Tofacitinib and Baricitinib Are Taken up by Different Uptake Mechanisms Determining the Efficacy of Both Drugs in RA

被引:18
作者
Amrhein, Jan [1 ]
Drynda, Susanne [2 ]
Schlatt, Lukas [3 ]
Karst, Uwe [3 ]
Lohmann, Christoph H. [2 ]
Ciarimboli, Giuliano [1 ]
Bertrand, Jessica [2 ]
机构
[1] Univ Hosp Munster, Dept Internal Med D, Expt Nephrol, D-48149 Munster, Germany
[2] Otto von Guericke Univ, Dept Orthoped Surg, D-39120 Magdeburg, Germany
[3] Univ Munster, Inst Inorgan & Analyt Chem, D-48149 Munster, Germany
关键词
RA; Tofacitinib; Baricitinib; organic cation transporter; MATE1; RHEUMATOID-ARTHRITIS; SYNOVIAL FIBROBLASTS; PHARMACOKINETICS; INHIBITOR; FLUID; JAK;
D O I
10.3390/ijms21186632
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Background: Rheumatoid arthritis (RA) is a systemic autoimmune disease in which synovial fibroblasts (SF) play a key role. Baricitinib and Tofacitinib both act intracellularly, blocking the ATP-binding side of JAK proteins and thereby the downstream signalling pathway via STAT-3. Therefore, we investigated the role of organic cation transporters (OCTs) in Baricitinib and Tofacitinib cellular transport. Methods: OCT expression was analysed in SF isolated from RA and osteoarthritis (OA) patients, as well as peripheral blood mononuclear cells. The interaction of Baricitinib and Tofacitinib with OCTs was investigated using quenching experiments. The intracellular accumulation of both drugs was quantified using LC/MS. Target inhibition for both drugs was tested using Western blot for phosphorylated JAK1 and STAT3 upon stimulation with IL-6. Results: MATE-1 expression increased in OASF compared to RASF. The other OCTs were not differentially expressed. The transport of Baricitinib was not OCT dependent. Tofacitinib; however, was exported from RASF in a MATE-1 dependent way. Tofacitinib and Baricitinib showed comparable inhibition of downstream signalling pathways. Conclusion: We observed different cellular uptake strategies for Baricitinib and Tofacitinib. Tofacitinib was exported out of healthy cells due to the increased expression of MATE1. This might make Tofacitinib the favourable drug.
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页码:1 / 13
页数:13
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