Sulfasalazine is a potent inhibitor of the reduced folate carrier: Implications for combination therapies with methotrexate in rheumatoid arthritis

Abstract

Objective. To investigate whether interactions of sulfasalazine (SSZ) with reduced folate carrier (RFC), the dominant cell membrane transporter for natural folates and methotrexate (MTX), may limit the efficacy of combination therapy with MTX and SSZ in patients with rheumatoid arthritis. Conclusion. At clinically relevant plasma concentrations, interactions of SSZ with RFC provide a biochemical rationale for 2 important clinical observations: 1) the onset of (sub)clinical folate deficiency during SSZ treatment, and 2) the lack of additivity/synergism of the combination of SSZ and MTX when these diseasemodifying antirheumatic drugs are administered simultaneously. Thus, when considering use of these drugs in combination therapies, the present results provide a rationale both for the use of folate supplementation and for spacing administration of these drugs over time.

Cellular folate status modulates the expression of BCRP and MRP multidrug transporters in cancer cell lines from different origins

“…Interestingly, essentially the same phenotype of BCRP induction as described herein for WiDr LF cells was also observed for human CEM leukemia cells in which folate deficiency was induced by blocking folate uptake via the RFC using the anti-arthritic drug sulfasalazine (38,39). Consistent with the observation for Caco-2 cells, WiDr LF cells were also more sensitive to methotrexate than the HF counterpart (16).…”

Acquired resistance to chloroquine in human CEM T cells is mediated by multidrug resistance–associated protein 1 and provokes high levels of cross‐resistance to glucocorticoids

“…The expanding knowledge of the physiologic substrates and functions of an increasing number of multidrug resistance transporters, along with their tentative role in inflammatory and immunologic processes (10,45), deserves further attention, particularly in diseases such as RA, in which patients receive long-term treatment with DMARDs. The present study also indicates potential types of drug interactions or secondary effects of DMARD combinations in RA treatment, as we have previously demonstrated for a combination of MTX and SSZ (49). HCQ has proven to be an attractive drug in DMARD combination treatment for RA (4,13), but its long-term use may compromise the activity of other antiinflammatory drugs, particularly glucocorticoids.…”

Determinants of red blood cell methotrexate polyglutamate concentrations in rheumatoid arthritis patients receiving long‐term methotrexate treatment

“…For example, in vitro sulfasalazine is a potent noncompetitive inhibitor of RFC-mediated cellular uptake of MTX and folate (21). In a small study of MTX and hydroxychlo-roquine in 10 healthy volunteers, the plasma MTX area under the curve (AUC) was increased and the maximum plasma MTX concentration was decreased when MTX was administered with hydroxychloroquine (22).…”