HEPATOCELLULAR TRANSPORT OF MITOXANTRONE IN RELATION WITH MULTIDRUG-RESISTANCE

We have examinated the effect of cyclosporin A on transport processes (uptake, efflux, binding) of mitoxantrone in isolated rat liver cells. Accumulation and binding of mitoxantrone was rapid with or without cy closporin A. The initial uptake was linear over a wide concentration r ange (1 to 1000 mu M). For the first 100 s, the rate of uptake is cons tant. The uptake clearance ranged from 12.53 +/- 3.9 to 33.77 +/- 15.1 nl.min.cell(-1) for different extracellular concentrations of mitoxan trone. Also cyclosporin A did not modified this coefficient. Initial b inding of mitoxantrone to cell plasma membrane was estimated and it wa s modified by different extracellular concentrations of mitoxantrone b ut not by cyclosporin A. Respectively at 60 seconds it accounted to 79 .6% and 81.6% of the total transport. Influx of mitoxantrone was not t emperature sensitive. We next examined the efflux of mitoxantrone mito xantrone from cells that were preloaded with drug. Initial efflux was rapid for the first 5 minutes. Cyclosporin A slightly decrease this ef flux (7%). The data suggest that the mechanism of uptake of mitoxantro ne is passive diffusion and that ciclosporin A a p-glycoprotein 170 in hibitor agent has only a weak effect on efflux.