The effects of nonsteroidal antiinflammatory drugs on methotrexate (MTX) pharmacokinetics: impairment of renal clearance of MTX at weekly maintenance doses but not at 7.5 mg.

OBJECTIVE

To determine the pharmacokinetics of methotrexate (MTX) with and without nonsteroidal antiinflammatory drugs (NSAID) at a 7.5 mg dose and higher usual maintenance doses of the drug. To determine the difference in pharmacokinetic variables when salicylate and nonsalicylate NSAID are administered with MTX at these doses.

METHODS

Thirty patients receiving MTX chronically underwent a study of MTX pharmacokinetics after 7.5 mg doses of MTX with their usual NSAID and after the NSAID were withheld for 5 half-lives. Sixteen additional patients underwent pharmacokinetics studies with and without NSAID while receiving their usual weekly maintenance dose of MTX of 16.6 (3.6) mg (Mean +/- SD).

RESULTS

No significant differences in pharmacokinetic variables were observed with and without NSAID at the 7.5 mg weekly dose of MTX. When patients received usual maintenance doses of MTX the renal clearance of MTX NSAID was 91.7 (26.4) ml/min versus 115.3 (34.4) ml/min without NSAID (p = 0.004). Creatinine clearance in patients taking usual maintenance doses increased from 77.5 (13.9) ml/min with NSAID to 95.3 (26.3) ml/min without NSAID (p = 0.05). A reduction in renal clearance of MTX was observed with maintenance dose MTX in both the 4 patients taking salicylates (p = 0.016) and the 12 patients taking nonsalicylate NSAID (p = 0.024).

CONCLUSION

NSAID produce significant decreases in renal clearance of MTX and creatinine when patients consume their usual weekly dose of the drug, but not when they take a 7.5 mg dose. This effect is likely to achieve clinical relevance across the dose ranges used to treat patients with rheumatoid arthritis.