Sulfasalazine is a potent inhibitor of the RFC: Implications for combination therapies with MTX in RA

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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.

Jansen G, Van Der Heijden J, Oerlemans R, Lems WF, Ifergan I, Scheper

RJ, Assaraf YG, Dijkmans BA.

Vrije Universiteit Medisch Centrum, Amsterdam, The Netherlands.

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

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