Gene name: Solute carrier family 22 member 2 (SLC22A2)
OCT2 is a primarily renal uptake transporter that is expressed on the basolateral (blood) side of proximal tubule cells. It plays a key role in the disposition and renal clearance of mostly cationic drugs and endogenous compounds. It functions in conjunction with MATE1 and MATE2-K which facilitate the elimination of OCT2 substrates into the urine. Important clinical substrates include metformin and cisplatin. Gene polymorphisms of OCT2 are associated with altered metformin and cisplatin pharmacokinetics and toxicity, but the role of other cation transporters, and their functional SNPs are also important. Since the discovery of MATEs, DDIs ascribed to OCT2 are being re-evaluated, and it is likely that some interactions may be re-assigned to MATEs. Regardless of this, the role of OCT2 as the first step in active renal secretion of cationic drugs remains important. Current FDA and EMA guidances recommend evaluation of OCT2 liabilities for drugs with high renal elimination, or which are likely to be co-administered with OCT2 substrates such as metformin. Although there is no guidance for MATEs either, simultaneous evaluation of their interactions is also advisable.
OCT2 is primarily expressed on the basolateral (blood side) membrane of renal proximal tubule cells, along all three segments of the proximal tubule. It is not expressed in the liver, but is found in some other tissues at lower levels (e.g. small intestine, trachea and bronchi, skin, placenta, brain and the choroid plexus, and the inner ear) [1-3]. There are significant differences in relative tissue expression (notably in the liver and kidney) between rodents and humans.
Function, physiology, and clinically significant polymorphisms
OCT2 is a polyspecific, bi-directional, facilitative diffusional transporter. The driving force is believed to be the electrochemical gradient of the transported compounds. OCT2 has 12 predicted membrane-spanning domains, and is predominantly expressed on the blood side (basolateral membrane) of kidney proximal tubules. Although bi-directional, it typically behaves as an uptake transporter in vivo, extracting substrates from the blood into the proximal tubular cell as the first step in the renal elimination of its drug substrates. In addition to organic cations, OCT2 transports some anionic and zwitterionic compounds. OCT2 also transports endogenous substances, such as monoamine neurotransmitters , thereby participating in the regulation of interstitial and intracellular concentrations of these substances.
A large number of drugs has been identified as substrates or inhibitors of OCT2. Important drug substrates, due to their significant renal elimination, include the oral antidiabetic drug metformin, chemotherapeutics such as cisplatin and oxaliplatin, proton-pump inhibitors such as cimetidine and ranitidine, antivirals such as lamivudine, and the antiarrhythmic dofetilide.
OCT2 shares many substrates and inhibitors with OCT1 and OCT3, as well as with OCTNs and members of the MATE family of transporters. This cross-specificity is important. Firstly, MATE1 and MATE2-K in the kidney constitute the final step in the elimination of drugs from the proximal tubule cells into the lumen (urine), thus complementing OCT2 uptake from the blood. Secondly, as being primarily hepatic, OCT1 provides an alternative systemic clearance mechanism. The roles of OCT3 and OCTNs are more difficult to quantify. Oct3-deficient mice showed significant reduction of MPP+ accumulation in the heart as compared with wild-type mice .
Because rodent Oct1 and Oct2 are both significantly expressed in the liver and the kidney, preclinical to clinical predictions are challenging. For example, Oct2 single knockout mice showed no major alteration in PK or renal elimination of the classical renally cleared OCT substrate tetraethyl ammonium (TEA). In Oct1/2 double knockout mice, however, renal secretion of TEA was completely abrogated with consequent higher plasma levels .
A single splice variant of OCT2 was identified in kidney. Termed OCT2-A, this truncated form of OCT2 appears to have lower Km (or greater affinity) for substrates than OCT2 .
Functional variants of OCT2 have been identified. Their clinical relevance is actively under investigation, and may be clinically significant where other cation transporters are also affected.
