Ross D D, Doyle L A, Yang W, Tong Y, Cornblatt B
University of Maryland Cancer Center, Baltimore, USA.
Biochem Pharmacol. 1995 Nov 9;50(10):1673-83. doi: 10.1016/0006-2952(95)02069-1.
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)
在药物敏感的HL-60/W人白血病细胞以及两个多药耐药（MDR）亚系HL-60/Vinc（过表达P-糖蛋白，Pgp）和HL-60/Adr（过表达多药耐药相关蛋白，MRP）中，研究了伊达比星（IDA）、柔红霉素（DNR）及其相应的C-13醇代谢产物伊达比星醇（IDAol）和柔红霉素醇（DNRol）的细胞内药代动力学和细胞毒性。通过流式细胞术测量细胞内药物蓄积（1微克/毫升）和潴留情况。计算细胞内稳态浓度（Css，荧光单位/细胞）和细胞内药物浓度-时间曲线下面积（AUC，荧光单位/细胞·分钟）。相对于HL-60/W细胞中各药物的值，在MDR细胞系中，IDA的Css和AUC远高于DNR，IDAol的Css和AUC介于IDA和DNR之间。在MDR细胞系中，浓度为0.3至30微摩尔/升的MDR调节剂环孢素A（CsA）对3小时的IDA蓄积影响最小，对IDAol蓄积有中等程度增强，对DNR蓄积增强作用最大。MDR细胞系对IDA的耐药性（3至16倍）远低于对DNR的耐药性（65至117倍）。这种差异并非由于IDA比DNR更有效，因为HL-60/W细胞对IDA的敏感性与其对DNR的敏感性相差不到2倍。在过表达假定的MDR转运蛋白P-95的MDR人乳腺癌细胞MCF-7/AdrVp中，IDA的细胞药代动力学和细胞毒性远优于DNR，且与亲本MCF-7/W细胞中IDA的这些参数相当。这些研究表明，在过表达MRP、Pgp或P-95的MDR细胞系中，IDA的细胞药理学和细胞毒性比DNR更具优势，这表明IDA较不易受到转运介导的MDR机制的影响。然而，IDA并非完全不受MDR影响，因为与药物敏感的对应细胞相比，所研究的MDR亚系对IDA确实表现出一定程度的耐药性。IDAol是IDA的主要血浆代谢产物，其行为介于对MDR敏感的药物DNR及其母体化合物之间，这表明其细胞毒性作用受到转运介导的细胞防御机制的影响。（摘要截短至400字）
