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Aliases: HBLRR, LST-2, LST-3TM13, LST3, OATP-8, OATP8, SLC21A8
Gene name: Solute carrier organic anion transporter family member 1B3 (SLCO1B3)
OATP1B3 is an uptake transporter exclusively expressed in the liver on the sinusoidal (basolateral) side of centrilobular hepatocytes. In conjunction with OATP1B1, it is responsible for the hepatic uptake of some important drug classes, notably statins, for the uptake of bile acids (in conjunction with OATP1B1 and NTCP) and bilirubin, as well as some other endogenous molecules. It is a mediator of drug interactions, but as it shares many substrates and inhibitors with another major hepatic uptake transporter, OATP1B1, its role may not be fully appreciated. The FDA and EMA recommend in vitro testing of OATP1B3 interactions for drug candidates that are eliminated in part via the liver and/or will be co-administered with OATP1B3 substrates.
OATP1B3 is predominantly expressed on the sinusoidal (basolateral) membrane of centrilobular hepatocytes (i.e. those located around the central vein). It is generally considered to be exclusive to the liver; however, low mRNA expression was also reported in the prostate, testes, colon, and some other tissues, as well as many types of tumors .
Function, physiology, and clinically significant polymorphisms
OATP1B3 is an integral membrane protein predicted to contain 12 membrane-spanning domains. It is generally regarded as a unidirectional, facilitated-diffusion uptake transporter, although there is evidence for bi-directional transport. In common with many other OATPs, the driving forces facilitating its transport activity are still incompletely elucidated.
OATP1B3 is important in the hepatic clearance of drugs and endogenous molecules from the blood and has considerable substrate overlap with OATP1B1. Endogenous substrates include bilirubin, coproporphyrins I and III, bile acids, conjugated steroids, eicosanoids, and thyroid hormones [2, 3]. Important drug substrates and inhibitors include some of the HMG-CoA inhibitors (i.e. statins), gemfibrozil, rifampin/rifamycin, cyclosporine, and HIV protease inhibitors, amongst others. The gastrointestinal peptide cholecystokinin was reported to be exclusively transported by OATP1B3 [4, 5], although this view is recently being challenged. Other reportedly specific OATP1B3 substrates (within the OATP family) include docetaxel, digoxin, glibenclamide, glipizide , and the mushroom toxin amanitin . Despite these reports, for the purposes of evaluating DDI risks, OATP1B3 is usually grouped with OATP1B1, because of the high degree of overlap in their substrate and inhibitor profiles, and because of their common tissue distribution in the liver.
In common with other OATP members, the SLCO1B3 gene is polymorphic, and some sequence variations (334T>G, 699G>A, c.1564G>T, 699G>A, -5035G>A) are associated with reduced in vitro transporter activity or expression [8, 9]. From the few reports of clinically relevant OATP1B3 polymorphisms it appears that the SNPs 334T>G and 699G>A increased mycophenolic acid and tacrolimus exposure in renal transplant recipients [10, 11], and the 699G>A variation was shown to significantly decrease the transport capacity for glibenclamide and glipizide .
PXR, AhR, CAR, FXR, HNF1α and HNF3β transcriptionally regulate OATP1B3, resulting variously in decreased or increased mRNA and/or protein expression [13-16]. The clinical impact of this regulation has yet to be demonstrated.
Although not cited as often as OATP1B1, OATP1B3 is an important transporter for the hepatic uptake of xenobiotics, particularly of members of the widely prescribed statin class. Where clinical DDIs have been noted, these are often ascribed more generally to OATPs or to both OATP1B1 and 1B3 (e.g. rosuvastatin). Given the cross-specificity of the two OATP1Bs, consideration of both as potential mediators of DDI is advisable . Substrate drugs for OATP1B3 include telmisartan and imatinib, while endogenous substrates include bilirubin, bile acids, conjugated hormones such as estrone sulfate, and metabolic side products of heme synthesis such as coproporphyrins I (CPI) and III (CPIII) . The use of endogenous biomarkers such as coproporphyrins is a new approach for predicting clinically relevant transporter-mediated drug-drug interactions (DDIs) [17, 18]. These molecules are stable in the systemic circulation and are not metabolized further in the liver, therefore they are excreted into bile and urine in their intact forms, and changes in their renal elimination accurately reflect hepatic transporter function . CPI and CPIII were shown to be selective and sensitive clinical biomarkers to quantify OATP1B-mediated DDIs . A physiologically-based pharmacokinetic (PBPK) model of CPI supported the accurate prediction of the blood concentration-time profiles of four statins affected by rifampicin .
A role for OATP1B3 in liver toxicity may be relevant. OATP1B3, 1B1, and NTCP transport bile acids, and OATP1B3 and 1B1 transport bilirubin; thus, these transporters may play a role in cholestasis and hyperbilirubinemia, respectively. In addition, the potent hepatotoxins phalloidin and microcystin-LR are transported by OATP1B1 and 1B3, possibly contributing to their hepatotoxicity.
Of the reported in vitro functional polymorphisms of OATP1B3, clinical evaluations have generally failed to demonstrate significant changes in the PK of OATP1B3 substrates (e.g. docetaxel, telmisartan). In one study, two deletion polymorphisms in the 5’ regulatory region were reported to result in a significantly higher concentration-to-dose ratios of digoxin in hemodialysis patients . Hence, the possibility of altered drug efficacy and/or toxicity due to SNPs cannot be excluded.
