HMG-CoA还原酶抑制剂与P-糖蛋白调节

HMG-CoA reductase inhibitors and P-glycoprotein modulation.

Bogman K, Peyer A K, Török M, Küsters E, Drewe J

Department of Clinical Pharmacology and Toxicology, University Hospital/Kantonsspital, Basel, Switzerland.

Br J Pharmacol. 2001 Mar;132(6):1183-92. doi: 10.1038/sj.bjp.0703920.

Five 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), (e.g. atorvastatin, fluvastatin, lovastatin, pravastatin and simvastatin), were investigated for their ability to reverse P-glycoprotein (P-gp) mediated rhodamine 123 (R123) transport in a murine monocytic leukaemia cell line that over-expresses the multi-drug resistance protein 1a/b (mdr1a/1b). 2. P-gp modulation was studied by a fluorimetric assay and confocal microscopy by means of R123 efflux and uptake experiments, respectively. 3. Atorvastatin acid, methyl ester and lactone, lovastatin lactone and simvastatin lactone inhibited R123 transport in a concentration-dependent manner. Lovastatin acid, simvastatin acid, fluvastatin and pravastatin did not show a significant inhibition of the R123 transport in our cell system. Atorvastatin methyl ester and lactone showed the highest affinities for P-gp and results were comparable for both methods. 4. In conclusion, monitoring of R123 transport in living cells by confocal microscopy in addition to fluorimetric assay is a sensitive tool to study P-gp affinity in drug screening that is especially useful for early phases of drug development.

研究了五种3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂（他汀类药物），即阿托伐他汀、氟伐他汀、洛伐他汀、普伐他汀和辛伐他汀，在过表达多药耐药蛋白1a/1b（mdr1a/1b）的小鼠单核细胞白血病细胞系中逆转P-糖蛋白（P-gp）介导的罗丹明123（R123）转运的能力。2. 分别通过R123外排和摄取实验，利用荧光测定法和共聚焦显微镜研究P-gp调节。3. 阿托伐他汀酸、甲酯和内酯、洛伐他汀内酯和辛伐他汀内酯以浓度依赖性方式抑制R123转运。洛伐他汀酸、辛伐他汀酸、氟伐他汀和普伐他汀在我们的细胞系统中未显示出对R123转运的显著抑制作用。阿托伐他汀甲酯和内酯对P-gp表现出最高亲和力，两种方法的结果具有可比性。4. 总之，除荧光测定法外，通过共聚焦显微镜监测活细胞中的R123转运是一种在药物筛选中研究P-gp亲和力的灵敏工具，对药物开发的早期阶段特别有用。

HMG-CoA reductase inhibitors and P-glycoprotein modulation.