Mechanistic in vitro studies confirm that inhibition of the renal apical efflux transporter multidrug and toxin extrusion (MATE) 1, and not altered absorption, underlies the increased metformin exposure observed in clinical interactions with cimetidine, trimethoprim or pyrimethamine. Issue 5 (21st September 2017)

• Record Type: Journal Article
• Authors: Elsby, Robert; Chidlaw, Stephen; Outteridge, Samuel; Pickering, Sarah; Radcliffe, Amy; Sullivan, Rebecca; Jones, Hayley; Butler, Philip
• Is Part Of: Pharmacology research & perspectives. Volume 5:Issue 5(2017)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2017-09-21
• Subjects: Drug‐drug interaction -- MATE1 -- metformin -- OCT2 -- pharmacokinetics; Pharmacology -- Periodicals; Drug development -- Periodicals; 615.105
• DOI: 10.1002/prp2.357
• Languages: English
• ISSNs: 2052-1707

Abstract

Abstract: Metformin is a common co‐medication for many diseases and the victim of clinical drug‐drug interactions (DDIs) perpetrated by cimetidine, trimethoprim and pyrimethamine, resulting in decreased active renal clearance due to inhibition of organic cation transport proteins and increased plasma exposure of metformin. To understand whether area under the plasma concentration–time curve (AUC) increases relate to absorption, in vitro inhibitory potencies of these drugs against metformin transport by human organic cation transporter (OCT) 1, and the apical to basolateral absorptive permeability of metformin across Caco‐2 cells in the presence of therapeutic intestinal concentrations of cimetidine, trimethoprim or pyrimethamine, were determined. Whilst all inhibited OCT1, none enhanced metformin's absorptive permeability (~0.5 × 10 −6 cm/sec) suggesting that DDI AUC changes are not related to absorption. Subsequently, to understand whether inhibition of renal transporters are responsible for AUC increases, in vitro inhibitory potencies against metformin transport by human OCT2, multidrug and toxin extrusion (MATE) 1 and MATE2‐K were determined. Ensuing IC50 values were incorporated into mechanistic static equations, alongside unbound maximal plasma concentration and transporter fraction excreted values, in order to calculate theoretical increases in metformin AUC due to inhibition by cimetidine, trimethoprim or pyrimethamine. Calculated theoretical fold‐increases in metformin exposure confirmed solitary inhibition of renal MATE1 to be the likely mechanism underlying the observed exposure changes in clinical DDIs. Interestingly, clinically observed increases in metformin AUC were predicted more closely when the renal transporter fraction excreted value derived from oral metformin administration, rather than intravenous, was utilized in theoretical calculations, likely reflecting the "flip‐flop" pharmacokinetic profile of the drug.