DHFR and Renal insufficiency: Some major predisposing factors for developing chronic MTX toxicity are older age, renal failure, hypoalbuminemia, and simultaneous use of drugs which interact with MTX including salicylates, nonsteroidal anti-inflammatory drugs (by decreasing renal excretion and tubular secretion of MTX), trimethoprim/sulfamethoxazole and sulfasalazine (by accentuating the cytotoxic effects of MTX via concomitant inhibition of dihydrofolate reductase), and leflunomide and azathioprine (by imposing myelosuppressive effects).