Toward a better understanding of methotrexate

174

136

Objective. There is evidence supporting a therapeutic range for methotrexate polyglutamate ( Conclusion. There is wide interpatient variability of RBC MTXGlu 1-5 accumulation and elimination in adults with RA. These data also suggest that after a dose change, >6 months are required for RBC MTXGlu 1-5 to reach steady state. Such delays in achieving steady state suggest that more rapid dose escalation or subcutaneous administration from the outset should be considered.

mentioning

confidence: 99%

Pharmacokinetics of oral methotrexate in patients with rheumatoid arthritis

Dalrymple¹,

Stamp²,

O’Donnell³

et al. 2008

174

136

“…The disease-modifying antirheumatic drugs (DMARDs) methotrexate (MTX), leflunomide (LEF), sulfasalazine, and (hydroxy)chloroquine have an established place in the treatment of patients with rheumatoid arthritis (RA), either as single agents or in combination with other DMARDs or biologic agents (1,2). Despite the potent disease-modifying effects of these DMARDs, it is well recognized that long-term treatment is often accompanied by a gradual loss of efficacy, requiring dosage escalation up to a stage where treatment has to be discontinued for reasons of inefficacy and/or toxicity (3)(4)(5).…”

mentioning

confidence: 99%

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

Heijden¹,

Oerlemans²,

Tak³

et al. 2009

Objective. To determine whether multidrugresistance efflux transporters are expressed on immune effector cells in synovial tissue from patients with rheumatoid arthritis (RA) and compromise the efficacy of methotrexate (MTX) and leflunomide (LEF).Methods. Synovial tissue biopsy samples obtained from RA patients before treatment and 4 months after starting treatment with MTX (n ‫؍‬ 17) or LEF (n ‫؍‬ 13) were examined by immunohistochemical staining and digital image analysis for the expression of the drug efflux transporters P-glycoprotein, multidrug resistance-associated protein 1 (MRP-1) through MRP-5, MRP-8, MRP-9, and breast cancer resistance protein (BCRP), and the relationship to clinical efficacy of MTX and LEF was assessed.Results. BCRP expression was observed in all RA synovial biopsy samples, both pretreatment and posttreatment, but not in control noninflammatory synovial tissue samples from orthopedic patients. BCRP expression was found both in the intimal lining layer and on macrophages and endothelial cells in the synovial sublining. Total numbers of macrophages in RA patients decreased upon treatment; in biopsy samples with persistently high macrophage counts, 2-fold higher BCRP expression was observed. Furthermore, median BCRP expression was significantly increased (3-fold) in nonresponders to disease-modifying antirheumatic drugs (DMARDs) compared with responders to DMARDs (P ‫؍‬ 0.048). Low expression of MRP-1 was found on synovial macrophages, along with moderate expression in T cell areas of synovial biopsy specimens from one-third of the RA patients.Conclusion. These findings show that the drug resistance-related proteins BCRP and MRP-1 are expressed on inflammatory cells in RA synovial tissue. Since MTX is a substrate for both BCRP and MRP-1, and LEF is a high-affinity substrate for BCRP, these transporters may contribute to reduced therapeutic efficacy of these DMARDs.

“…In 1951, Gubner discovered that MTX was effective in controlling disease activity both in patients with psoriatic arthritis and in those with rheumatoid arthritis (RA) (2). MTX is currently the most widely used disease-modifying antirheumatic drug (DMARD), and a large body of data suggests that its mechanism of action is associated with inhibition of several folatedependent enzymes, such as dihydrofolate reductase, amino imidazole ribonucleotide transformylase (ATIC), and thymidylate synthase (TSER) (3). Folates are critical to cellular function because they provide a single carbon for the synthesis of purines, pyrimidines, and methionine.…”

mentioning

confidence: 99%

Risk genotypes in folate‐dependent enzymes and their association with methotrexate‐related side effects in rheumatoid arthritis

Weisman

Fürst

Park

et al. 2006

Self Cite

131

Objective. Methotrexate (MTX) is an antifolate agent that is often associated with toxicity. This study investigated whether risk genotypes for folatedependent enzymes are associated with the toxicity of MTX in patients with rheumatoid arthritis (RA).Methods. Blood was collected for analysis in a muticenter, cross-sectional study of RA patients who had been receiving MTX for at least 1 month prior to enrollment, and side effects occurring at the time of a single study visit were recorded. Low-penetrance risk genotypes in methylenetetrahydrofolate reductase (MTHFR) 677TT, thymidylate synthase (TSER) *2/*2 (variable number of tandem repeats), amino imidazole ribonucleotide transformylase (ATIC) 347GG, and serine hydroxymethyltransferase (SHMT1) 1420CC were measured and summed to constitute the toxicogenetic index specific to each patient. Statistical analyses consisted of logistic regression models with clusteredcenter effects, and associations with risk genotypes were expressed as adjusted odds ratios (ORs).Results. Among 214 patients enrolled at 4 study sites, a total of 67 patients (31%) presented with a side effect (gastrointestinal event, headache, lethargy, alopecia, cough, or dyspnea). Risk genotypes associated with side effects in the central nervous system were MTHFR 677TT (OR 3.3, P < 0.01) and SHMT1 1420CC (OR 2.4, P < 0.05). ATIC 347GG was associated with gastrointestinal side effects (OR 3.0, P < 0.01), while TSER*2/*2 (OR 5.4, P < 0.01) and SHMT1 1420CC (OR 3.2, P < 0.01) were associated with alopecia. The toxicogenetic index ranged from 0 to 3 (median 1). An index of 3 was associated with an ϳ7-fold higher likelihood of having a side effect compared with an index of 0 (P < 0.01).Conclusion. These data suggest that a composite index of the cumulative risk genotypes in folatedependent enzymes may be an effective means of profiling RA patients who develop side effects to MTX.