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OAT3

OAT3 Transporter (Organic Anion Transporter 3 / SLC22A8)

SLC22A8, more commonly referred to as OAT3 (Organic Anion Transporter 3), is a renal uptake transporter that plays a key role in drug disposition and renal clearance of drugs and endogenous compounds.  OAT3 substrate drugs have the potential for drug-drug interactions with 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 cause severe toxicities. The FDA and EMA recommend in vitro testing for OAT3 transporter liability with drug candidates that are eliminated at least in part via the kidneys.

Localization

OAT3 transporter belongs to the SLC22 family and is expressed primarily in the basolateral membrane of the proximal tubule in the kidney [1].  OAT3 is also present in the choroid plexus in the brain, liver, kidney, lung and muscles [2].  In the brain, OAT3 is the most abundant of the OAT transporters localized to the basolateral membrane of capillaries, where it appears to play a vital role in the entry of substrates into choroid plexus and in the exclusion of anionic metabolites of neurotransmitters from the brain [1, 3].

Function, physiology and clinically significant polymorphisms

OAT3 transporter has overlapping specificities with OAT1, although kinetic parameters differ. Substrates of OAT3 include cyclic adenosine monophosphate, cortisol, dehydroepiandrosterone sulfate, estrone-3-sulfate, indoxyl sulfate, PAH, ochratoxin A, PGE2, benzylpenicillin, cephaloridine, glutarate, methotrexate, pravastatin, rosuvastatin and the OATP model substrate estradiol-17β-glucuronide. OAT3 is also able to transport, albeit with low affinities, the cationic drugs cimetidine, famotidine and ranitidine, whereas OAT1 appears able to transport only the uncharged form of cimetidine [4, 5]. 

Studies in kidney slices from Oat3-/- mice showed reduced renal taurocholate, estrone-3-sulfate, and PAH concentrations relative to the wild-type, with no differences in the liver, which does not express Oat3 [1].  Penicillin PK was reduced by one-half in Oat3-/-  male mice, and by two-thirds in female Oat3-/- mice [6], indicating gender-related differences that were also observed in methotrexate CL [7].  Gender based differences in OAT3 have not been reported in humans.

There are relatively limited reports on polymorphisms of OAT3 transporter and none demonstrating responsibility for failure of therapeutics, or for renal toxicities.  OAT3 variants were identified from 270 ethnically diverse donor kidneys and just three of these had allele frequencies of >1%.  In vitro assays with three variants (p. Arg149Ser, p. Gln239Stop, and p. Ile260Arg) demonstrated complete loss of function.  Reduced function was observed with some other variants and p. Ile305Phe, found in 3.5% of Asian-Americans, appeared to have altered substrate specificity [8].  In another study with 120 healthy individuals, 1 nonsynonymous variant was observed in the OAT3 gene but this did not result in a change in renal clearance or pharmacokinetics of pravastatin [9]. 

OAT3 expression is transactivated by HNF1α and HNF1β and OAT3 promoter activity is repressed by DNA methylation [10].

Clinical significance

Many of the anti-infective drugs are predominately eliminated by renal OATs e.g. tamiflu and olmesartan [11, 12].  Renal tubular secretion is inhibited by the co-administration of probenecid, which increases the circulating levels of penicillin and cephalosporin antibiotics [13].  Probenecid inhibits active renal transport processes via inhibition of OAT1 and OAT3 [14, 15].  Probenecid alters the exposure of several antibiotics, pravastatin, fexofenadine and some antiviral drugs from 10% to 260% change in AUC. 

Regulatory Requirements

The FDA and EMA require that the drug interaction liability of this transporter be evaluated in vitro for drug candidates that are renally eliminated.  OAT3 contributes to renal drug clearance and transporter – mediated renal drug interactions.  Based on the in vitro substrate and inhibition data, decisions are made for OAT transporter–based clinical drug interaction trials, typically with probenecid.

Localization
Endogenous substrates
Substrates used experimentally
Substrate drugs
Inhibitors
Kidney, proximal tubule, basolateral membrane. Brain, choroid plexus and blood–brain barrier
prostaglandin, uric acids, bile acids; conjugated hormones
E3S, furosemide, bumetanide
NSAIDs, cefaclor, ceftizoxime
probenecid, novobiocin

References

  1. Sweet, D.H., et al., Impaired organic anion transport in kidney and choroid plexus of organic anion transporter 3 (Oat3 (Slc22a8)) knockout mice. J Biol Chem, 2002. 277(30): p. 26934-43.
  2. Buist, S.C., et al., Gender-specific and developmental influences on the expression of rat organic anion transporters. J Pharmacol Exp Ther, 2002. 301(1): p. 145-51.
  3. Breen, C.M., et al., Confocal imaging of organic anion transport in intact rat choroid plexus. Am J Physiol Renal Physiol, 2002. 282(5): p. F877-85.
  4. Koepsell, H. and H. Endou, The SLC22 drug transporter family. Pflugers Arch, 2004. 447(5): p. 666-76.
  5. Tahara, H., et al., A species difference in the transport activities of H2 receptor antagonists by rat and human renal organic anion and cation transporters. J Pharmacol Exp Ther, 2005. 315(1): p. 337-45.
  6. Vanwert, A.L., R.M. Bailey, and D.H. Sweet, Organic anion transporter 3 (Oat3/Slc22a8) knockout mice exhibit altered clearance and distribution of penicillin G. Am J Physiol Renal Physiol, 2007. 293(4): p. F1332-41.
  7. VanWert, A.L. and D.H. Sweet, Impaired clearance of methotrexate in organic anion transporter 3 (Slc22a8) knockout mice: a gender specific impact of reduced folates. Pharm Res, 2008. 25(2): p. 453-62.
  8. Erdman, A.R., et al., The human organic anion transporter 3 (OAT3; SLC22A8): genetic variation and functional genomics. Am J Physiol Renal Physiol, 2006. 290(4): p. F905-12.
  9. Nishizato, Y., et al., Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics. Clin Pharmacol Ther, 2003. 73(6): p. 554-65.
  10. Kikuchi, R., et al., Regulation of the expression of human organic anion transporter 3 by hepatocyte nuclear factor 1alpha/beta and DNA methylation. Mol Pharmacol, 2006. 70(3): p. 887-96.
  11. Hill, G., et al., The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretion-correlation of in vivo and in vitro studies. Drug Metab Dispos, 2002. 30(1): p. 13-9.
  12. Ma, S.F., et al., Hydrolysis of angiotensin II receptor blocker prodrug olmesartan medoxomil by human serum albumin and identification of its catalytic active sites. Drug Metab Dispos, 2005. 33(12): p. 1911-9.
  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. 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.
  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.

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