After initial rapid [14C]doxorubicin distribution into drug-sensitive HL-60 and SU-4 cells, slow uptake continues for more than 4 hr, accounting for up to 80% of the total intracellular drug. In contrast, in P- glycoprotein-expressing drug-resistant HL-60R and SU-4R cells, doxorubicin distribution rapidly approaches equilibrium. The simplest kinetic model of this behavior consists of rapid diffusion from extracellular fluid into the cell, followed by uptake into a nonexchangeable intracellular pool. At 3.4 μM doxorubicin, transmembrane diffusion clearance was similar for all cell lines (0.78-0.98 μl sec-1). There was no decrease in the normalized apparent volume of distribution in the P-glycoprotein-expressing cell lines, as would be expected if an active, unidirectional efflux were present. However, in resistant cells, doxorubicin accumulation in the nonexchangeable pool was up to 15-fold slower than in sensitive cells (0.004 vs. 0.050 μl sec-1 in HL-60R vs. HL-60; 0.004 vs. 0.058 μl sec-1 in SU-4R vs. SU-4). No pool inflow could be detected in either SU-4 or SU-4R cells exposed to doxorubicin at 0°C, indicating that the nonexchangeable accumulation requires energy. The process preventing accumulation began to saturate in SU- 4R cells at 20 μM doxorubicin, whereas no evidence of saturation was seen with HL-60R, which is more highly resistant than SU4R. We propose that alteration in compartmentalization is primarily responsible for the doxorubicin resistance observed in these cell lines.
|Original language||English (US)|
|Number of pages||5|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - 1994|
ASJC Scopus subject areas
- Molecular Medicine