A recent research paper authored by Cyprotex, and published in the journal of Pharmacology Research & Perspectives, has furthered understanding of the mechanism underlying the clinically observed DDIs between the common co-medication metformin with perpetrator drugs cimetidine, trimethoprim or pyrimethamine. Such DDIs manifest as 1) decreased active renal clearance of metformin due to inhibition of the apical transporter MATE1, and 2) increased plasma exposure (AUC) of metformin. However, it is not clear whether the observed AUC increases above relate to the decreased renal elimination of metformin (via MATE1 inhibition) or some other factor relating to the drug’s absorption.
In the article authored by Elsby et al (2017), an aim of the study was to understand whether metformin AUC increases relate to absorption. To establish this, firstly, the in vitro inhibitory potency of cimetidine, trimethoprim and pyrimethamine against metformin transport by human OCT1 was investigated, and secondly, their effect at therapeutically relevant intestinal concentrations on the apical to basolateral absorptive permeability of metformin across Caco‑2 cell monolayers was assessed.
The results from these investigations indicated that DDI AUC increases are unlikely to be a consequence of a change in absorption, and therefore must be related to the reduction in metformin renal elimination due to solitary inhibition of renal MATE1 transport. This was confirmed using in vitro generated transporter inhibition data against OCT2, MATE1 and MATE2-K followed by mechanistic static equations for which calculated theoretical fold-increases in metformin AUC due to MATE1 inhibition by these drugs were similar to the clinically observed values using a transporter fraction excreted value (fe) derived from oral metformin disposition in human; reflecting the “flip-flop” pharmacokinetic profile of metformin.