INTERACTIONS OF VINBLASTINE AND VINCRISTINE WITH METHOTREXATE TRANSPORT IN ISOLATED RAT HEPATOCYTES

The accumulation of methotrexate (MTX) in the presence of vinblastine (VBL) and vincristine (VCR) was studied in isolated rat hepatocytes. I n accordance with our recent study on vindesine (VDS), we found VBL an d VCR to reduce net MTX accumulation significantly at 15 min after MTX addition. Drug concentrations of 100 muM VBL and 500 muM VCR led to 6 7% and 82% reductions in intracellular MTX, respectively. Since there was only a slight inhibition of MTX efflux by 100 muM VBL, the accumul ation data demonstrate that the major effect of VBL is on MTX influx. Dixon-plot analyses are suggestive of competitive inhibition of the MT X influx, yielding inhibition constants (K(i) values) of 55 muM for VB L and 110 muM for VCR. Since the K(i) values correspond grossly to pla sma levels obtained in humans shortly after the infusion of therapeuti c doses of the vinca alkaloids studied herein, the interaction with MT X uptake could serve to diminish the toxicity of MTX to nonmalignant c ells.