MATE1

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MATE1 (multidrug and toxin extrusion 1)

Aliases: none
Gene name: Solute carrier family 47 member 1 (SLC47A1)

Summary

MATE1 is an apically expressed poly-specific proton antiporter which mediates the efflux of diverse substrates, primarily organic cations, in the kidney and the liver. Following its relatively recent discovery, MATE1 has rapidly emerged as an important transporter in the renal and biliary excretion of endogenous and exogenous organic cations, particularly metformin. It appears that clinical inhibitors of organic cation transporters (OCTs) are also potent inhibitors of MATEs, and therefore modulation of the activity of both OCTs and MATEs, or predominantly of MATEs, may better describe DDIs currently ascribed to OCTs. The major focus of investigation for MATE1 has been on its role in renal drug disposition and elimination, notably on the renal elimination of metformin and the renal toxicity of cisplatin. Various studies of the impact of functional gene polymorphisms of MATE1, MATE2K, OCT1, and OCT2 on metformin pharmacokinetics, efficacy and safety, as well as preclinical assessments in Mate1 knockout mice, imply a significant role for these transporters.
Although the current FDA and EMA guidelines do not strictly recommend MATE1 transporter evaluation, expert opinion issued by the International Transporter Consortium encourages investigation of MATE1 and MATE2K interactions for NCEs which are cationic, are likely to be co-administered with substrates of MATEs (e.g. metformin), or undergo significant renal elimination.

Localization

MATE1 is highly expressed in the liver and the kidney, and is located on the canalicular membrane (apical, bile side) of hepatocytes, and the brush-border membrane (apical, urine side) of proximal tubule cells [1, 2]. In addition to the liver and kidney, skeletal muscle also has high expression of MATE1, and lower expression has been reported in the adrenal gland, testes, and heart [1, 3].

Function, physiology, and clinically significant polymorphisms

MATE1 is an electroneutral, Na+-independent, pH-dependent proton antiporter with 13 predicted membrane-spanning domains. The direction of MATE1 transport is defined by the proton concentration gradient: when assayed in vitro at pH 7.4 or higher, MATE1 behaves as an uptake transporter, whereas in the proximal tubule in vivo it exchanges intracellular (cat)ions for urinary protons and thus creates an efflux of its substrates [4-6]. This latter behavior is rather unusual for an SLC drug transporter.
MATE1 is a poly-specific transporter mainly specialized on cations, but it also has affinity for some zwitterionic and anionic molecules. It shares many of its substrates with organic cation transporters (OCTs) and other MATEs.
In the liver and the kidney, apically expressed MATE transporters appear to form a functional unit with basolaterally expressed OCTs for the active, vectorial transport of organic cations across the hepatocyte and the proximal tubule epithelium. In this functional unit, OCTs clear organic cations from the bloodstream, and MATEs (MATE1 in liver and MATE1 and 2-K in kidney) eliminate them by apical efflux into the lumen of the respective organ. The co-location and overlapping specificities of MATE1 and MATE2-K in the kidney suggest a redundant system [3, 7], albeit their substrate specificities are not entirely identical.
There are also reports of interplay between MATE1 and organic anion transporter 3 (OAT3) in the renal excretion of an oxazolidinone antibiotic and fexofenadine [8, 9].
The physiological role of MATE transporters in skeletal muscle is unknown. A possible role in the regulation of homeostasis of positively charged endogenous electrolytes and/or metabolites is proposed [1].
In vitro, MATE1 has been shown to mediate the cellular uptake of structurally diverse, low molecular weight organic cations, such as tetraethylammonium (TEA), N-methylphenylpyridinium (MPP+), metformin, paraquat, agmatine, cimetidine, procainamide, pramipexole, atenolol, serotonin, quinidine, verapamil, and oxaliplatin. The panel of substrates shows a good overlap with OCT and OCTN transporters [10-15]. In addition, some anionic (estrone-3-sulfate, acyclovir, and ganciclovir) and zwitterionic (cephalexin and cephradine) substrates were identified [7]. DAPI (4',6-diamidino-2-phenylindole, a nuclear stain commonly used in fluorescence microscopy) has also been shown to be an in vitro substrate [16]. Potent in vitro inhibitors of MATE1 include cimetidine, pyrimethamine, levofloxacin, ciprofloxacin, and moxifloxacin [17].
Functional genetic polymorphisms of SLC47A1 are known [18, 19], and while their clinical relevance is still under investigation, there are reports of altered metformin efficacy and concerns for metformin-induced toxicity which are linked to polymorphisms of both SLC47A1 and SLC22A1 (OCT1) [18, 19].
Interestingly, the SLC47 genes are located on chromosome 17p11.2in, which is a commonly deleted segment in patients with Smith-Magenis syndrome. This syndrome is characterized by multiple congenital anomalies, mild mental retardation, and behavioral issues. The relevance of MATEs to the development of the syndrome is unknown [20, 21].

