MATE2-K
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MATE2-K Transporter (Multidrug and toxin extrusion protein 2 / SLC47A2)
SLC47A2, more commonly referred to as MATE2 (Multidrug and toxin extrusion protein 2), is a renal transporter (an organic cation/H antiporter) responsible for brush border secretory transport, and as such, plays a key role in drug disposition and renal clearance of drugs and endogenous compounds. Drugs that are substrates of MATE2 have the potential to be victims of co-administered therapeutics that are inhibitors of this transporter.
SOLVO Biotechnology suggests in vitro testing for MATE2-K transporter with drug candidates that are eliminated at least in part via the kidneys.
Two splice variants of the human MATE2 transporter have been identified, hMATE2-K and hMATE2-B (1, 2). The wild-type hMATE2 and hMATE2-K are expressed most abundantly and specifically in the kidney, where they can be found at the luminal membrane of renal tubular cells. The hMATE2 wild type, when expressed in HEK 293 cells, remains stuck into intracellular compartment, whereas the hMATE2-K is normally expressed at the membrane. Both MATE2 and MATE2K have been described to be functional and to contribute to substrate transport and are believed to share identical substrate specificity (2). As MATE2 cannot be expressed in classic in-vitro system, MATE2-K expressing cell lines became an ideal model for assessing MATE2-K involvement in substrate transport in the kidney.
Localization
MATE2-K (SLC47A2) is localized in the brush border membranes of proximal tubules, and found specific to the kidney (1).
Function, physiology and clinically significant polymorphisms
MATE2-K is a multispecific exchanger that plays a critical role in the renal elimination of organic cations in collaboration with OAT2. MATE2-K substrates include metformin, cimetidine, tetraethylammonium (TEA), N-methylnicotinamide, procainamide, MPP. Upon treatment of MATE2-K expressing cells with ammonium-chloride, transport of creatinine, guanidine, quinidine, quinine, thiamine and verapamil was also observed (1, 3, 4).
Pyrimethamine was demonstrated as a potent competitive inhibitor of MATE2-K mediated metformin transport besides MATE1 inhibition, while it did not inhibit OCT2 (5). Based on the above results pyrimethamine was recommended as a MATE1 and MATE2/-K inhibitor for in vivo studies.
Regulatory Requirements
MATE2/-K has relevance to renal drug clearance, drug disposition and interactions. Although no regulatory recommendation covers this transporter to date, the second workshop of the International Transporter Consortium (ITCW2) aims to continue the ongoing discussion on MATE1 and MATE2 besides other emerging transporters.
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References
- Masuda et al. 2006. JASN Vol. 17
- Kotsuma et al, 2011. IJBCB Vol 10.
- Terada et al. 2006. Pharma Res. Vol. 23
- Tsuda et al. 2007. AJP Vol. 292
- Ito S et al., 2010. J.Pharmacol. Exp.Ther. Vol 333
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