P-glycoprotein lowers the intracellular concentration of a variety of unrelated compounds including doxorubicin by actively removing them from the cell. Mathematical modeling techniques have been applied to the transmembrane transport of doxorubicin in a nonresistant HL-60 cell line and in a P- glycoprotein-containing resistant subclone, HL-60R, to obtain clearances for inward and outward transport. Distribution of [14C]doxorubicin from extracellular fluid into the cell pellet was analyzed with a closed two- compartment system that fitted experimental measurements of drug concentrations in the extracellular fluid and in the cell pellet, represented by a third compartment that includes trapped extracellular doxorubicin along with the intact cells. Transmembrane diffusion clearance was similar for the two cell lines (1.00 vs. 1.06 μl sec-1), yielding an apparent doxorubicin permeability coefficient of 7.4 x 10-5 cm sec-1. However, the total efflux clearance averaged 0.99 ± 0.05 μl sec-1 in HL-60 and 2.29 ± 0.62 μl sec-1 in HL-60R. The estimated P-glycoprotein-mediated efflux clearance in HL-60R averaged 1.23 ± 0.51 μl sec-1. This experimental approach provides direct estimates of transport parameters in intact cells and should be useful in studying the mechanism of action and interactions of inhibitors of P-glycoprotein.
|Original language||English (US)|
|Number of pages||5|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Jan 1 1992|
ASJC Scopus subject areas
- Molecular Medicine