OATP1B3 (699G > A) and CYP2C92,3 significantly influenced the transport and metabolism of glibenclamide and glipizide
OATP1B3 (699G > A) and CYP2C92,3 significantly influenced the transport and metabolism of glibenclamide and glipizide
复制标题
OATP1B3 (699G > A) 和 CYP2C92,3 显着影响格列本脲和格列吡嗪的转运和代谢
DOI：
10.1038/s41598-018-36212-7
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发表时间：
2018
影响因子：
4.6
通讯作者：
Xia Chunhua
中科院分区：
文献类型：
--
作者：
Yang Fayou;Liu Linlin;Chen Lin;Liu Mingyi;Liu Fanglan;Xiong Yuqing;Hu Xiao;Xia Chunhua
Glibenclamide and glipizide show large substantial inter-individual variation in clinical efficacy, which may be resulted from the genetic differences of metabolic enzymes and transporters in individuals. This study purposed to investigate the effect of OATP1B3 and CYP2C9 genetic polymorphisms on the transport and metabolism of glibenclamide and glipizide in human. An LC-MS method was used to determine the uptake of glibenclamide and glipizide in OATP1B3, OATP1B3 (344T > G) and OATP1B3 (699G > A)-HEK293T cells and their metabolism in CYP2C9*1, *2 and *3 recombinase system. Glibenclamide can be taken in OATP1B3 (wild-type), OATP1B3 (344T > G) and OATP1B3 (699G > A)-HEK293T cells with the Vmaxvalues of 44.91 ± 7.97, 46.08 ± 8.69, and 37.31 ± 5.04 pmol/min/mg, while glipizide was taken in with Vmaxof 16.50 ± 3.64, 16.87 ± 4.23, and 13.42 ± 2.79 pmol/min/mg, respectively. The internal clearance of glibenclamide and glipizide in OATP1B3 (699G > A) was less than that in wild-type. Glibenclamide can be metabolized in CYP2C9*1, *2 and *3 recombinase system with the Vmaxvalues of 1.58 ± 0.71, 0.69 ± 0.25, and 0.41 ± 0.13 nmol/min/mg protein, while glipizide was metabolized with Vmaxof 8.82 ± 2.78, 5.99 ± 1.95, and 2.87 ± 1.03 nmol/min/mg protein, respectively. The internal clearance of glibenclamide and glipizide in CYP2C9*2 and *3 was markedly reduced compared to that in CYP2C9*1. These results collectively demonstrate that OATP1B3 (699G > A) and CYP2C9*2 and *3 have a significant influence on the transport and metabolism of glibenclamide and glipizide.