Clinical significance

Given the strong association of MATEs with OCTs, the greater body of data citing OCT DDIs, and the relatively recent discovery of MATEs in 2005, citations of strictly MATE-specific DDIs in humans are scarce. Much of the research on the clinical relevance of MATEs has focused on metformin disposition, efficacy and toxicity, and the modulation of the renal elimination or toxicity of drugs by cimetidine. Prior to the discovery of MATEs, OCTs were the only drug transporters implicated in these processes, but it is now widely accepted that MATE transporters are at least as important.
In vitro and preclinical evaluations of the relative contributions of OCTs and MATE1 to the disposition and elimination of paraquat (herbicide, extremely toxic to humans, excreted renally), cisplatin (chemotherapeutic with significant renal toxicity, treated by administration of cimetidine), and metformin (antidiabetic drug, substrate of liver and kidney cation transporters, eliminated unchanged in urine) have provided compelling evidence of MATE1 and MATE2K involvement [12, 22-25]. Similar approaches exploring the effect of pyrimethamine (antimalarial, increases serum creatinine), and cimetidine (inhibitor of the renal elimination of cationic drugs) on renal function have also been persuasive [26]. Recently, MATEs have been implicated in the detoxification of cadmium ions [27]. The zwitterionic drugs cephalexin and cephradine are also mainly transported by MATE1 [7], and reduced renal clearance of cephalexin was observed in Mate1-/- mice relative to the wild-type [28].
Functional SNPs of MATE1 and MATE2-K are associated with increased glucose-lowering activity of metformin, although a significant role for OCT1 polymorphisms is also probable [18, 19]. Mate1-/- mice had a 2-fold increase in systemic exposure to metformin compared to the wild-type mice, as a result of the reduced renal clearance [22]. They also had greatly increased liver concentrations of metformin, and showed clinical changes consistent with the development of lactic acidosis, a serious but rare and unpredictable side effect of metformin. The rs2289669 polymorphism affected the renal clearance of metformin when it was co-administered with ranitidine, a traditional antacid and inhibitor of MATE1 [29]. The same polymorphism interfered with the disposition of metformin even in the absence of interacting co-medication: type 2 diabetes patients with the AA genotype proved to be slow eliminators of metformin and responded better to the drug [18, 30, 31]. On the other hand, pharmacologic inhibition of MATEs by pyrimethamine increased metformin AUC but failed to enhance its antihyperglycemic effect [32].
Mate1-/- mice were hypersensitive to cisplatin-induced nephrotoxicity and had increased cisplatin plasma and renal concentrations relative to wild-type mice [23]. More importantly, ondansetron as a MATE inhibitor exacerbated the nephrotoxic effect of cisplatin, which may imply a warning to the co-administration of this widely used antiemetic with cisplatin-based chemotherapeutic regimens [33].
In vitro, cimetidine inhibited MATE1-mediated transport of fexofenadine [9] and metformin [24]. Thus, the clinical observation that metformin tubular secretion is inhibited by cimetidine [34] may be due not only to inhibition of OCT2-mediated metformin uptake [35], but also to inhibition of MATE1-mediated luminal metformin efflux [24].
Clinical studies exploring the impact of pyrimethamine (a proposed selective MATE1 inhibitor) on the renal elimination of metformin after oral microdose and therapeutic doses in healthy subjects showed that pyrimethamine significantly reduced the renal clearance of metformin at both the microdose and therapeutic doses [24].
Studies exploring the metabolomics of cation transporters have suggested that thiamine and perhaps carnitine may be useful biomarkers to demonstrate the impact of drugs on renal cation transporters [36].

Regulatory Requirements

The current FDA and EMA guidances do not strictly recommend MATE1 transporter evaluation, although it is recommended for consideration in the 2012 EMA guideline. In any case, since the International Transporter Consortium (ITC) has highlighted the importance of MATEs in drug exposure and elimination [37], it can be assumed that regulatory agencies will soon expect investigation of MATE1 and MATE2-K interactions in submissions. For the time being, evaluation of MATE interactions should be considered for NCEs which are cationic, are likely to be co-administered with substrates of MATEs (e.g. metformin), or undergo significant renal elimination.

