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

Amrhein J, Drynda S, Schlatt L, Karst U, Lohmann C, Ciarimboli G, Bertrand J. - Int. J. Mol. Sci. 2020; 21:6632 DOI: 10.3390/ijms21186632

Amrhein et al examined the different uptake and expulsion mechanisms of BARI and TOF in cellular assays. Different cellular uptake mechanism for BARI and TOF was observed and showed that BARI’s transport was not dependent on organic cation transporters. Results indicated TOF was exported from RASF in a MATE-1 dependent way. TOF might be exported from healthy cells, thereby not inhibiting JAK pathway in these cells

The interaction of BARI and TOF with OCTs was investigated using quenching experiments on three sets of HEK293, in which one set HEK293 transfected with hOCT1 and hOCT3; second set was transfected with a hMATE1 plasmid; and last set of HEK293 cells was transfected with cDNA of hOCTN1. OCT expression was analysed in SF isolated from RA and osteoarthritis (OA) patients, as well as peripheral blood mononuclear cells (PBMC). 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. The transport of BARI was not OCT dependent. TOF; however, was exported from RASF in a MATE-1 dependent way. TOF and BARI showed comparable inhibition of downstream signalling pathways.

The reported demonstrated that hMATE1 was mediating OCT for TOF accumulation in human RASF, while there was no interaction with any of the expressed OCTs with BARI. Thus, the differences in cellular uptake mechanism for BARI and TOF might explain differences in clinical performance. Differences in cellular uptake strategies for BARI and TOF were observed, this could be explained by an increased expression of MATE1 transporting TOF from healthy cells.

Keywords: JAK, Tofacitinib, Preclinical, MOA

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Upload date: October 2020

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