Methotrexate resistance is due to :

Mechanisms of pharmacokinetic and cellular resistance to methotrexate. Metabolism of methotrexate in the liver to paly inactive 7-hydroxymethotrexate reduces plasma concentrations of methotrexate and creates competition for cellular uptake RFC, which also internalizes reduced folates and folic acid, although with low affinity for the latter. Folate receptors mediate low affinity endocytosis of methotrexate. Quantitative or qualitative alterations in RFCs or folate-receptor expression confer transpo-related resistance to methotrexate, as do high levels of exogenous folates competing for cell entry. Intracellularly, methotrexate is metabolized to polyglutamated forms by FPGS, and these are broken down by FPGH. The monoglutamated forms and, to some extent, polyglutamated forms are expelled transpoers ABCC1-ABCC5 and ABCG2. ABCB1 does not transpo anionic drugs such as methotrexate. Polyglutamated forms of methotrexate can inhibit several key enzymes in folate metabolism, such as DHFR and TS, preventing de novo purine biosynthesis by APFase and AICAFase. Enzyme inhibition, folate depletion, and direct or indirect effects on cytokine release signaling pathways (such as those mediated by NFkB and IKK) all create routes which methotrexate could suppress RA. REFERENCE: www.medscape.com