Abstract

The mechanism of methotrexate (MTX) renal elimination and the interaction of MTX with the nonsteroidal anti-inflammatory drugs, indomethacin and flurbiprofen, were characterized in the isolated perfused rat kidney. Perfusion studies elucidating MTX renal disposition were performed in perfusate (4.0% bovine serum albumin) at initial MTX concentrations of 1, 5, 12 and 25 micrograms/ml and in controls without MTX. Interaction studies were performed at clinically relevant indomethacin and flurbiprofen concentrations of 2.5 and 10 micrograms/ml, respectively, and a MTX concentration of 25 micrograms/ml (representative of an oncolytic MTX dose). MTX unbound fractions were concentration and interactant independent. Kidney viability was within normal limits for this technique among all perfusions. MTX renal clearance was nonlinear, increasing from 0.310 to 0.434 ml/min over the concentration range studied. Corresponding excretion ratios increased from 0.933 to 1.52, indicative of MTX renal elimination involving the processes of filtration, secretion and reabsorption. Excretion ratio results were supported by tubular transit rate calculations. Interaction studies indicated that there was secretory inhibition of MTX as evidenced by a decrease in both excretion ratio and tubular clearance at 25 micrograms/ml of MTX. Therefore, the secretory component was significantly inhibited by indomethacin and flurbiprofen after concomitant administration of oncolytic doses of MTX.