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OAT1

OAT1 Transporter (Organic Anion Transporter 1/SLC22A6)

SLC22A6, more commonly referred to as OAT1 (Organic Anion Transporter 1), is a renal uptake transporter that plays a key role in drug disposition and renal clearance of drugs and endogenous compounds. Drugs that are substrates of OAT1 have the potential to be victims of co-administered therapeutics that are inhibitors of this transporter.  This is especially true for drugs with a narrow therapeutic index, such as methotrexate, where higher concentrations in the plasma due to reduced renal elimination can result in severe toxicities. The FDA and EMA require in vitro testing for OAT1 transporter liability with drug candidates that are eliminated at least in part via the kidneys.

Localization

OAT1 transporter belongs to the SLC22 family of uptake transporters and is primarily expressed in the basolateral membrane of proximal tubule cells in the kidneys, with highest levels in the middle segment [1, 2]. OAT1 is also present in the choroid plexus in brain, skeletal muscle and placenta [1, 3]. 

Function, physiology and clinically significant polymorphisms

OAT1 is a multispecific exchanger that plays a critical role in maintaining homeostasis of endogenous substances and detoxification of exogenous compounds by renal elimination of therapeutic agents, in collaboration with OAT2, OAT3 and MATE. An α-ketoglutarate gradient provides the driving force for the uptake of organic anions via OAT1 [27] and facilitates the renal excretion of many anionic drugs and endogenous anions.  Substrates include antibiotics, antivirals, H2 blockers, diuretics, nonsteroidal anti-inflammatory drugs, statins and toxins e.g. ochratoxin, and uricosurics and drugs such as methotrexate.  Some neutral compounds (e.g., cimetidine) are also transported by OAT1 at a lower affinity [6-8].  Inhibitors of OAT1 include probenecid (which is also a substrate), rifampicin and novobiocin.

While SNPs have been identified in the SLC22A6 gene, these have not been related to clinically significant drug drug interactions (DDI) or changes in the amino acids transcribed [9]. For example, rs10792367, an intergenic polymorphism between OAT1 and OAT3, is involved in antihypertensive responses to hydrochlorothiazide but not in transport activity [10]. 

OAT1 transporter expression is regulated by LXR (down regulation) [11], hepatocyte nuclear factor 1 α/β and DNA methylation [12].  OAT1 transporter expression may be modulated by disease states e.g. increased Oat1 expression is found in rats with bilateral ureteral obstruction [4]  and chronic renal failure induced by nephrectomy can decrease OAT1 expression [5].

Clinical significance

Decrease in renal secretion and clearance may produce an increase in systemic drug exposure, thereby resulting in clinically significant changes in the overall drug PK.  Clinically relevant changes in clearance of therapeutics can occur when OAT1 transporter activity is inhibited.  Renal tubular secretion is inhibited by the co-administration of probenecid (an OAT substrate and inhibitor), which increases the circulating levels of OAT substrates such as penicillin, cephalosporin, pravastatin, fexofenadine and some antiviral drugs from 10% to 260%, by inhibition of OAT1 and OAT3 [1, 13-15]. 

Probenecid can be used to reduce nephrotoxicity of therapeutics by inhibiting transport of potentially nephrotoxic drugs into the renal proximal tubular cells.  Both cidofovir or cephaloridine are toxic in the proximal tubular cells and co-administration with probenecid results in reduced nephrotoxicity [16].

Modulation of transporter expression under disease conditions can potentially modify the renal excretion of substrate drugs.

Regulatory Requirements

OAT1 has relevance to renal drug clearance, drug disposition and interactions.  Based on this data, decisions are made for OAT1 transporter – based clinical drug interaction trials, typically with probenecid.  The FDA and EMA require that the drug drug interaction liability of this transporter be evaluated in vitro for drug candidates that are renally eliminated. 

Localization
Endogenous substrates
Substrates used experimentally
Substrate drugs
Inhibitors
Kidney, proximal tubule, basolateral membrane, Placenta
cyclic nucleotides, prostaglandin E2 and F2α, uric acids, folate
Para-aminohippurate (PAH)
adefovir, zidovudine, ciprofloxacin, cephaloridin, methotrexate, pravastatin
probenecid, novobiocin


References

  1. Hosoyamada, M., et al., Molecular cloning and functional expression of a multispecific organic anion transporter from human kidney. Am J Physiol, 1999. 276(1 Pt 2): p. F122-8.
  2. Motohashi, H., et al., Gene expression levels and immunolocalization of organic ion transporters in the human kidney. J Am Soc Nephrol, 2002. 13(4): p. 866-74.
  3. Choudhuri, S., et al., Constitutive expression of various xenobiotic and endobiotic transporter mRNAs in the choroid plexus of rats. Drug Metab Dispos, 2003. 31(11): p. 1337-45.
  4. Villar, S.R., et al., Renal elimination of organic anions in rats with bilateral ureteral obstruction. Biochim Biophys Acta, 2004. 1688(3): p. 204-9.
  5. Torres, A.M., Renal elimination of organic anions in cholestasis. World J Gastroenterol, 2008. 14(43): p. 6616-21.
  6. Koepsell, H. and H. Endou, The SLC22 drug transporter family. Pflugers Arch, 2004. 447(5): p. 666-76.
  7. Rizwan, A.N. and G. Burckhardt, Organic anion transporters of the SLC22 family: biopharmaceutical, physiological, and pathological roles. Pharm Res, 2007. 24(3): p. 450-70.
  8. Burckhardt, B.C. and G. Burckhardt, Transport of organic anions across the basolateral membrane of proximal tubule cells. Rev Physiol Biochem Pharmacol, 2003. 146: p. 95-158.
  9. Shin, H.J., et al., Identification of genetic polymorphisms of human OAT1 and OAT2 genes and their relationship to hOAT2 expression in human liver. Clin Chim Acta, 2010. 411(1-2): p. 99-105.
  10. Han, Y.F., et al., Association of intergenic polymorphism of organic anion transporter 1 and 3 genes with hypertension and blood pressure response to hydrochlorothiazide. Am J Hypertens, 2011. 24(3): p. 340-6.
  11. Kittayaruksakul, S., et al., Liver x receptors activation downregulates organic anion transporter 1 (OAT1) in renal proximal tubule. Am J Physiol Renal Physiol, 2011.
  12. Jin, L., et al., Regulation of Tissue-specific Expression of Renal Organic Anion Transporters by Hepatocyte Nuclear Factor 1 alpha/beta and DNA Methylation. J Pharmacol Exp Ther, 2011.
  13. Griffith, R.S., et al., Effect of probenecid on the blood levels and urinary excretion of cefamandole. Antimicrob Agents Chemother, 1977. 11(5): p. 809-12.
  14. Mischler, T.W., et al., Influence of probenecid and food on the bioavailability of cephradine in normal male subjects. J Clin Pharmacol, 1974. 14(11-12): p. 604-11.
  15. Takeda, M., et al., Characterization of organic anion transport inhibitors using cells stably expressing human organic anion transporters. Eur J Pharmacol, 2001. 419(2-3): p. 113-20.
  16. Ueo, H., et al., Human organic anion transporter hOAT3 is a potent transporter of cephalosporin antibiotics, in comparison with hOAT1. Biochem Pharmacol, 2005. 70(7): p. 1104-13.

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