CYP2C9 and OATP1B1 genetic polymorphisms affect the metabolism and transport of glimepiride and gliclazide.
CYP2C9 and OATP1B1 genetic polymorphisms affect the metabolism and transport of glimepiride and gliclazide.
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CYP2C9和OATP1B1基因多态性影响格列美脲和格列齐特的代谢和转运
DOI：
10.1038/s41598-018-29351-4
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发表时间：
2018-07-20
影响因子：
4.6
通讯作者：
Xia C
中科院分区：
文献类型：
--
作者：
Yang F;Xiong X;Liu Y;Zhang H;Huang S;Xiong Y;Hu X;Xia C
格列美脲和格列齐特的治疗使用显示出人群中药代动力学和药效学的巨大个体差异，这可能是由个体之间的遗传差异引起的。本研究的目的是评估CYP2C9和OATP1B1基因多态性对格列美脲和格列齐特代谢和转运的影响。测定OATP1B1*1a、*5和*15-HEK293T细胞对格列美脲和格列齐特的摄取，采用LC-MS检测CYP2C9*1、*2和*3重组酶对其代谢的影响。格列美脲在OATP1B1*1a、*5和*15-HEK293T细胞中的vmax值分别为155±18.7、80±9.6和84.5±8.2 pmol/min/mg，格列齐特的vmax值分别为15.7±4.6、7.2±2.5和8.7±2.4 pmol/min/mg。与野生型相比，OATP1B1*5和*15对格列美脲和格列齐特的清除率显著降低。CYP2C9*1、*2和*3重组酶存在时，格列美脲的vmax值分别为21.58±7.78、15.69±5.59和9.17±3.03 nmol/min/mg蛋白，格列齐特的vmax值分别为15.73±3.11、10.53±4.06和6.21±2.94 nmol/min/mg蛋白。与野生型相比，格列美脲和格列齐特对CYP2C9*2和*3的清除率明显降低。综上所述，OATP1B1*5和*15以及CYP2C9*2和*3对格列美脲和格列齐特的转运和代谢有显著影响。
The therapeutic use of glimepiride and gliclazide shows substantial inter-individual variation in pharmacokinetics and pharmacodynamics in human populations, which might be caused by genetic differences among individuals. The aim of this study was to assess the effect of CYP2C9 and OATP1B1 genetic polymorphisms on the metabolism and transport of glimepiride and gliclazide. The uptake of glimepiride and gliclazide was measured in OATP1B1*1a, *5 and *15-HEK293T cells, and their metabolism was measured using CYP2C9*1, *2 and *3 recombinase by LC-MS. Glimepiride in OATP1B1*1a, *5 and *15-HEK293T cells had Vmaxvalues of 155 ± 18.7, 80 ± 9.6, and 84.5 ± 8.2 pmol/min/mg, while gliclazide had Vmaxvalues of 15.7 ± 4.6, 7.2 ± 2.5, and 8.7 ± 2.4 pmol/min/mg, respectively. The clearance of glimepiride and gliclazide in OATP1B1*5 and *15 was significantly reduced compared to the wild-type. Glimepiride in the presence of CYP2C9*1, *2 and *3 recombinase had Vmaxvalues of 21.58 ± 7.78, 15.69 ± 5.59, and 9.17 ± 3.03 nmol/min/mg protein, while gliclazide had Vmaxvalues of 15.73 ± 3.11, 10.53 ± 4.06, and 6.21 ± 2.94 nmol/min/mg protein, respectively. The clearance of glimepiride and gliclazide in CYP2C9*2 and *3 was significantly reduced compared to the wild-type. These findings collectively indicate that OATP1B1*5 and *15 and CYP2C9*2 and *3 have a significant effect on the transport and metabolism of glimepiride and gliclazide.
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影响因子：
45.3
作者：
Trevin, Lisa R.;Shimasaki, Noriko;Relling, Mary V.
通讯作者：
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作者：
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