OCT2 Transporter (Organic Cation Transporter 2 / SLC22A2)
SLC22A2, more commonly referred to as OCT2 (Organic Cation Transporter 2), is a renal uptake transporter that plays a key role in disposition and renal clearance of drugs and endogenous compounds. OCT2 substrate drugs have the potential for drug drug interactions with co-administered therapeutics that are inhibitors of this transporter. The FDA and EMA require in vitro testing for OCT2 liability with drug candidates that are eliminated at least in part via the kidneys.
OCT2 is most strongly expressed in the kidney and is also expressed in the small intestine, lung, skin, placenta, brain and choroid plexus [1, 2]. In the human kidney OCT2 is expressed in all three segments of proximal tubules and in small intestine, OCT2 is localized to the basolateral membrane of epithelial cells and to the luminal membrane of epithelial cells in trachea and bronchi [1, 3, 4]. In the brain, OCT2 is expressed on the apical (ventricular) membrane in epithelial cells of the choroid plexus.
Function, physiology and clinically significant polymorphisms
In the basolateral membrane of the distal tubule in the kidney, OCT2 transporter mediates uptake from the blood to the proximal tubular cells during the renal secretion of organic cations. OCT2 transports many organic cations and play an important role on the pharmacological, pharmacokinetic and toxicological properties of therapeutics. OCT2 transports monoamine neurotransmitters , thereby participating in the regulation of interstitial and intracellular concentrations of monoamine neurotransmitters and cationic drugs.
Since the OCT transporters have overlapping substrates, it is difficult to quantitate the contribution of individual isoforms without knocking out individual isoforms. Oct2 single knockout and Oct1/2 double knockout mice showed that while removal of Oct2 did not have a significant effect on TEA elimination, renal secretion of TEA was completely eliminated and higher plasma levels were observed in the double knock-outs . Oct3-deficient mice showed significant reduction in MPP+ accumulation into the heart as compared with wild-type mice .
A single splice variant of OCT2 was identified in kidney, termed OCT2-A, a truncated form of OCT2, appears to have lower Km (or greater affinity) for substrates than OCT2 .
A majority of clinical studies to assess OCT2 transporter activity are conducted using cimetidine as the probe substrate. Drug interactions with procainamide/cimetidine result in a 42% decrease in procainamide renal clearance (CLR) and with metformin/cimetidine, result in a 28% decrease in metformin CLR 28 % ↓); nephrotoxicity and ototoxicity of cisplatin is decreased after inhibition of OCT2 [3, 4, 9, 10]. 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 ABC efflux transporters such as P-gp and BCRP . For example, creatinine is secreted by OCT2-mediated uptake at the basolateral membrane and efflux by MDR1 at the apical membrane.
Few polymorphisms have been reported for this transporter. Genetic polymorphism of OCT2 was evaluated in the Chinese population and the 808G>T polymorphism was attributed to a reduced metformin renal tubular clearance. Furthermore, this mutation correlated with the extent of cimetidine mediated inhibition of metformin renal tubular secretion .
OCT2 transporter contributes to renal drug uptake, clearance and transporter – mediated drug interactions. The FDA and EMA require that the drug interaction liability of OCT2 be evaluated in vitro for drug candidates that are eliminated via the kidneys. If there is no OCT2 liability, there is no requirement for clinical renal transporter based drug interaction studies. Cimetidine is the preferred substrate for clinical studies.
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- Koepsell, H. and H. Endou, The SLC22 drug transporter family. Pflugers Arch, 2004. 447(5): p. 666-76.
- Motohashi, H., et al., Different transport properties between famotidine and cimetidine by human renal organic ion transporters (SLC22A). Eur J Pharmacol, 2004. 503(1-3): p. 25-30.
- 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.
- Koepsell, H., Polyspecific organic cation transporters: their functions and interactions with drugs. Trends Pharmacol Sci, 2004. 25(7): p. 375-81.
- 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.
- 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.
- 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.
- 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.
- Urakami, Y., et al., Creatinine transport by basolateral organic cation transporter hOCT2 in the human kidney. Pharm Res, 2004. 21(6): p. 976-81.
- 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.
- 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.
- 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.
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