OATP1B3 is gaining importance in oncology research, as it is over-expressed in a multitude of carcinoma types including tumors of the liver, colon, pancreas, lung, prostate, breast, and testes [23, 24]. For instance, tumoral mRNA expression of OATP1B3 was ~100-fold higher in colon cells from adenocarcinoma patients than in normal colon samples, leading to significantly reduced levels of apoptosis in cancer cells . In prostate tumor cells, de novo expression of OATP1B3 is responsible for increased androgen uptake resulting in resistance to androgen deprivation therapy . In some cancer cells, a specific OATP1B3 protein is produced from an alternative mRNA transcript . This cancer-specific OATP1B3 variant (csOATP1B3) shows a cytoplasmatic localization , and its biological role is as yet unknown, as it does not show any contribution to the uptake of OATP1B3 substrates into cancer cells . However, it represents a promising target for therapeutic intervention e.g. via the cancer-specific expression of the suicide gene herpes simplex virus 1 thymidine kinase (HSV-tk) by a spliceosome mediated RNA trans-splicing (SMaRT) approach .
OATP1B3, like OATP1B1, is relevant to the hepatic uptake and disposition of drugs, and drug interactions. The FDA and EMA guidances recommend evaluation of the drug interaction liability of both transporters for all drug candidates as an inhibitor, and as a substrate for drugs that are eliminated predominantly or in part by the liver. Initial in vitro assessments to predict DDI potential aid the development of an OATP1B transporter-based clinical drug interaction strategy.
|Location||Endogenous substrates||In vitro substrates used experimentally||Substrate drugs||Inhibitors|
|liver: hepatocyte, basolateral membrane||
bile acids, bilirubin, cholecystokinin
bromosulphophthalein, coproporphyrin I, coproporphyrin III,
cholecystokinin 8, estradiol-17β-glucuronide,atorvastatin, rosuvastatin, pravastatin, pitavastatin
|statins, fexofenadine, valsartan, telmisartan, enalapril, erythromycin, mycophenolic acid, tacrolimus, (phalloidin, microcystin-LR),
ritonavir,letermovir, myrcludex B,
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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. Gui, C. and B. Hagenbuch, Amino acid residues in transmembrane domain 10 of organic anion transporting polypeptide 1B3 are critical for cholecystokinin octapeptide transport. Biochemistry, 2008. 47(35): p. 9090-7.
6. Chen, Y., et al., Interaction of Sulfonylureas with Liver Uptake Transporters OATP1B1 and OATP1B3. Basic Clin Pharmacol Toxicol, 2018. 123(2): p. 147-154.
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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. Boivin, A.A., et al., Influence of SLCO1B3 genetic variations on tacrolimus pharmacokinetics in renal transplant recipients. Drug Metab Pharmacokinet, 2013. 28(3): p. 274-7.
12. Yang, F., et al., OATP1B3 (699G>A) and CYP2C9*2, *3 significantly influenced the transport and metabolism of glibenclamide and glipizide. Sci Rep, 2018. 8(1): p. 18063.
13. 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.
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15. 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.
16. 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.
17. Shen, H., et al., Coproporphyrins I and III as Functional Markers of OATP1B Activity: In Vitro and In Vivo Evaluation in Preclinical Species. J Pharmacol Exp Ther, 2016. 357(2): p. 382-93.
18. Rodrigues, A.D., et al., Endogenous Probes for Drug Transporters: Balancing Vision With Reality. Clin Pharmacol Ther, 2018. 103(3): p. 434-448.
19. Lai, Y., et al., Coproporphyrins in Plasma and Urine Can Be Appropriate Clinical Biomarkers to Recapitulate Drug-Drug Interactions Mediated by Organic Anion Transporting Polypeptide Inhibition. J Pharmacol Exp Ther, 2016. 358(3): p. 397-404.
20. Kunze, A., et al., Clinical Investigation of Coproporphyrins as Sensitive Biomarkers to Predict Mild to Strong OATP1B-Mediated Drug-Drug Interactions. Clin Pharmacokinet, 2018. 57(12): p. 1559-1570.
21. Yoshikado, T., et al., PBPK Modeling of Coproporphyrin I as an Endogenous Biomarker for Drug Interactions Involving Inhibition of Hepatic OATP1B1 and OATP1B3. CPT Pharmacometrics Syst Pharmacol, 2018. 7(11): p. 739-747.
22. 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.
23. Thakkar, N., A.C. Lockhart, and W. Lee, Role of Organic Anion-Transporting Polypeptides (OATPs) in Cancer Therapy. AAPS J, 2015. 17(3): p. 535-45.
24. Liu, T. and Q. Li, Organic anion-transporting polypeptides: a novel approach for cancer therapy. J Drug Target, 2014. 22(1): p. 14-22.
25. Sissung, T.M., et al., Differential Expression of OATP1B3 Mediates Unconjugated Testosterone Influx. Mol Cancer Res, 2017. 15(8): p. 1096-1105.
26. Nagai, M., et al., Identification of a new organic anion transporting polypeptide 1B3 mRNA isoform primarily expressed in human cancerous tissues and cells. Biochem Biophys Res Commun, 2012. 418(4): p. 818-23.
27. Chun, S.E., et al., The N-terminal region of organic anion transporting polypeptide 1B3 (OATP1B3) plays an essential role in regulating its plasma membrane trafficking. Biochem Pharmacol, 2017. 131: p. 98-105.
28. Sun, Y., et al., Cancer-type organic anion transporting polypeptide 1B3 is a target for cancer suicide gene therapy using RNA trans-splicing technology. Cancer Lett, 2018. 433: p. 107-116.