Susceptibility of idarubicin, daunorubicin, and their C-13 alcohol metabolites to transport-mediated multidrug resistance.
The intracellular pharmacokinetics and cytotoxicity of idarubicin (IDA), daunorubicin (DNR), and their corresponding C-13 alcohol metabolites, idarubicinol (IDAol) and daunorubicinol (DNRol), were studied in drug-sensitive HL-60/W human leukemia cells, and in two multidrug-resistant (MDR) sublines, HL-60/Vinc (overexpress P-glycoprotein, Pgp) and HL-60/Adr (overexpress multidrug resistance-associated protein, MRP). Intracellular drug accumulation (1 micrograms/mL) and retention were measured by flow cytometry. Mean intracellular steady-state concentration (Css, fluorescence units/cell) and area under the intracellular drug concentration x time curve (AUC, Fl.U/cell.min) were calculated. Relative to the values for the respective drugs in HL-60/W cells, the Css and AUC of IDA were much higher than those of DNR in the MDR cell lines, with Css and AUC of IDAol intermediate between IDA and DNR. In the MDR cell lines, the MDR modulator cyclosporine A (CsA), in concentrations of 0.3 to 30 mumol/L, caused minimal effects on 3-hr IDA accumulation, intermediate enhancement of IDAol accumulation, and greatest enhancement of DNR accumulation. The MDR cell lines were much less resistant to IDA (3- to 16-fold) than to DNR (65- to 117-fold). This difference was not the result of IDA being more potent than DNR, since the sensitivity of HL-60/W cells to IDA differed from their sensitivity to DNR by < 2-fold. The cellular pharmacokinetics and cytotoxicity of IDA in MDR human breast carcinoma cells MCF-7/AdrVp, which overexpress the putative MDR transporter P-95, were far superior to those of DNR, and were comparable to these parameters for IDA in parental MCF-7/W cells. These studies demonstrate that the cellular pharmacology and cytotoxicity of IDA in MDR cell lines that overexpress MRP, Pgp, or P-95 are more advantageous than those of DNR, suggesting that IDA is less susceptible to the transport-mediated MDR mechanism manifested. IDA is not completely invulnerable to MDR, however, since the MDR sublines studied did display a demonstrable level of resistance to IDA, compared with their drug-sensitive counterparts. IDAol, the major plasma metabolite of IDA, demonstrated behavior intermediate between the MDR-susceptible drug DNR and its parent compound, suggesting that its cytotoxic action is subject to transport-mediated cellular defenses.(ABSTRACT TRUNCATED AT 400 WORDS)
Ross
D D
DD
University of Maryland Cancer Center, Baltimore, USA.
Doyle
L A
LA
Yang
W
W
Tong
Y
Y
Cornblatt
B
B
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003470:Culture Media; D016572:Cyclosporine / Q000494:pharmacology; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004355:Drug Stability; D018922:HL-60 Cells; D006801:Humans; D015255:Idarubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D007424:Intracellular Fluid / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D003470:Culture Media; D016572:Cyclosporine; C054440:idarubicinol; C000847:daunorubicinol; D015255:Idarubicin; D003630:Daunorubicin