School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Department of Pharmacy, The First Affiliated Hospital of Jinan University (Guangzhou Overseas Chinese Hospital), Guangzhou 510630, China.
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Biochem Pharmacol. 2021 Mar;185:114413. doi: 10.1016/j.bcp.2021.114413. Epub 2021 Jan 9.
Due to the elevated presence of cytokines, the expressions of metabolic enzymes and drug transporters are altered in rheumatoid arthritis (RA). Given the high incidence of diabetes in patients with RA, the aim of the present study was to investigate the metformin pharmacokinetics of a single oral dose in rats with collagen-induced arthritis (CIA). Blood and urine samples were collected at different timepoints, and analyzed by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Tissue samples were also collected to investigate the expression of metabolic enzymes and drug transporters by quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and western blot. The results indicated that the bioavailability of metformin was markedly decreased in the CIA rats. Moreover, metformin was not metabolized by enzymes of rat liver microsomes, suggesting that the decreased bioavailability of metformin was independent of the liver metabolism. In addition, the mRNA, protein expression level and activity of the renal organic cation transporter 2 (OCT2) was markedly increased, suggesting that the enhanced renal clearance of metformin in CIA rats may be due to the up-regulated activity of OCT2. In conclusion, our study suggested that the reduced bioavailability of metformin in CIA rats is possibly related to the up-regulated function of the renal protein OCT2.
由于细胞因子的存在水平升高，类风湿关节炎（RA）患者的代谢酶和药物转运体的表达发生改变。鉴于 RA 患者糖尿病的发病率较高，本研究旨在探讨胶原诱导关节炎（CIA）大鼠中单剂量口服二甲双胍的药代动力学。采集不同时间点的血样和尿样，并用超高效液相色谱串联质谱法（UPLC-MS/MS）进行分析。还收集组织样本，通过定量逆转录聚合酶链反应（RT-qPCR）和蛋白质印迹法来研究代谢酶和药物转运体的表达。结果表明，CIA 大鼠中的二甲双胍生物利用度显著降低。此外，二甲双胍未被大鼠肝微粒体中的酶代谢，表明二甲双胍生物利用度的降低与肝脏代谢无关。此外，肾脏有机阳离子转运体 2（OCT2）的 mRNA、蛋白表达水平和活性显著增加，提示 CIA 大鼠中二甲双胍的肾清除率增加可能是由于 OCT2 活性上调所致。综上所述，我们的研究表明，CIA 大鼠中二甲双胍的生物利用度降低可能与肾脏蛋白 OCT2 功能上调有关。
