摘要
本文探讨了基于药物转运体介导中药组分丹参素与瑞舒伐他汀相互作用的机制。首先初步探讨瑞舒伐他汀合用丹参素后瑞舒伐他汀在大鼠体内的药代动力学变化;然后建立大鼠原代肝细胞模型,探索丹参素对大鼠原代肝细胞摄取瑞舒伐他汀的影响,最后利用慢病毒载体技术构建稳定表达OATP1B1*1a与OATP1B1*5的HEK293T细胞模型,探索丹参素对表达OATP1B1*1a与OATP1B1*5的HEK293T细胞摄取瑞舒伐他汀的影响。合用丹参素后,大鼠体内瑞舒伐他汀的药代动力学参数C_(max)、AUC_(0-t)、AUC_(0-∞)分别增加约123%、194%和195%,而CL_z/F值降低了60%;20、40和80μmol·L^(-1)丹参素对肝细胞摄取瑞舒伐他汀均有抑制作用,并使其摄取分别减少了3.13%、41.15%和74.62%;抑制参数IC_(50)为(53.04±2.43)μmol·L^(-1)。丹参素对OATP1B1介导瑞舒伐他汀转运的抑制作用与OATP1B1基因型有关,对突变型OATP1B1*5的转运表现出明显的竞争抑制作用,药物浓度为1和10μmol·L^(-1)时,对OATP1B1*5转运瑞舒伐他汀分别减少了(39.11±4.94)%和(63.61±3.94)%,而当为野生型OATP1B1*1a时,丹参素的抑制作用较轻,1和10μmol·L^(-1)丹参素对OATP1B1*1a转运瑞舒伐他汀分别减少了(8.22±2.40)%和(11.56±3.04)%。丹参素可显著影响瑞舒伐他汀在大鼠体内的药代动力学特征,这与竞争抑制特异表达于肝细胞的OATP1B1介导瑞舒伐他汀的转运密切相关,但由于OATP1B1基因突变导致其转运能力的改变,丹参素只对OATP1B1*5介导瑞舒伐他汀转运表现出竞争抑制作用,对OATP1B1*1a并无明显抑制作用。
The study was designed to explore the drug-drug interactions mechanisms mediated by OATP1B1 between traditional Chinese medicine Danshensu and rosuvastatin. First, the changes of rosuvastatin pharmacokinetics were investigated in presence of Danshensu in rats. Then, the primary rat hepatocytes model was established to explore the effects of Danshensu on the uptake of rosuvastatin by hepatocytes. Finally, HEK293 T cells with overexpression of OATP1B1＊1a and OATP1B1＊5 were established using a lentiviral delivery system to explore the effects of Danshensu on the uptake of rosuvastatin. Rosuvastatin pharmacokinetic parameters of C_（max）, AUC_（0-t）, AUC_（0-∞） were increased about 123%, 194% and 195%, by Danshensu in rats, while the CL_z/F value was decreased by 60%. Uptake of rosuvastatin in the primary rat hepatocytes was decreased by 3.13%, 41.15% and 74.62%, respectively in the presence of 20, 40 and 80 μmol·L^（-1） Danshensu. The IC_（50） parameters was（53.04 ± 2.43） μmol·L^（-1）. The inhibitory effect of Danshensu on OATP1B1 mediated transport of rosuvastatin was related to the OATP1B1 gene type. In OATP1B1＊5-HEK293 T mutant cells, transport of rosuvastatin were reduced by（39.11 ± 4.94） % and（63.61 ± 3.94） %, respectively, by Danshensu at 1 and 10 μmol·L^（-1）. While transport of rosuvastatin was reduced by（8.22 ± 2.40） % and（11.56 ± 3.04） % and in OATP1B1＊1a cells, respectively. Danshensu significantly altered the pharmacokinetics of rosuvastatin in rats, which was related to competitive inhibition of transport by OATP1B1. Danshensu exhibited a significant activity in the inhibition of rosuvastatin transport by OATP1B1＊5-HEK293 T, but not by OATP1B1＊1a, suggesting a dependence on OATP1B1 sequence.
出处
《药学学报》
CAS
CSCD
北大核心
2016年第1期75-79,共5页
Acta Pharmaceutica Sinica
基金
国家自然科学基金资助项目(81202583)
江西省科技厅支撑计划重大项目(20151BBB70265)
江西省科技厅支撑项目(20151BBG70214)
江西省卫生厅科技项目(20151045)
江西省卫生厅中医药科研计划课题资助项目(2012A137)
江西省青年自然科学基金资助项目(20142BAB215019)
