and Western Medicine, Wannan Medical College, Wuhu 241001, Anhui, China
  • Received:2022-03-01 Revised:2022-05-11 Online:2022-05-26 Published:2022-06-06

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摘要：

目的：探究炎症条件下对甲氨蝶呤（MTX）的药代动力学的影响及其相关机制的研究。方法：建立佐剂诱导性关节炎（AIA）模型，通过免疫组化、蛋白免疫印迹法和QPCR法检测肾脏中有机阴离子转运体3（OAT3）的表达，并通过LC-MS/MS法检测MTX的血药浓度，采用离体大鼠肾灌注、肾切片以及体外细胞摄取和转运实验对比给药不同时间后的药物代谢动力学行为。结果：在AIA大鼠肾脏中OAT3表达显著增加，同时通过优化的LC-MS/MS方法检测MTX的浓度，结果发现AIA大鼠肾切片对MTX的摄取显著增加，丙磺舒可以通过抑制OAT3，减少MTX的排泄；此外，体外证实了炎症病理可以通过增加OAT3的表达和功能活性促进MTX经肾脏排泄。 结论：炎症病理条件下通过增加肾脏中OAT3的表达，增强其功能活性，加速了肾脏对MTX的摄取，从而促进了MTX的排泄。

关键词: 类风湿性关节炎, 甲氨蝶呤, 有机阴离子转运体3, 药代动力学, 排泄

Abstract:

AIM: To explore the effects of inflammatory conditions on the pharmacokinetics of methotrexate (MTX) and its related mechanisms.  METHODS: The model of adjuvant induced arthritis (AIA) was established. The expression of organic anion transporter 3 (OAT3) in kidney was detected by immunohistochemistry, Western blotting and QPCR. The plasma concentration of MTX was detected by LC-MS/MS, and the pharmacokinetics of MTX after different administration time were compared by isolated rat kidney perfusion, kidney slices, in vitro cell uptake and transport experiments. RESULTS: The expression of OAT3 was significantly increased in the kidneys of AIA rats by immunohistochemistry, Western blotting and QPCR. At the same time, the concentration of MTX was detected by the optimized LC-MS/MS. The results showed that the uptake of MTX in the kidney slices of AIA rats was significantly increased, and Pro could reduce the excretion of MTX by inhibiting OAT3. Furthermore, it was demonstrated in vitro that inflammatory pathology can promote renal excretion of MTX by increasing the expression and functional activity of OAT3.CONCLUSION: Under inflammatory pathological conditions, it can increase the expression of OAT3 in the kidney, enhance its functional activity, accelerate the uptake of MTX by the kidney, and promote the excretion of MTX.

Key words: rheumatoid arthritis, methotrexate, organic anion transporter 3, pharmacokinetics, excretion

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