Discovery of Potent, Selective Multidrug and Toxin Extrusion Transporter 1 (MATE1, SLC47A1) Inhibitors Through Prescription Drug Profiling and Computational Modeling
The human multidrug and toxin extrusion (MATE) transporter 1 contributes to the tissue distribution and excretion of many drugs. Inhibition of MATE1 may result in potential drug-drug interactions (DDIs) and alterations in drug exposure and accumulation in various tissues. The primary goals of this project were to identify MATE1 inhibitors with clinical importance or in vitro utility and to elucidate the physicochemical properties that differ between MATE1 and OCT2 inhibitors. Using a fluorescence assay of ASP+ uptake in cells stably expressing MATE1, over 900 prescription drugs were screened and 84 potential MATE1 inhibitors were found. We identified several MATE1 selective inhibitors including four FDA-approved medications that may be clinically relevant MATE1 inhibitors and could cause a clinical DDI. In parallel, a QSAR model identified distinct molecular properties of MATE1 versus OCT2 inhibitors and was used to screen the DrugBank in silico library for new hits in a larger chemical space.
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- "After refinement by low-throughput experiment validation, the performance of the model was improved. The refined model was then applied to the screening of compound libraries in order to find novel ligands binding to MATE1 (Wittwer et al., 2013). With the number of resolved membrane transporter structures increasing and the development of computational tools, in silico analysis are expected to greatly facilitate substrate or inhibitor discovery in transporter study. "
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ABSTRACT: Transporters comprise the largest family of membrane proteins in human organism, including members of solute carrier transporter and ATP-binding cassette transporter families. They play pivotal roles in the absorption, distribution and excretion of xenobiotic and endogenous molecules. Transporters are widely expressed in various human tissues and are routinely evaluated during the process of drug development and approval. Over the past decade, increasing evidence shows that drug transporters are important in both normal physiology and disease. Currently, transporters are utilized as therapeutic targets to treat numerous diseases such as diabetes, major depression, hypertension and constipation. Despite the steady growth of the field of transporter biology, more than half of the members in transporter superfamily have little information available about their endogenous substrate(s) or physiological functions. This review outlines current research methods in transporter studies, and summarizes the drug-transporter interactions including drug-drug and drug-endogenous substrate interactions. In the end, we also discuss the therapeutic perspective of transporters based on their physiological and pathophysiological roles.
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- "The results of the present study, showing an initial increase in plasma metformin levels, indicated that the possibility of OCT1 inhibition could not be excluded. Multidrug and toxin extrusion protein (MATE) transporters and OCT2 are mainly involved in urinary excretion of metformin, and PPIs may also inhibit these transporters (Nies et al., 2011; Wittwer et al., 2013). However, the impact of OCT2 inhibition on the renal clearance of metformin is controversial (Ito et al., 2012). "
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ABSTRACT: As inhibitors of organic cation transporters (OCTs), proton pump inhibitors (PPIs) may affect the plasma levels of metformin, an OCT substrate. We investigated the effects of two PPIs, pantoprazole and rabeprazole, on metformin pharmacokinetics and glucose levels in healthy subjects. In this open, randomized, 6 × 3 cross-over study, 24 participants were administered metformin, either alone or in combination with pantoprazole or rabeprazole. The plasma concentrations of metformin and serum concentrations of glucose after a 75 g oral glucose tolerance test (OGTT) were determined. The area under the concentration-time curve (AUC) for metformin was 15% and 16% greater following co-administration with pantoprazole and rabeprazole, respectively. The maximum plasma metformin concentrations (Cmax) also increased by 15% and 22%, respectively, compared to when it was administered without the PPIs. The percentage change in the AUC for glucose concentration versus time for metformin plus rabeprazole was significantly lower than that for metformin plus pantoprazole (geometric mean ratio: 0.96 [90% CI: 0.92 - 0.99] and 0.77 [0.63 - 0.93], respectively). There was no significant difference in the maximum glucose concentration. In conclusion, concomitant administration of PPIs with metformin significantly increased plasma metformin exposure, but the effects on glucose disposition were minor and varied depending on the PPI administered.
- "In a recent study, Wittwer et al. (2013) surveyed >900 prescription drugs as inhibitors of MATE1-mediated transport of the fluorescent cationic dye, 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP). The authors used these data to identify several physicochemical properties that distinguished effective inhibitors from those of molecules that interacted weakly or not at all with MATE1; good inhibitors of MATE1 tended to be larger, with a higher-molecular weight and a larger number of bonds and ring structures, than poor inhibitors. "
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ABSTRACT: Transporters within the SLC22, SLC44, and SLC47 families of solute carriers mediate transport of a structurally diverse array of organic electrolytes, that is, molecules that are generally charged (cationic, anionic, or zwitterionic) at physiological pH. Transporters in the SLC22 family-all of which are members of the major facilitator superfamily (MFS) of transporters-represent a mechanistically diverse set of processes, including the organic anion transporters (OATs and URAT1) that physiologically operate as organic anion (OA) exchangers, the organic cation transporters (OCTs) that operate as electrogenic uniporters of organic cations (OCs), and the so-called "novel" organic cation transporters (OCTNs) that support Na-cotransport of selected zwitterions. Whereas the OCTNs display a high degree of substrate selectivity, the physiological hallmark of the OATs and OCTs is their multiselectivity-consistent with a principal role in renal and hepatic clearance of a wide array of both endogenous and xenobiotic compounds. SLC47 consists of members of the multidrug and toxin extruder (MATE) family, which are carriers that are obligatory exchangers and that physiologically support electroneutral H(+) exchange. The MATEs also display a characteristic multiselectivity and are frequently paired with OCTs to mediate transepithelial OC secretion, with the OCTs typically supporting basolateral OC entry and the MATEs supporting apical OC efflux. The SLC44 family contains the choline transporter-like (CTL) transporters. Largely restricted to choline and a limited set of structural congeners, the CTLs appear to support the Na-independent, electrogenic uniport of choline, thereby providing choline for membrane biogenesis. The solution of X-ray crystal structures of representative prokaryotic MFS and MATE transporters has led to the development of homology models of mammalian OAT, OCT, and MATE transporters that, in turn, have supplemented studies of the molecular basis of the complex interactions of ligands with these multiselective proteins.
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