[Hepatic transport of mitoxantrone in relation to multiple resistance]

We have examined 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 cyclosporin A. The initial uptake was linear over a wide concentration range (1 to 1000 microM). For the first 100 s, the rate of uptake is constant. The uptake clearance ranged from 12.53 +/- 3.9 to 33.77 +/- 15.1 nl.min-cell-1 for different extracellular concentrations of mitoxantrone. Also cyclosporin A did not modified this coefficient. Initial binding of mitoxantrone to cell plasma membrane was estimated and it was modified by different extracellular concentrations of mitoxantrone but 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 temperature sensitive. We next examined the efflux of mitoxantrone from cells that were preloaded with drug. Initial efflux was rapid for the first 5 minutes. Cyclosporin A slightly decrease this efflux (7%). The data suggest that the mechanism of uptake of mitoxantrone is passive diffusion and that cyclosporin A a p-glycoprotein 170 inhibitor agent has only a weak effect on efflux.