Given the strong association of OCT substrates and inhibitors with those of MATEs, and the significant time gap between the discovery of OCTs (1995) and MATEs (2005), DDIs previously ascribed to OCT2 are under re-evaluation. This has resulted in an enormous revival of interest in OCT-mediated DDI mechanisms in general. However, even where DDIs may be primarily re-assigned to MATEs, the role of OCT2 as the first step in active renal secretion remains important. Therefore, the evaluation of OCT2 transporter interactions will continue to be necessary for NCEs.
Much of the research on the clinical relevance of OCT2 has focused on metformin disposition, efficacy, and toxicity, and cimetidine modulation of the renal elimination or toxicity of drugs . Prior to the discovery of MATEs, OCTs were the only drug transporters implicated in these processes; however, it is now widely accepted that MATE transporters are at least as important.
The majority of clinical studies to assess OCT2 transporter activity have been conducted using cimetidine as the probe inhibitor. Drug interactions with procainamide/cimetidine result in a 42% decrease in procainamide renal clearance (CLR), and those with metformin/cimetidine result in a 28% decrease in metformin CLR. Substrates taken up by OCT2 from the systemic circulation may subsequently undergo efflux across the brush-border membrane of the proximal tubule cells by various efflux transporters such as MATE1, MATE2-K, P-gp, and BCRP . For example, creatinine is secreted by OCT2-mediated uptake at the basolateral membrane and efflux by MATEs and/or MDR1 at the apical membrane.
OCT2 and MATE1 are implicated in the nephro- and ototoxicity observed with cisplatin, and these toxic side effects are reduced by the inhibition of OCT2 [1, 2, 10, 11]. Using wild-type and Oct1/2 knockout mice, cisplatin treatment elicited a toxic effect in wild-type mice but not in the knockouts. Co-medication of wild-type mice with cisplatin and cimetidine protected them from ototoxicity and partly from nephrotoxicity. Also, an SNP in SLC22A2, c.808G>T (rs316019), was associated with reduced cisplatin-induced nephro- and ototoxicity in patients. Collectively, these results indicate a critical role of OCT2 in the renal handling and related renal toxicity of cisplatin [12-14].
The clinical relevance of SLC22A2 gene polymorphisms is under active evaluation. SNPs of OCT2 were assessed in the Chinese population and the c.808G>T polymorphism was attributed to a reduced metformin renal tubular clearance. This mutation also correlated with the extent of cimetidine-mediated inhibition of metformin renal tubular secretion . In a healthy volunteer study of the impact of OCT2 and MATE1 polymorphisms on the DDI between trimethoprim and metformin, trimethoprim significantly reduced metformin systemic and renal clearance, and increased Cmax and AUC overall. However, no relevant inhibitory effects on metformin kinetics were observed in volunteers polymorphic for both OCT2 and MATE1. Trimethoprim was also associated with a decrease in creatinine clearance and an increase in plasma lactate in this study .
In a retrospective data analysis to examine the effect of polymorphisms in organic cation transporter genes OCT1-3, OCTN1, MATE1, and MATE2-K on metformin pharmacokinetics using metformin bioequivalence studies, the SNPs OCT2 c.808G>T and OCTN1 c.917C>T were significant (P<0.001 and P<0.05, respectively). Higher Cmax and increased AUC values were observed for these variants .
More recently, an association between the SNP c.808G>T in OCT2 and the gene-gene interactions between this SNP and the promoter SNP g.-66T>C (rs2252281) in MATE1 was reported, which results in counteracting the effects of the c.808G>T and g.-66T>C SNPs on the renal elimination of metformin. In their analysis of this complex interaction, the investigators suggest that the c.808G>T SNP could have a dominant genotype to phenotype correlation .
In contrast, the effects of a potentially relevant SNP in Asian populations c.602C > T was found to have no relevant effect on the pharmacokinetics of lamivudine in healthy Korean subjects .
