Effect of ketoprofen and indomethacin on methotrexate pharmacokinetics in mice plasma and tumor tissues

Abstract

Methotrexate (MTX) has been used in combination with nonsteroidal antiinflammatory drugs (NSAIDs) in the treatment of inflammatory diseases and malignancies. Severe adverse effects with this combination may occur, usually resulting from inhibition of renal transporters. Solid Ehrlich Carcinoma was induced by implantation of Ehrlich Ascites Carcinoma (EAC) cells subcutaneously into the thigh of mice and after 30 days, mice were divided into 3 groups , Group I served as control group received MTX (50 mg/kg, i.p.), Group II received Ketoprofen (100 mg/kg, i.p.) then after half an hour received MTX (50 mg/kg, i.p.), Group III received Indomethacin (10 mg/kg, i.p.) then after half an hour received MTX (50 mg/kg, i.p.). Plasma and tissue samples were collected at different times then MTX concentrations were determined by HPLC. The injection of Ketoprofen or Indomethacin before MTX injection caused significant increase in the AUC and CPmax of MTX (p < 0.05) and significant decrease in CL/F and Vd/F of MTX (p < 0.05) in mice plasma. The study showed that administration of ketoprofen or indomethacin prior to MTX caused significant decrease in MTX elimination and significant increase in MTX extent of absorption which may lead to severe adverse effects if coadministered in human.