Interaction of human MATE1 and MATE2‐K with N‐Butylpyridinium chloride and other cationic Ionic liquids

Abstract

‘Ionic Liquids’ (ILs; salts in the liquid state) are seeing increasing use in industrial applications and, consequently, are of increasing interest with respect to their potential toxicity. Three cationic ILs (NBuPy‐Cl, Bmim‐Cl and BmPy‐Cl) have been shown to be excreted in the urine of rats and mice and are inhibitors of the human ortholog of the Organic Cation Transporter, hOCT2, which is the entry step for secretion of type I OCs across the basolateral membrane of renal proximal tubule (RPT) cells. In the present study we assessed the interaction of these model ILs with the human Multidrug and Toxin Extrusion transporters, hMATE1 and hMATE2‐K, which mediate the apical exit of OCs from RPT cells into the filtrate. The uptake of [3H]1‐methyl‐4‐phenylpyridinium ([3H]MPP) and [3H]triethylmethylammonium ([3H]TEMA) into Chinese hamster ovary CHO cells that stably expressed hMATE1 or hMATE2‐K was inhibited by the model ILs with comparatively high affinity (IC50 values from 3 to 70 μM). In addition, all three ILs trans‐stimulated MATE's mediated [3H]MPP efflux, supporting the conclusion that these model ILs are transported substrates as well as inhibitors of the human MATE homologs. Together, these data suggest that cationic ILs are secreted by the human kidney through the OCT2‐MATE1/2‐K pathway, and that inhibition of MATE transporters by ILs may influence the pharmacokinetics of (at least) some cationic drugs.