CP-25 enhances OAT1-mediated absorption of methotrexate in synoviocytes of collagen-induced arthritis rats

Chun Wang1,2, Hao Tang1,2, Yong Wang1,2, Yan Chang1,2, Yi-jin Wu1,2, Bin Wang1,2, Wei Sun1,2, Feng Xiao1,2, Wei Wei1,2
1 Institute of Clinical Pharmacology, Anhui Medical University
2 Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei 230032, China
Correspondence to: Wei Wei:,
DOI: 10.1038/s41401-022-00931-5
Received: 8 July 2021
Accepted: 26 May 2022
Advance online: 22 June 2022


Organic anion transporter 1 (OAT1) plays a major role in mediating the absorption, distribution and excretion of drugs and other xenobiotics in the human body. In this study we explored the OAT1 status in rheumatoid arthritis (RA) patients and arthritic animals and its role in regulating the anti-arthritic activity of methotrexate (MTX). We showed that OAT1 expression was significantly downregulated in synovial tissues from RA patients compared with that in the control patients. In collagen-induced arthritis (CIA) rats, synovial OAT1 expression was significantly decreased compared with the control rats. In synoviocytes isolated from CIA rats, PGE2 (0.003–1.75 μM) dose-dependently downregulated OAT1 expression, resulting in decreased absorption of MTX. Silencing OAT1 in synoviocytes caused a 43.7% reduction in the uptake of MTX. Furthermore, knockdown of OAT1 impaired MTX-induced inhibitory effects on the viability and migration of synoviocytes isolated from CIA rats. Moreover, injection of OAT1-shRNA into articular cavity of CIA rats significantly decreased synovial OAT1 expression and impaired the anti-arthritic action of MTX, while injection of lentivirus containing OAT1 sequences led to the opposite results. Interestingly, we found that paeoniflorin-6’-O- benzene sulfonate (CP-25) upregulated OAT1 expression both in vitro and in vivo and promoted MTX uptake by synoviocytes via regulating OAT1 expression and function. Taken together, OAT1 plays a major role in regulating MTX uptake by synoviocytes and the anti-arthritic activity of MTX. OAT1 is downregulated in RA and CIA rats, which can be improved by CP-25.
Keywords: rheumatoid arthritis; synoviocyte; organic anion transporter 1; methotrexate; CP-25; drug absorption; collagen-induced arthritis (CIA) model

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