Kinetic analysis of P-glycoprotein-mediated doxorubicin efflux

M. S. Dordal*, J. N. Winter, A. J. Atkinson

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


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 languageEnglish (US)
Pages (from-to)762-766
Number of pages5
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number2
StatePublished - Jan 1 1992

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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