Organic Cation Transporters (OCTs, MATEs), In Vitro and In Vivo Evidence for the Importance in Drug Therapy

Abstract

Organic cation transporters (OCTs) of the solute carrier family (SLC) 22 and multidrug and toxin extrusion (MATE) transporters of the SLC47 family have been identified as uptake and efflux transporters, respectively, for xenobiotics including several clinically used drugs such as the antidiabetic agent metformin, the antiviral agent lamivudine, and the anticancer drug oxaliplatin. Expression of human OCT1 (SLC22A1) and OCT2 (SLC22A2) is highly restricted to the liver and kidney, respectively. By contrast, OCT3 (SLC22A3) is more widely distributed. MATEs (SLC47A1, SLC47A2) are predominantly expressed in human kidney. Data on in vitro studies reporting a large number of substrates and inhibitors of OCTs and MATEs are systematically summarized. Several genetic variants of human OCTs and in part of MATE1 have been reported, and some of them result in reduced in vitro transport activity corroborating data from studies with knockout mice. A comprehensive overview is given on currently known genotype-phenotype correlations for variants in OCTs and MATE1 related to protein expression, pharmacokinetics/-dynamics of transporter substrates, treatment outcome, and disease susceptibility.

Organic cation transporter function in different in vitro models of human lung epithelium

“…is also a high affinity ligand of monoamine transporter such as NET, DAT and SERT (). and K m values reported for ASP + in heterologous systems over-expressing monoamine transporters were about 1000-times lower than those measured in OCT transfectants (Nies et al, 2011;Haunsø and Buchanan, 2007;Mason et al, 2005;Oz et al, 2010). Hence, in this study, TEA was used, which appears to be somewhat less promiscuous (Nies et al, 2011).…”

“…Several different modulators of OCT activity were chosen according to their inhibitory potential (Nies et al, 2011) and their effects were corrected for nonspecific binding at 4°C (Fig. 4).…”

“…OCTs operate electrogenically and independent of sodium gradients and transport in both directions following the substrates' concentration gradient (Ciarimboli, 2010;Koepsell et al, 2007). OCT physiology in tissues such as the liver, gut and kidneys has by and large been well characterised (Nies et al, 2011), nonetheless, the lungs remain somewhat understudied in this regard. Moreover, OCT expression data concerning the respiratory epithelium is often limited to gene or PCR-based in vitro studies (Bleasby et al, 2006;Courcot et al, 2012;Endter et al, 2009;Mukherjee et al, 2012) and only a small number of reports show OCT immunocytochemistry or indeed transporter function (Lips et al 2005;Macdonald et al, 2013;Nakanishi et al, 2013).…”

The Kidney and Uremic Toxin Removal: Glomerulus or Tubule?

“…MATE1 is expressed throughout the body, but predominantly in liver and kidneys, whereas MATE2-K is located exclusively in kidney proximal tubules. 77 The transporters may have a profound effect on pharmacokinetics of drugs because genetic polymorphisms of MATE1 and MATE2-K have been linked to variability in renal drug handling and drug-induced nephrotoxicity, 78 but their role in uremic toxin clearance still needs to be investigated.…”

Pharmacogenetics of Organic Cation Transporters

“…Среди лекар-ственных препаратов-субстатов ОСТ наиболее хорошо изучены метформин, ганцикловир, прокаинамид, цисплатин, циметидин и др. [8]. Разработана фармакофорная модель для ОСТ1, с помощью которой было показало, что субстратами для ОСТ1 могут быть вещества, обладающие следующими характеристиками: 1) сайт возникновения положительного заряда;…”