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OATP1B3

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OATP1B3 Transporter (Organic Anion Transporting Polypeptide 1B3 /SLCO1B3)

SLCO1B3, more commonly referred to as OATP1B3 (Organic Anion Transporter Protein 1B3), is an uptake transporter that plays an important role in drug disposition and is responsible for the hepatic uptake of drugs and endogenous compounds. Drugs that are substrates of OATP1B3 have the potential to be victims of co-administered therapeutics that are inhibitors of this transporter.  The FDA and EMA require in vitro testing for OATP1B3 liability for drug candidates that are eliminated at least in part via the liver.

Localization

The highest expression of OATP1B3 is in the sinusoidal membranes of hepatocytes located around the central vein.  OATP1B3 transporter expression is also reported in prostate, colon and pancreatic tumors [1].

Function, physiology and clinically significant polymorphisms

OATP1B3 transporter is important in hepatic drug elimination and has considerable substrate overlap with OATP1B1.  Endogenous substrates include bilirubin, bile acids, conjugated steroids, eicosanoids and thyroid hormones [2, 3].  The gastrointestinal peptide cholecystokinin, is reported to be exclusively transported by OATP1B3 [4].  Other specific OATP1B3 substrates (amongst the OAT transporters)  include docetaxel, digoxin, paclitaxel and the toxin amanitin [5].  CCK-8 is a specific inhibitor of OATP1B3 [6] and cyclosporine and CI-1034 are inhibitors of the three major OATP isoforms [7].

The SLCO1B3 gene is polymorphic and some of the sequence variations ( 334T>G and 699G>A ) are associated with reduced in vitro transporter activity.  The c.1564G>T (G522C) variant demonstrates decreased in vitro transport of substrates such as estradiol 17-Glucuronide, cholyl taurine and CCK-8 [8].  Thirty-six genetic variations in OATP1B3 were identified and -5035G>A reported to have lowered gene expression, suggesting reduction in OATP1B3 expression. In vitro cell line based assays showed 699G>A to have reduced uptake activity for testosterone, but not for estradiol 17β-d-glucuronide or methotrexate, indicating that the functional impact of the variations is substrate specific [9].
There are relatively few reports on clinically relevant drug-related adverse events attributed to OATP1B3 polymorphisms. SNP T334G, G699A increases mycophenolic acid exposure in renal transplant patients [10].

PXR, FXR, HNF1α, HNF3β and HNF4α transcriptionally regulate OATP1B3 [11-14].

Clinical significance:

Substrate drugs for OATP1B3 include telmisartan, exanes and imatinib and endogenous substrates include bile acids and conjugated hormones such as estrone sulfate.  Any inhibition of clearance of these drugs would affect the PK.  While polymorphisms have been reported and evaluated clinically, a majority of these studies do not show significant changes in drug PK of OATP1B3 substrates.  In one study, two deletion polymorphisms in the 5’-regulatory region were reported to result in a significantly higher concentration-to-dose ratio of digoxin in hemodialysis patients [15].
OATP1B3 is gaining importance in oncology research, as it is over-expressed in adenocarcinomas. In a study comparing 17 colon tumors samples with 20 normal colon samples, tumoral overexpression of OATP1B3 was ~100-fold that in cancer samples [1].  HCT116 (p53+/+) cells overexpressing OATP1B3 had significantly lower apoptotic levels compared with empty vector control and this may be associated with its transport activity, suggesting that OATP1B3 overexpression in colorectal cancer cells may provide a survival advantage [1].

Regulatory Requirements

OATP1B3 has relevance to hepatic drug uptake, drug disposition and interactions and both the FDA and EMA require that the drug interaction liability of this transporter be evaluated in vitro for all drug candidates that are eliminated via the liver.  Based on the in vitro transporter data, decisions are made for OATP1B3 transporter – based clinical drug interaction trials. 

Localization
Endogenous substrates
Substrates used experimentally
Substrate drugs
Inhibitors
Liver, hepatocyte basolateral membrane
bile acids, steroid hormones
Bromosulphophthalein, cholecystokinin 8, estradiol-17β-glucuronide
statins, fexofenadine, valsartan, telmisartan, enalapril, erythromycin, phaloidin, valsartan
Rifampicin, ritonavir, cyclosporin

References

  1. Lee, W., et al., Overexpression of OATP1B3 confers apoptotic resistance in colon cancer. Cancer Res, 2008. 68(24): p. 10315-23.
  2. Konig, J., et al., A novel human organic anion transporting polypeptide localized to the basolateral hepatocyte membrane. Am J Physiol Gastrointest Liver Physiol, 2000. 278(1): p. G156-64.
  3. Kullak-Ublick, G., et al., Hepatic transport of bile salts. Seminars in Liver Disease, 2000. 20: p. 273-292.
  4. Ismair, M.G., et al., Hepatic uptake of cholecystokinin octapeptide by organic anion-transporting polypeptides OATP4 and OATP8 of rat and human liver. Gastroenterology, 2001. 121(5): p. 1185-90.
  5. Letschert, K., et al., Molecular characterization and inhibition of amanitin uptake into human hepatocytes. Toxicol Sci, 2006. 91(1): p. 140-9.
  6. 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.
  7. Sahi, J., et al., Metabolism and transporter-mediated drug-drug interactions of the endothelin-A receptor antagonist CI-1034. Chem Biol Interact, 2006. 159(2): p. 156-68.
  8. Letschert, K., D. Keppler, and J. Konig, Mutations in the SLCO1B3 gene affecting the substrate specificity of the hepatocellular uptake transporter OATP1B3 (OATP8). Pharmacogenetics, 2004. 14(7): p. 441-52.
  9. Chae, Y.J., et al., Functional consequences of genetic variations in the human organic anion transporting polypeptide 1B3 (OATP1B3) in the Korean population. J Pharm Sci, 2012. 101(3): p. 1302-13.
  10. Miura, M., et al., Influence of SLCO1B1, 1B3, 2B1 and ABCC2 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients. Eur J Clin Pharmacol, 2007. 63(12): p. 1161-9.
  11. Jung, D., et al., Characterization of the human OATP-C (SLC21A6) gene promoter and regulation of liver-specific OATP genes by hepatocyte nuclear factor 1 alpha. J Biol Chem, 2001. 276(40): p. 37206-14.
  12. Jung, D. and G.A. Kullak-Ublick, Hepatocyte nuclear factor 1 alpha: a key mediator of the effect of bile acids on gene expression. Hepatology, 2003. 37(3): p. 622-31.
  13. Kamiyama, Y., et al., Role of human hepatocyte nuclear factor 4alpha in the expression of drug-metabolizing enzymes and transporters in human hepatocytes assessed by use of small interfering RNA. Drug Metab Pharmacokinet, 2007. 22(4): p. 287-98.
  14. Ohtsuka, H., et al., Farnesoid X receptor, hepatocyte nuclear factors 1alpha and 3beta are essential for transcriptional activation of the liver-specific organic anion transporter-2 gene. J Gastroenterol, 2006. 41(4): p. 369-77.
  15. Tsujimoto, M., et al., Influence of SLCO1B3 gene polymorphism on the pharmacokinetics of digoxin in terminal renal failure. Drug Metab Pharmacokinet, 2008. 23(6): p. 406-11.
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