Expression of resistance markers to methotrexate predicts clinical improvement in patients with rheumatoid arthritis

Abstract

Background: Methotrexate is transported into the cell by the reduced folate carrier (RFC) and out of the cell by members of the multidrug resistance protein family (MRP). Transport proteins may affect the therapeutic efficacy of this drug in patients with rheumatoid arthritis. Objective: To investigate the potential benefit of the presence of RFC and the absence of functional MRP for the efficacy of methotrexate treatment. Methods: The study involved 163 patients (116 female, 47 male; mean age 59.5 years) on methotrexate (mean weekly dose 12.2 mg). RFC was determined using reverse transcriptase polymerase chain reaction, and MRP function by flow cytometry, using a calcein acetoxymethylesther/probenecid assay. Clinical response to methotrexate was evaluated by the EULAR response criteria and the ACR 20% improvement criteria. The clinical data were obtained at the beginning of methotrexate treatment and at the time of blood sampling during ongoing therapy. Patients were divided into four groups according to the presence (+) or absence (2) of RFC and functional (f) MRP. Results: fMRP+/RFC+ and fMRP2/RFC2 patients more often had good EULAR response rates (60%, p = 0.014, and 53%, p = 0.035, respectively) in comparison with the fMRP2/RFC+ group (29%); fMRP+/ RFC2 patients had a low frequency of good disease activity responses. Conclusions: Absence of fMRP plus presence of RFC did not prove to be related to beneficial effects of methotrexate, but the lack or the presence of both fMRP and RFC led to a significantly better therapeutic outcome. Determination of these markers may predict responsiveness to methotrexate.

Assessment of HBEC-5i endothelial cell line cultivated in astrocyte conditioned medium as a human blood-brain barrier model for ABC drug transport studies

“…The value of the ER for methotrexate was in agreement with the presence of MRPs at the basolateral and apical membrane of the endothelial cells. Methotrexate was transported by MRPs, its active efflux by one MRP transporter in the apical compartment could be balanced by the active efflux in the basolateral compartment by other MRPs (Wolf et al, 2005). We have clearly demonstrated that our BBB model can evaluate interaction or not with ABC transporters.…”

Interaction of immunosuppressive drugs with human organic anion transporter (OAT) 1 and OAT3, and multidrug resistance-associated protein (MRP) 2 and MRP4

“…The data provide a better understanding of renal mechanisms underlying drugdrug interactions and nephrotoxicity concerning combination regimens with these compounds in the clinic. (Translational Research 2013;-: [1][2][3][4][5][6][7][8][9][10][11] Abbreviations: ATP ¼ adenosine triphosphate; BSA ¼ bovine serum albumin; HEK ¼ human embryonic kidney; IC 50 ¼ median inhibition concentration; MRP ¼ multidrug resistance-associated protein; MTX ¼ methotrexate; OAT ¼ organic anion transporter Immunosuppressants are a structurally and functionally heterogeneous group of drugs that are often administered concomitantly in combination regimens to treat cancer, organ transplant rejection, and/or autoimmune diseases. Having a narrow therapeutic index, immunosuppressant cotreatment underlies the hazard of toxic adverse effects.…”

Involvement of breast cancer resistance protein expression on rheumatoid arthritis synovial tissue macrophages in resistance to methotrexate and leflunomide

“…In a crosssectional study, Wolf et al (16) demonstrated that, counterintuitively, patients with functional MRP-1 expression who were treated with MTX had better response rates based on the European League Against Rheumatism response criteria (17) than did patients with low MRP-1 activity. Hider et al (18) showed that MRP-1 expression on peripheral blood cells declined from baseline to 6 months with MTX therapy.…”