TY - JOUR
T1 - Sulfasalazine is a potent inhibitor of the reduced folate carrier
T2 - implications for combination therapies with methotrexate in rheumatoid arthritis
AU - Jansen, Gerrit
AU - van der Heijden, Joost
AU - Oerlemans, Ruud
AU - Lems, Willem F
AU - Ifergan, Ilan
AU - Scheper, Rik J
AU - Assaraf, Yehuda G
AU - Dijkmans, Ben A C
PY - 2004/7
Y1 - 2004/7
N2 - 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.
AB - 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.
KW - ATP-Binding Cassette, Sub-Family B, Member 1/metabolism
KW - Antirheumatic Agents/administration & dosage
KW - Arthritis, Rheumatoid/drug therapy
KW - Biological Transport/drug effects
KW - Cell Line
KW - Dose-Response Relationship, Drug
KW - Drug Interactions
KW - Drug Resistance
KW - Drug Therapy, Combination
KW - Folic Acid/metabolism
KW - Humans
KW - Leucovorin/pharmacokinetics
KW - Membrane Transport Modulators
KW - Membrane Transport Proteins/antagonists & inhibitors
KW - Methotrexate/pharmacokinetics
KW - Reduced Folate Carrier Protein
KW - Sulfasalazine/administration & dosage
U2 - 10.1002/art.20375
DO - 10.1002/art.20375
M3 - Article
C2 - 15248210
SN - 0004-3591
VL - 50
SP - 2130
EP - 2139
JO - Arthritis & Rheumatism
JF - Arthritis & Rheumatism
IS - 7
ER -