Inhibition of the multidrug and toxin extrusion (MATE) transporter by pyrimethamine increases the plasma concentration of metformin but does not increase antihyperglycaemic activity in humans

Abstract

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.

Physiologically‐Based Pharmacokinetic Modeling Analysis for Quantitative Prediction of Renal Transporter–Mediated Interactions Between Metformin and Cimetidine

“…A number of DDI cases have been reported between metformin and other drugs that can inhibit both OCT2 and MATEs (e.g., pyrimethamine, dolutegravir, trimethoprim, and vandetanib). For pyrimethamine, in vitro Ki values for MATEs (0.059–0.15 μM) are much lower than those for OCT2 (4.1–23 μM) .…”

Comparative effects of proximal and distal small intestinal administration of metformin on plasma glucose and glucagon‐like peptide‐1, and gastric emptying after oral glucose, in type 2 diabetes

“…In the current study, plasma metformin concentrations were not assessed, given that these concentrations would be unlikely to alter our conclusions, particularly because there is compelling evidence that plasma metformin concentrations do not relate closely to the impact of metformin on blood glucose concentrations in humans. For example, inhibition of the multidrug and toxin extrusion (MATE) transporter in healthy males, despite substantially increasing plasma metformin concentrations, had little effect on blood glucose . Furthermore, intravenous administration of metformin to yield “therapeutic” plasma concentrations in patients with T2DM failed to affect either hepatic glucose production or peripheral glucose disposal during hyperglycaemia .…”

Optimization of a drug transporter probe cocktail: potential screening tool for transporter‐mediated drug–drug interactions

“…This effect was simulated in our second trial by increasing the metformin dose fivefold from 10 mg to 50 mg , which produced increases of 4.1‐fold in metformin AUC 0–tz and 3.6‐fold in C max . These had no effect on rosuvastatin systemic exposure , and cover the range of metformin systemic exposure increases that have so far been attributed to OCT/MATE inhibition . Therefore, the use of the 10 mg metformin dose in the cocktail should allow for an approximately fourfold no‐effect margin with respect to a secondary effect on rosuvastatin AUC and C max , if an NME that is coadministered as a potential perpetrator increases the plasma exposure of metformin.…”