Relation among the resistance factor, kinetics of uptake, and kinetics of the P-glycoprotein-mediated efflux of doxorubicin, daunorubicin, 8- (S) -fluoroidarubicin, and idarubicin in multidrug-resistant K562 cells
Mankhetkorn, S.; Dubru, F.; Hesschenbrouck, J.; Fiallo, M.; Garnier-Suillerot, A.
Molecular Pharmacology 49(3): 532-539
1996
ISSN/ISBN: 0026-895X PMID: 8643093 Document Number: 458779
Multidrug resistance (MDR) is frequently associated with decreased cellular drug accumulation resulting from enhanced drug efflux. This is correlated with the presence of a membrane protein, the P-glycoprotein, which pumps a wide variety of drugs out of cells, reducing their intracellular concentration and thus their toxicity. The influx and efflux of drugs across the cell membrane are in large part responsible for their intracellular concentrations, and in the search for new compounds able to overcome MDR, it is of prime importance to determine the molecular parameters whose modification would lead to an increase in the kinetics of uptake and/or to a decrease in the P-glycoprotein-mediated efflux. Four anthracycline derivatives, doxorubicin, daunorubicin, 8-(S)-fluoroidarubicin, and idarubicin, which have the same amino sugar, were used to analyze the respective contribution of the kinetics of uptake and the P-glycoprotein-mediated efflux in their impaired accumulation in MDR cells. The kinetics of uptake of the four drugs vary over a very large range: the kinetics of uptake of daunorubicin, 8-(S)-fluoroidarubicin, and idarubicin are 16, 200, and 400 times higher than that of doxorubicin, respectively. However, the four drugs are extruded by P-glycoprotein at comparable rates. The apparent K-m values for P-glycoprotein-mediated transport, the intracellular free cytosolic drug concentrations at half-maximal velocity for the cell lines used, were apprx 2.2 mu-M for daunorubicin and apprx 1 mu-M for idarubicin and 8-(S)-fluoroidarubicin.