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Oh, J.; Chung, H.; Park, S.-I.; Yi, S. J.; Jang, K.; Kim, A. H.; Yoon, J.; Cho, J.-Y.; Yoon, S. H.; Jang, I.-J.; Yu, K.-S.; Chung, J.-Y.
Diabetes, obesity & metabolism, January 2016, Volume: 18, Issue: 1Journal Article
We hypothesized that the pharmacodynamic (PD) characteristics of metformin would change with inhibition of the multidrug and toxin extrusion (MATE) transporter, which mediates renal elimination of metformin. Twenty healthy male subjects received two doses (750/500 mg) of metformin, with and without 50 mg of pyrimethamine (a potent MATE inhibitor), with 1 week of washout in between each dose. The PD characteristics of metformin were assessed using oral glucose tolerance tests (OGTTs) before and after the metformin dose. Metformin concentrations in plasma and urine were determined using liquid chromatography‐electrospray ionization‐tandem mass spectrometry. When metformin was co‐administered with pyrimethamine, its area under the concentration–time curve from 0 to 12 h was 2.58‐fold greater (p < 0.05), whereas the antihyperglycaemic effects of metformin were decreased. The mean differences (90% confidence interval) in mean and maximum serum glucose concentrations and in 2‐h‐post‐OGTT serum glucose concentration were −0.6 (−1, −0.2), −0.9 (−1.6, −0.3) and −0.5 (−1.1, 0.1) mmol/l, respectively. These findings indicate that the response to metformin is not only related to the plasma exposure of metformin but is also related to other factors, such as inhibition of uptake transporters and the gastrointestinal‐based pharmacology of metformin.
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