PT - JOURNAL ARTICLE AU - Giuliana Decorti AU - Ilaria Peloso AU - Daniela Favarin AU - Fiora Bartoli Klugmann AU - Luigi Candussio AU - Enrico Crivellato AU - Franco Mallardi AU - Luciano Baldini TI - Handling of Doxorubicin by the LLC-PK<sub>1</sub> Kidney Epithelial Cell Line DP - 1998 Jul 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 525--530 VI - 286 IP - 1 4099 - http://jpet.aspetjournals.org/content/286/1/525.short 4100 - http://jpet.aspetjournals.org/content/286/1/525.full SO - J Pharmacol Exp Ther1998 Jul 01; 286 AB - The characteristics of doxorubicin handling have been studied in the cultured kidney epithelial cell line LLC-PK1, which has structure and function similar to those of renal tubular cells and expresses P-glycoprotein. The uptake of doxorubicin by LLC-PK1 cells was time dependent, reaching a steady state at about 4 hr, and reduced at low temperature; the initial uptake was saturable. The efflux of doxorubicin from LLC-PK1 cells was also temperature dependent but, even at 37°C, a significant percentage of the drug remained associated with the cells after 180 min, which suggests a strong cellular binding, and the fluorescence microscopy revealed that the drug was concentrated in intracellular organelles. Substances that are substrates for P-glycoprotein, such as verapamil, vinblastine, vincristine and quinidine, significantly increased doxorubicin concentrations in LLC-PK1 cells. Similar results were obtained with the metabolic inhibitors sodium metavanadate and 2,4-dinitrophenol. On the other hand, the uptake was not affected by the classic organic cation transport drugs cimetidine, decynium 22 or decynium 24, nor by the organic anion drug probenecid. These results indicate that, in LLC-PK1 cells, doxorubicin enters by passive diffusion, is trapped in intracellular organelles and then is extruded from cells by a mechanism that probably involves P-glycoprotein. On the contrary, substances that interfere with the renal organic cation or anion secretory system have no effect on doxorubicin net accumulation in these cells. The American Society for Pharmacology and Experimental Therapeutics