Location Endogenous substrates In vitro substrates used experimentally Substrate drugs Inhibitors

Kidney: proximal tubular cells, apical membrane

Liver: hepatocytes, apical membrane. Skeletal muscle

peptides and nucleosides, creatinine, guanidine, thiamine, estrone-3-sulfate

Tetraethylammonium (TEA), methylphenylpyridinium ( MPP+)

cimetidine, metformin, cephalexin, acyclovir, ganciclovir, cephalexin, cephradine, fexofenadine, oxaliplatin, procainamide, topotecan, pramipexole, atenolol, (paraquat)

quinidine, cimetidine, verapamil, procainamide

levofloxacin, ciprofloxacin, moxifloxacin,

pyrimethamine, ranitidine, ondansetron

 

References

1.    Otsuka, M., et al., A human transporter protein that mediates the final excretion step for toxic organic cations. Proc Natl Acad Sci U S A, 2005. 102(50): p. 17923-8.
2.    Dresser, M.J., M.K. Leabman, and K.M. Giacomini, Transporters involved in the elimination of drugs in the kidney: organic anion transporters and organic cation transporters. J Pharm Sci, 2001. 90(4): p. 397-421.
3.    Masuda, S., et al., Identification and functional characterization of a new human kidney-specific H+/organic cation antiporter, kidney-specific multidrug and toxin extrusion 2. J Am Soc Nephrol, 2006. 17(8): p. 2127-35.
4.    Terada, T., et al., Molecular cloning, functional characterization and tissue distribution of rat H+/organic cation antiporter MATE1. Pharm Res, 2006. 23(8): p. 1696-701.
5.    Tsuda, M., et al., Oppositely directed H+ gradient functions as a driving force of rat H+/organic cation antiporter MATE1. Am J Physiol Renal Physiol, 2007. 292(2): p. F593-8.
6.    Terada, T. and K. Inui, Physiological and pharmacokinetic roles of H+/organic cation antiporters (MATE/SLC47A). Biochem Pharmacol, 2008. 75(9): p. 1689-96.
7.    Tanihara, Y., et al., Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H(+)-organic cation antiporters. Biochem Pharmacol, 2007. 74(2): p. 359-71.
8.    Lai, Y., et al., Preclinical and clinical evidence for the collaborative transport and renal secretion of an oxazolidinone antibiotic by organic anion transporter 3 (OAT3/SLC22A8) and multidrug and toxin extrusion protein 1 (MATE1/SLC47A1). J Pharmacol Exp Ther, 2010. 334(3): p. 936-44.
9.    Matsushima, S., et al., The inhibition of human multidrug and toxin extrusion 1 is involved in the drug-drug interaction caused by cimetidine. Drug Metab Dispos, 2009. 37(3): p. 555-9.
10.    Inui, K.I., S. Masuda, and H. Saito, Cellular and molecular aspects of drug transport in the kidney. Kidney Int, 2000. 58(3): p. 944-58.
11.    Koepsell, H., K. Lips, and C. Volk, Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications. Pharm Res, 2007. 24(7): p. 1227-51.
12.    Chen, Y., et al., Transport of paraquat by human organic cation transporters and multidrug and toxic compound extrusion family. J Pharmacol Exp Ther, 2007. 322(2): p. 695-700.
13.    Winter, T.N., W.F. Elmquist, and C.A. Fairbanks, OCT2 and MATE1 provide bidirectional agmatine transport. Mol Pharm, 2011. 8(1): p. 133-42.
14.    Knop, J., et al., Renal tubular secretion of pramipexole. Eur J Pharm Sci, 2015. 79: p. 73-8.
15.    Yin, J., et al., Atenolol Renal Secretion Is Mediated by Human Organic Cation Transporter 2 and Multidrug and Toxin Extrusion Proteins. Drug Metab Dispos, 2015. 43(12): p. 1872-81.
16.    Yasujima, T., et al., Evaluation of 4',6-diamidino-2-phenylindole as a fluorescent probe substrate for rapid assays of the functionality of human multidrug and toxin extrusion proteins. Drug Metab Dispos, 2010. 38(4): p. 715-21.
17.    Te Brake, L.H., et al., Moxifloxacin Is a Potent In Vitro Inhibitor of OCT- and MATE-Mediated Transport of Metformin and Ethambutol. Antimicrob Agents Chemother, 2016. 60(12): p. 7105-7114.
