Sitagliptin attenuates metformin-mediated AMPK phosphorylation through inhibition of organic cation transporters
Sitagliptin attenuates metformin-mediated AMPK phosphorylation through inhibition of organic cation transporters
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DOI：
10.3109/00498254.2010.520349
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发表时间：
2010-12-01
期刊：
影响因子：
1.8
通讯作者：
Song, Im-Sook
中科院分区：
文献类型：
--
作者：
Choi, Min-Koo;Jin, Qing-Ri;Song, Im-Sook
1.为了评估西格列汀和二甲双胍之间的潜在相互作用，我们试图表征西格列汀对甲氧西格列汀(MPP(+))和二甲双胍(OCTs的代表性底物)摄取的体外抑制效力，并评价西格列汀和西格列汀联合使用可能影响的药理途径。在所筛选的燕麦和OCTs中，西格列汀抑制了OAT3介导的水杨酸摄取以及OCT1和OCT2介导的MPP(+)摄取。西格列汀对OCT1和OCT2介导的二甲双胍摄取的K(I)值分别为34.9和40.8 mU M。由于OCT1是肝脏中二甲双胍作用的门蛋白，我们研究了西格列汀介导的OCT1抑制是否影响了二甲双胍诱导的AMPK信号的激活。西格列汀处理MDCK-OCT1和HepG2细胞后，AMPK的磷酸化水平降低，K(I)值分别为38.8和43.3mU。这些结果表明，西格列汀对OCT1的抑制作用可能减弱了二甲双胍作用的第一步，即AMPK的磷酸化。然而，在通常的临床环境中，西格列汀和二甲双胍之间发生药物相互作用的可能性被认为是很小的。
1. To assess potential interactions between sitagliptin and metformin, we sought to characterize the in vitro inhibitory potency of sitagliptin on the uptake of MPP(+) and metformin, representative substrates for OCTs, and to evaluate the pharmacological pathways that may be affected by the combination of metformin and sitagliptin.2. Among the OATs and OCTs screened, OAT3-mediated salicylate uptake and OCT1- and OCT2-mediated MPP(+) uptake were inhibited by sitagliptin. The K(i) values of sitagliptin for OCT1- and OCT2-mediated metformin uptake were 34.9 and 40.8 mu M, respectively.3. As OCT1 is the gate protein for metformin action in the liver, we investigated whether sitagliptin-mediated OCT1 inhibition affected metformin-induced activation of AMPK signalling. Treatment with sitagliptin in MDCK-OCT1 and HepG2 cells resulted in a reduced level of phosphorylated AMPK, with K(i) values of 38.8 and 43.3 mu M, respectively.4. These results suggest that the inhibitory potential of sitagliptin on OCT1 may attenuate the first step of metformin action, that is, the phosphorylation of AMPK. Nevertheless, the likelihood of a drug-drug interaction between sitagliptin and metformin is believed to be remote in usual clinical setting.