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

Jan Amrhein,Giuliano Ciarimboli,Christoph H Lohmann,Susanne Drynda,Uwe Karst,Jessica Bertrand,Lukas Schlatt

doi:10.3390/ijms21186632

Abstract

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.

Highlights

Rheumatoid arthritis (RA) is a systemic autoimmune disease that predominantly affects synovial joints, causing progressive polyarthritis, joint destruction and disability [1]
We observed no difference in the expression of hOCT1 and hOCT3 between RA and OA synovial fibroblasts. hOCT2 was not detectable. hOCTN2 was only weakly expressed and no difference was seen between Rheumatoid Arthritis synovial fibroblasts (RASF) and OASF
RASF, expressed significantly more hOCTN1 (F (9, 44) = 12.06, 95% CI: 0.4480 to 1.157, p < 0.0001)

Summary

Introduction

Rheumatoid arthritis (RA) is a systemic autoimmune disease that predominantly affects synovial joints, causing progressive polyarthritis, joint destruction and disability [1]. RASF acquire an aggressive phenotype with increased proliferation, loss of cell–cell contacts and joint invasiveness, where they secrete proinflammatory cytokines and interact with other immune and stroma cells to perpetuate the inflammatory reaction [2]. Rheumatoid arthritis (RA) is a systemic autoimmune disease in which synovial fibroblasts (SF) play a key role. We investigated the role of organic cation transporters (OCTs) in Baricitinib and Tofacitinib cellular transport. Results: MATE-1 expression increased in OASF compared to RASF. Tofacitinib; was exported from RASF in a MATE-1 dependent way. Tofacitinib and Baricitinib showed comparable inhibition of downstream signalling pathways. 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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