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 IC 50 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.
Highlights
Metformin is a biguanide drug used for the treatment of type 2 diabetes and is becoming a common comedication in patients due to the prevalence of diabetes as a comorbidity in many disease areas
Cimetidine, trimethoprim, pyrimethamine, ammonium chloride, sodium butyrate, non-essential amino acids, MES, human serum albumin (HSA), lucifer yellow and HEPES were purchased from Sigma-Aldrich (Poole, Dorset, UK). [14C]-Metformin was purchased from American Radiolabeled Chemicals (St Louis, MO) and Optiphase Supermix liquid scintillation cocktail, 24well liquid scintillation counting visiplates and 96-well isoplates were purchased from PerkinElmer Life and 2017 | Vol 5 | Iss. 5 | e00357 Page 2
A similar trend was observed for trimethoprim which produced a MATE1 IC50 that was approximately 10-fold and 52-fold more potent compared to OCT1 and OCT2
Summary
Metformin is a biguanide drug used for the treatment of type 2 diabetes and is becoming a common comedication in patients due to the prevalence of diabetes as a comorbidity in many disease areas. As an organic cation at physiological pH, metformin has minimal passive membrane permeability and requires active transport to cross membranes in order to gain entry into cells. Based on metformin renal clearance values reported from eight clinical studies (3 mass balance above and 5 DDI), on average 75 % of metformin renal clearance is due to active transporter processes (deriving a fraction excreted value, ƒe, of 0.66) and 25% due to passive filtration (120 mL/min; GFR 9 fu = 1) (Somogyi et al 1987; Wang et al 2008; Kusuhara et al 2011; Gru€n et al 2013; Mu€ller et al 2015). The transporters responsible for the active renal elimination of metformin are organic cation transporter (OCT) 2, located on the basolateral membrane of renal proximal tubule epithelial cells, and multidrug and toxin extrusion (MATE) 1/2-K, located on the apical membrane of tubule epithelial cells, which are responsible for the vectorial uptake of metformin from blood and its efflux into urine, respectively (Song et al 2008, Tsuda et al 2009a; Glucophageâ label)
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