ALTERATIONS IN METHOTREXATE PHARMACOKINETICS BY NAPROXEN IN THE RAT AS MEASURED BY MICRODIALYSIS

Reports of a potentially life-threatening interaction between the anti folate methotrexate (MTX) and drugs belonging to the NSAID class insti gated a study of MTX pharmacokinetics by a microdialysis technique in the presence and absence of the NSAID naproxen in anesthetized rats. A fter pretreatment with naproxen, the animals received either 750 or 1, 000 mg/kg MTX as a 6 h continuous intravenous infusion. During infusio ns, microdialysis effluents were obtained from probes situated intrave nously, intrahepatically and intrarenally. In all three compartments, time-concentration AUCs for both MTX and its major extracellular metab olite, 7-hydroxymethotrexate (7-OH-MTX), increased about two-fold in t he presence of naproxen. The mechanisms responsible for the MTX-NSAID interaction are briefly discussed. The study demonstrate that the micr odialysis technique offers a means to investigate pharmacokinetic drug -drug interactions. (C) 1997 Elsevier Science Inc.