Sulfasalazine inhibits folate carrier, MTX efficacy

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Sulfasalazine inhibits folate carrier, MTX efficacy

Rheumawire

Aug 12, 2004

Janis

Amsterdam, the Netherlands - The arrival of multiple new drugs for

treating rheumatoid arthritis (RA) presents rheumatologists with the

challenge of learning how best to combine these agents. An in vitro

study published in the July 2004 issue of Arthritis & Rheumatism by

Gerrit Jansen PhD (Vrije Universiteit Medisch Centrum, Amsterdam, the

Netherlands) illustrates 1 aspect of this problem [1].

Clinicians have been puzzled by the fact that adding sulfasalazine (SSZ)

to methotrexate (MTX) not only provides no greater efficacy than MTX

alone but also increases the risk for folate-deficient anemias [2].

Jansen reports that both problems are related to SSZ inhibition of the

reduced folate carrier (RFC).

" When inflammatory-related cells are exposed simultaneously to SSZ and

MTX, inhibition of the cellular uptake system for MTX (RFC) by SSZ can

potentially diminish the uptake of MTX and thereby influence its

clinical efficacy. At the same time, since the physiological function of

the RFC is to mediate the cellular uptake of natural folates (eg, folic

acid and leucovorin), SSZ-induced inhibition of the RFC may evoke

diminished cellular uptake of natural folates. On extended SSZ exposure,

this may lead to folate deficiency. This type of drug interaction is

what rheumatologists should keep in mind when they experience clinical

signs of loss of efficacy and/or folate deficiency as a side effect in

MTX/SSZ-based treatment schedules for RA patients, " Jansen tells

rheumawire.

Jansen engineered human cells that overexpress RFC to study the effect

of SSZ on cellular uptake of radiolabeled MTX and of the natural folate

leucovorin. Both cells with and without acquired resistance to SSZ were

used to study the effects of MTX/SSZ combinations. This showed that SSZ

is a potent, noncompetitive inhibitor of RFC-mediated uptake of MTX and

of leucovorin.

The result was a marked loss of MTX efficacy when MTX was coadministered

with SSZ: up to 3.5-fold in the presence of 0.25 mmol SSZ and more than

400-fold for SSZ-resistant cells in the presence of 2.5 mmol of SSZ.

" Our study is a laboratory/in vitro study, and a direct translation of

its outcome into the clinic should be made with caution. Nevertheless,

we are fully confident that the mechanism of drug interaction between

MTX and SSZ at the level of RFC is of clinical relevance, " Jansen says.

He tells rheumawire that the most important implication of these data is

that they provide a mechanistic explanation of why the combination of

MTX and SSZ was not superior to either of the drugs alone.

" Given the potential drug interaction, it does not seem wise to

administer MTX and SSZ simultaneously but rather delay SSZ

administration until after MTX administration. The same may hold for

folic acid and leucovorin supplementation. Pharmacokinetically guided

studies may be warranted to reveal the optimal window of spacing the

administration of MTX/folic acid-leucovorin and SSZ in time to avoid

plasma levels of SSZ that can exert inhibitory effects on the RFC before

MTX administration and folic acid/leucovorin supplementation, " Jansen

says.

Sources

Jansen G, van der Heijden J, Oerlemans R, Lems WF,

Ifergan I, Scheper RJ, Assaraf YG, Dijkmans BA. Sulfasalazine is a

potent inhibitor of the reduced folate carrier: implications for

combination therapies with methotrexate in rheumatoid arthritis.

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

Cronstein BN. Therapeutic cocktails for rheumatoid

arthritis: the mixmaster's guide. Arthritis Rheum 2004 Jul;

50(7):2041-3.

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org