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Xenobiotica
the fate of foreign compounds in biological systems
Volume 40, 2010 - Issue 12
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General Xenobiochemistry

Sitagliptin attenuates metformin-mediated AMPK phosphorylation through inhibition of organic cation transporters

, , , &
Pages 817-825 | Received 24 Jun 2010, Accepted 30 Aug 2010, Published online: 23 Sep 2010
 

Abstract

  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 Ki values of sitagliptin for OCT1- and OCT2-mediated metformin uptake were 34.9 and 40.8 μM, 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 Ki values of 38.8 and 43.3 μM, 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.

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