Human Transporters

MATE2

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MATE2 (multidrug and toxin extrusion 2)

Aliases: MATE2-B, MATE2-K, MATE2K
Gene name: Solute carrier family 47 member 2 (SLC47A2)

Summary

MATE2 and its splice variant MATE2-K are proton antiporters which function as a poly-specific efflux transporters of diverse substrates, primarily of organic cations. MATE2 and MATE2-K are exclusively expressed in the apical membrane of kidney proximal tubular cells. This recently discovered transporter has rapidly grown appreciated as an important player in the renal excretion of endogenous and exogenous organic cations, particularly of 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 MATE2-K has been on metformin renal elimination. However, various studies of the impact of functional gene polymorphisms of MATE1, MATE2-K, OCT1 and OCT2 on metformin pharmacokinetics, efficacy and safety, imply a significant role for these transporters.
As MATE2 is not functionally expressed in classic in vitro transporter systems, cell lines expressing the splice variant MATE2-K have become the preferred model for assessing MATE2 modulation.
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

MATE2 and MATE2-K are exclusively expressed in the brush border (apical, urine side) membrane of proximal tubular cells [1, 2]. Another splice variant of MATE2, MATE2-B, is ubiquitously expressed, except in kidney, although this appears to be non-functional.

Function, physiology and clinically significant polymorphisms

MATE2 is an electroneutral, Na+-independent, pH-dependent proton antiporter with 13 predicted membrane-spanning domains. Unusually for SLC drug transporters, MATE2 functions as an efflux transporter in vivo [3-5][3-5][3-5].
In addition to MATE2, there are two splice variants of SLC47A2 whose protein products are MATE2-K and MATE2-B [1, 2]. MATE2 was only expressed intracellularly when transfected into HEK 293 cells, and was therefore non-functional in the in vitro system, whereas hMATE2-K was normally expressed at the membrane. When, however, membrane vesicles were extracted from the MATE2-expressing cell line, the protein was functional and had identical substrate specificity to MATE2-K [2].
The majority of knowledge on MATE2 function, physiology, and clinical significance has been derived from MATE2-K. There has been no demonstration of functional activity of MATE2-B thus far. Of note, in contrast to MATE1, rodent Mate2 is not closely related to MATE2 or its variants, and therefore data from rodent-based studies are not readily translated to humans.
MATE2-K 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 [1, 6].
In the kidney, apically expressed MATE1, MATE2 and MATE2-K transporters appear to form a functional unit with basolaterally expressed OCT2 for the active, vectorial transport of organic cations across the proximal tubule epithelium. In this functional unit, OCT2 clears organic cations from the bloodstream, and the MATEs eliminate them by apical efflux into the proximal tubule. The co-location and overlapping specificities of MATE1 and MATE2-K in kidney suggest a redundant system [1, 6], albeit their substrate specificities are not entirely identical.
MATE2-K substrates include metformin, cimetidine, tetraethylammonium (TEA), N-methylnicotinamide, procainamide, MPP+, creatinine, guanidine, quinidine, quinine, thiamine and verapamil [1, 3, 4].
Functional genetic polymorphisms of SLC47A2 are known [7, 8], 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) [7, 8].
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 [9, 10].

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 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. Additionally, MATE2-K has received less attention than MATE1 thus far.
Metformin, a widely prescribed oral antidiabetic drug, is a substrate of liver and kidney cation transporters and is eliminated unchanged into the urine. In vitro and preclinical evaluation of the relative contributions of OCTs and MATEs to the disposition and elimination of metformin have provided compelling evidence of MATE1 and MATE2-K involvement [7, 8, 11-13]. 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 [14].
Functional SNPs of MATE1 and MATE2K are associated with increased glucose-lowering activity of metformin, although a significant role for OCT1 polymorphisms is also probable [7, 8]. Clinical studies exploring the impact of pyrimethamine 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 [15]. Pyrimethamine was demonstrated to be a potent competitive inhibitor of MATE1- and MATE2-K-mediated metformin transport, but it did not inhibit OCT2 [16]. Based on these results pyrimethamine was recommended as a MATE1 and MATE2-K inhibitor for in vivo studies. Nizatidine, a histamine H2 receptor antagonist, was shown unique as being a selective inhibitor of MATE2-K, but inhibition of MATE2-K only was insufficient to cause clinically relevant DDI with metformin [17].
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 [16].

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 [18], 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 substrates drugs Inhibitors
kidney, proximal tubule, brush border (luminal) membrane estrone sulphate, creatinine, thiamine, carnitine TEA,MPP+, metformin

metformin, cimetidine, procainamide, guanidine, topotecan, acyclovir, ganciclovir, quinidine, lamivudine,

oxaliplatin, varenicline,

pyrimethamine,

levofloxacin, ciprofloxacin, cimetidine, trimethoprim

References

1.    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.
2.    Komatsu, T., et al., Characterization of the human MATE2 proton-coupled polyspecific organic cation exporter. Int J Biochem Cell Biol, 2011. 43(6): p. 913-8.
3.    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.
4.    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.
5.    Terada, T. and K. Inui, Physiological and pharmacokinetic roles of H+/organic cation antiporters (MATE/SLC47A). Biochem Pharmacol, 2008. 75(9): p. 1689-96.
6.    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.
7.    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.
8.    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.
9.    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.
10.    Slager, R.E., et al., Mutations in RAI1 associated with Smith-Magenis syndrome. Nat Genet, 2003. 33(4): p. 466-8.
11.    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.
12.    Chung, J.Y., et al., Functional characterization of MATE2-K genetic variants and their effects on metformin pharmacokinetics. Pharmacogenet Genomics, 2013. 23(7): p. 365-73.
13.    Choi, J.H., et al., A common 5'-UTR variant in MATE2-K is associated with poor response to metformin. Clin Pharmacol Ther, 2011. 90(5): p. 674-84.
14.    Nakamura, T., et al., Disruption of multidrug and toxin extrusion MATE1 potentiates cisplatin-induced nephrotoxicity. Biochem Pharmacol, 2010. 80(11): p. 1762-7.
15.    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.
16.    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.
17.    Morrissey, K.M., et al., The Effect of Nizatidine, a MATE2K Selective Inhibitor, on the Pharmacokinetics and Pharmacodynamics of Metformin in Healthy Volunteers. Clin Pharmacokinet, 2016. 55(4): p. 495-506.
18.    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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