![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
S Mankhetkorn, F Dubru, J Hesschenbrouck, M Fiallo and A Garnier-Suillerot
Laboratoire de Physicochimie Biomoleculaire et Cellulaire, Universite Paris Nord, Bobigny, France.
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- medicated 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 Km values for P-glycoprotein-mediated transport, the intracellular free cytosolic drug concentrations at half-maximal velocity for the cell lines used, were approximately 2.2 microM for daunorubicin and and approximately 1 microM for idarubicin and 8-(S)- fluoroidarubicin.
This article has been cited by other articles:
|
|
 |
|
  C. Saengkhae, C. Loetchutinat, and A. Garnier-Suillerot Kinetic Analysis of Rhodamines Efflux Mediated by the Multidrug Resistance Protein (MRP1) Biophys. J., September 1, 2003; 85(3): 2006 - 2014. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Rousselle, P. Clair, J.-M. Lefauconnier, M. Kaczorek, J.-M. Scherrmann, and J. Temsamani New Advances in the Transport of Doxorubicin through the Blood-Brain Barrier by a Peptide Vector-Mediated Strategy Mol. Pharmacol., April 1, 2000; 57(4): 679 - 686. [Abstract] [Full Text]
|
|
|
|
 |
|
 M. Heijn, S. Roberge, and R. K. Jain Cellular Membrane Permeability of Anthracyclines Does Not Correlate with Their Delivery in a Tissue-isolated Tumor Cancer Res., September 1, 1999; 59(17): 4458 - 4463. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Marbeuf-Gueye, H. J. Broxterman, F. Dubru, W. Priebe, and A. Garnier-Suillerot Kinetics of Anthracycline Efflux from Multidrug Resistance Protein-Expressing Cancer Cells Compared with P-Glycoprotein-Expressing Cancer Cells Mol. Pharmacol., January 1, 1998; 53(1): 141 - 147. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
