RESEARCH - Sulfasalazine is a potent inhibitor of reduced folate carrier

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Arthritis Rheum. 2004 Jul;50(7):2130-9.

Sulfasalazine is a potent inhibitor of the reduced folate carrier:

implications for combination therapies with methotrexate in rheumatoid

arthritis.

Department of Rheumatology, Vrije Universiteit Medisch Centrum, Amsterdam,

The Netherlands. g.jansen@...

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.

METHODS: Human RFC-(over)expressing CEM cells of T cell origin were used to

analyze the effect of SSZ on the RFC-mediated cellular uptake of

radiolabeled MTX and the natural folate leucovorin. Moreover, both cells

with and those without acquired resistance to SSZ were used to assess the

antiproliferative effects of MTX in combination with SSZ. RESULTS: Transport

kinetic analyses revealed that SSZ was a potent noncompetitive inhibitor of

RFC-mediated cellular uptake of MTX and leucovorin, with mean +/- SD K(i)

(50% inhibitory concentration) values of 36 +/- 6 microM and 74 +/- 7

microM, respectively. Consistent with the inhibitory interaction of SSZ with

RFC, a marked loss of MTX efficacy was observed when MTX was coadministered

with SSZ: up to 3.5-fold for CEM cells in the presence of 0.25 mM of SSZ,

and >400-fold for SSZ-resistant cells in the presence of 2.5 mM of SSZ.

Importantly, along with diminished efficacy of MTX, evidence for cellular

folate depletion was obtained by the demonstration of an SSZ dose-dependent

decrease in leucovorin accumulation.

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 disease-modifying 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.

PMID: 15248210

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed & cmd=Retrieve & dopt=Abstra\

ctPlus & list_uids=15248210

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