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

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 inves...

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Autores principales: Amrhein, Jan, Drynda, Susanne, Schlatt, Lukas, Karst, Uwe, Lohmann, Christoph H., Ciarimboli, Giuliano, Bertrand, Jessica
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556031/
https://www.ncbi.nlm.nih.gov/pubmed/32927842
http://dx.doi.org/10.3390/ijms21186632
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author Amrhein, Jan
Drynda, Susanne
Schlatt, Lukas
Karst, Uwe
Lohmann, Christoph H.
Ciarimboli, Giuliano
Bertrand, Jessica
author_facet Amrhein, Jan
Drynda, Susanne
Schlatt, Lukas
Karst, Uwe
Lohmann, Christoph H.
Ciarimboli, Giuliano
Bertrand, Jessica
author_sort Amrhein, Jan
collection PubMed
description 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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spelling pubmed-75560312020-10-19 Tofacitinib and Baricitinib Are Taken up by Different Uptake Mechanisms Determining the Efficacy of Both Drugs in RA Amrhein, Jan Drynda, Susanne Schlatt, Lukas Karst, Uwe Lohmann, Christoph H. Ciarimboli, Giuliano Bertrand, Jessica Int J Mol Sci Article 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. MDPI 2020-09-10 /pmc/articles/PMC7556031/ /pubmed/32927842 http://dx.doi.org/10.3390/ijms21186632 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Amrhein, Jan
Drynda, Susanne
Schlatt, Lukas
Karst, Uwe
Lohmann, Christoph H.
Ciarimboli, Giuliano
Bertrand, Jessica
Tofacitinib and Baricitinib Are Taken up by Different Uptake Mechanisms Determining the Efficacy of Both Drugs in RA
title Tofacitinib and Baricitinib Are Taken up by Different Uptake Mechanisms Determining the Efficacy of Both Drugs in RA
title_full Tofacitinib and Baricitinib Are Taken up by Different Uptake Mechanisms Determining the Efficacy of Both Drugs in RA
title_fullStr Tofacitinib and Baricitinib Are Taken up by Different Uptake Mechanisms Determining the Efficacy of Both Drugs in RA
title_full_unstemmed Tofacitinib and Baricitinib Are Taken up by Different Uptake Mechanisms Determining the Efficacy of Both Drugs in RA
title_short Tofacitinib and Baricitinib Are Taken up by Different Uptake Mechanisms Determining the Efficacy of Both Drugs in RA
title_sort tofacitinib and baricitinib are taken up by different uptake mechanisms determining the efficacy of both drugs in ra
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556031/
https://www.ncbi.nlm.nih.gov/pubmed/32927842
http://dx.doi.org/10.3390/ijms21186632
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