THE EFFECT OF VINDESINE ON METHOTREXATE HYDROXYLATION IN THE RAT

The effect of vindesine (VDS) on methotrexate (MTX) disposition was studied in bile-drained rats administered VDS prior to [H-3]MTX, and in isolated rat hepatocytes and rat liver homogenate concomitantly incubated with MTX and VDS at 37-degrees. In vivo, 7-hydroxylation was reduced by 0.65 mg/kg VDS. In VDS-treated animals, biliary recovery of the MTX dose (50 mg/kg) as 7-hydroxymethotrexate (7-OH-MTX) (1.75 +/- 0.2%, mean +/- SEM) was significantly reduced compared to controls (2.83 +/- 0.57%). In vitro, hydroxylation of MTX (10-200-mu-M) in hepatocytes was reduced by 14.3 and 66.4% (means) at 12.5 and 100-mu-M VDS, respectively. With increasing VDS concentrations up to 100-mu-M, a reduction in intracellular MTX accumulation could account for the decreased MTX hydroxylation. Experiments in a cell free system gave no evidence of inhibition of 7-OH-MTX formation by VDS. In vitro MTX transport studies demonstrated that VDS inhibited the hepatocellular influx of MTX, as (1) the accumulation of MTX corresponded inversely to increasing VDS concentrations and (2) the MTX efflux was not increased by VDS. The apparent K(i) for VDS inhibition of MTX influx was 57-mu-M. We suggest that VDS, by reducing the 7-OH-MTX formation in liver cells, may have implications for combination chemotherapy regimens which include MTX.