Current FDA and EMA guidances recommend evaluation of OCT2 liabilities for drugs with high renal elimination, or which are likely to be co-administered with OCT2 substrates such as metformin. Although there is no guidance for MATEs, simultaneous evaluation of their interactions is also advisable.
|Location||Endogenous substrates||In vitro substrates used experimentally||Substrate drugs||Inhibitors|
|epithelial cells in renal proximal tubules, neurons||creatinine, bile acids, choline,
acetylcholine and monoamine neuro-transmitters: dopamine, norepinephrine, epinephrine, serotonin, histamine.
putrescine, cyclo-(His-Pro), salsolinol, agmatine
oxaliplatin, varenicline, cisplastin, debrisoquine, proplanolol, guanidine,
picoplatin, ifosfamide, cimetidine, famotidine, zalcitabine, lamivudine, berberine,
(aflatoxin B1, paraquat, ethidium bromide)
rifampicin, naringin, ritonavir
1. Jonker, J.W. and A.H. Schinkel, Pharmacological and physiological functions of the polyspecific organic cation transporters: OCT1, 2, and 3 (SLC22A1-3). J Pharmacol Exp Ther, 2004. 308(1): p. 2-9.
2. Koepsell, H., Polyspecific organic cation transporters: their functions and interactions with drugs. Trends Pharmacol Sci, 2004. 25(7): p. 375-81.
3. Koepsell, H. and H. Endou, The SLC22 drug transporter family. Pflugers Arch, 2004. 447(5): p. 666-76.
4. Busch, A.E., et al., Human neurons express the polyspecific cation transporter hOCT2, which translocates monoamine neurotransmitters, amantadine, and memantine. Mol Pharmacol, 1998. 54(2): p. 342-52.
5. Zwart, R., et al., Impaired activity of the extraneuronal monoamine transporter system known as uptake-2 in Orct3/Slc22a3-deficient mice. Mol Cell Biol, 2001. 21(13): p. 4188-96.
6. Jonker, J.W., et al., Deficiency in the organic cation transporters 1 and 2 (Oct1/Oct2 [Slc22a1/Slc22a2]) in mice abolishes renal secretion of organic cations. Mol Cell Biol, 2003. 23(21): p. 7902-8.
7. Zolk, O., et al., Functional characterization of the human organic cation transporter 2 variant p.270Ala>Ser. Drug Metab Dispos, 2009. 37(6): p. 1312-8.
8. Wagner, D.J., T. Hu, and J. Wang, Polyspecific organic cation transporters and their impact on drug intracellular levels and pharmacodynamics. Pharmacol Res, 2016. 111: p. 237-46.
9. Deeley, R.G., C. Westlake, and S.P. Cole, Transmembrane transport of endo- and xenobiotics by mammalian ATP-binding cassette multidrug resistance proteins. Physiol Rev, 2006. 86(3): p. 849-99.
10. Urakami, Y., et al., Creatinine transport by basolateral organic cation transporter hOCT2 in the human kidney. Pharm Res, 2004. 21(6): p. 976-81.
11. Dresser, M.J., et al., Interactions of n-tetraalkylammonium compounds and biguanides with a human renal organic cation transporter (hOCT2). Pharm Res, 2002. 19(8): p. 1244-7.
12. Ciarimboli, G., et al., Organic cation transporter 2 mediates cisplatin-induced oto- and nephrotoxicity and is a target for protective interventions. Am J Pathol, 2010. 176(3): p. 1169-80.
13. Filipski, K.K., et al., Contribution of organic cation transporter 2 (OCT2) to cisplatin-induced nephrotoxicity. Clin Pharmacol Ther, 2009. 86(4): p. 396-402.
14. Lanvers-Kaminsky, C., et al., Human OCT2 variant c.808G>T confers protection effect against cisplatin-induced ototoxicity. Pharmacogenomics, 2015. 16(4): p. 323-32.
15. 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.
16. Grun, B., et al., Trimethoprim-Metformin Interaction and its Genetic Modulation by OCT2 and MATE1. Br J Clin Pharmacol, 2013.
17. Feng, N., et al., Local inhibition of organic cation transporters increases extracellular serotonin in the medial hypothalamus. Brain Res, 2005. 1063(1): p. 69-76.
18. Christensen, M.M., et al., A gene-gene interaction between polymorphisms in the OCT2 and MATE1 genes influences the renal clearance of metformin. Pharmacogenet Genomics, 2013.
19. Choi, C.I., et al., Effects of OCT2 c.602C > T genetic variant on the pharmacokinetics of lamivudine. Xenobiotica, 2013. 43(7): p. 636-40.