Journal
XENOBIOTICA
Volume 40, Issue 12, Pages 817-825Publisher
INFORMA HEALTHCARE
DOI: 10.3109/00498254.2010.520349
Keywords
Sitagliptin; metformin; OCT (organic cation transporter); drug-drug interaction; AMPK phosphorylation
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Funding
- National Research Foundation of Korea, Ministry of Education, Science and Technology, Korea [2010-0005370]
- Inje Research Grant
- National Research Council of Science & Technology (NST), Republic of Korea [SI-1003] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- National Research Foundation of Korea [08-2007-13-002-00, 2010-0005370] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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.
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