18.    Becker, M.L., et al., Genetic variation in the multidrug and toxin extrusion 1 transporter protein influences the glucose-lowering effect of metformin in patients with diabetes: a preliminary study. Diabetes, 2009. 58(3): p. 745-9.
19.    Becker, M.L., et al., Interaction between polymorphisms in the OCT1 and MATE1 transporter and metformin response. Pharmacogenet Genomics, 2010. 20(1): p. 38-44.
20.    Bi, W., et al., Genes in a refined Smith-Magenis syndrome critical deletion interval on chromosome 17p11.2 and the syntenic region of the mouse. Genome Res, 2002. 12(5): p. 713-28.
21.    Slager, R.E., et al., Mutations in RAI1 associated with Smith-Magenis syndrome. Nat Genet, 2003. 33(4): p. 466-8.
22.    Tsuda, M., et al., Targeted disruption of the multidrug and toxin extrusion 1 (mate1) gene in mice reduces renal secretion of metformin. Mol Pharmacol, 2009. 75(6): p. 1280-6.
23.    Nakamura, T., et al., Disruption of multidrug and toxin extrusion MATE1 potentiates cisplatin-induced nephrotoxicity. Biochem Pharmacol, 2010. 80(11): p. 1762-7.
24.    Tsuda, M., et al., Involvement of human multidrug and toxin extrusion 1 in the drug interaction between cimetidine and metformin in renal epithelial cells. J Pharmacol Exp Ther, 2009. 329(1): p. 185-91.
25.    Yonezawa, A. and K. Inui, Importance of the multidrug and toxin extrusion MATE/SLC47A family to pharmacokinetics, pharmacodynamics/toxicodynamics and pharmacogenomics. Br J Pharmacol, 2011. 164(7): p. 1817-25.
26.    Kusuhara, H., et al., Effects of a MATE protein inhibitor, pyrimethamine, on the renal elimination of metformin at oral microdose and at therapeutic dose in healthy subjects. Clin Pharmacol Ther, 2011. 89(6): p. 837-44.
27.    Yang, H., et al., Multidrug and toxin extrusion proteins mediate cellular transport of cadmium. Toxicol Appl Pharmacol, 2017. 314: p. 55-62.
28.    Watanabe, S., et al., Reduced renal clearance of a zwitterionic substrate cephalexin in MATE1-deficient mice. J Pharmacol Exp Ther, 2010. 334(2): p. 651-6.
29.    Cho, S.K. and J.Y. Chung, The MATE1 rs2289669 polymorphism affects the renal clearance of metformin following ranitidine treatment. Int J Clin Pharmacol Ther, 2016. 54(4): p. 253-62.
30.    He, R., et al., SLC47A1 gene rs2289669 G>A variants enhance the glucose-lowering effect of metformin via delaying its excretion in Chinese type 2 diabetes patients. Diabetes Res Clin Pract, 2015. 109(1): p. 57-63.
31.    Tkac, I., et al., Pharmacogenomic association between a variant in SLC47A1 gene and therapeutic response to metformin in type 2 diabetes. Diabetes Obes Metab, 2013. 15(2): p. 189-91.
32.    Oh, J., et al., Inhibition of the multidrug and toxin extrusion (MATE) transporter by pyrimethamine increases the plasma concentration of metformin but does not increase antihyperglycaemic activity in humans. Diabetes Obes Metab, 2016. 18(1): p. 104-8.
33.    Li, Q., et al., Ondansetron can enhance cisplatin-induced nephrotoxicity via inhibition of multiple toxin and extrusion proteins (MATEs). Toxicol Appl Pharmacol, 2013. 273(1): p. 100-9.
34.    Somogyi, A., et al., Reduction of metformin renal tubular secretion by cimetidine in man. Br J Clin Pharmacol, 1987. 23(5): p. 545-51.
35.    Wang, Z.J., et al., OCT2 polymorphisms and in-vivo renal functional consequence: studies with metformin and cimetidine. Pharmacogenet Genomics, 2008. 18(7): p. 637-45.
36.    Ito, S., et al., Potent and specific inhibition of mMate1-mediated efflux of type I organic cations in the liver and kidney by pyrimethamine. J Pharmacol Exp Ther, 2010. 333(1): p. 341-50.
37.    Hillgren, K.M., et al., Emerging transporters of clinical importance: an update from the international transporter consortium. Clin Pharmacol Ther, 2013. 94(1): p. 52-63.

 

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