Aliases: HBLRR, LST-1, LST1, OATP-C, OATP2, OATPC, SLC21A6
Gene name: Solute carrier organic anion transporter family member 1B1 (SLCO1B1)
OATP1B1 is an uptake transporter exclusively expressed on the sinusoidal side of hepatocytes. It is responsible for the hepatic uptake of drugs and endogenous compounds from the blood. OATP1B1 substrates often, but by no means always, contain a carboxylic acid moiety. Some important therapeutic drugs, most notably HMG-CoA inhibitors also known as statins, are substrates and/or inhibitors of OATP1B1. Inhibition of OATP1B1 can result in supra-proportional systemic exposure of the victim drug. This is particularly important for members of the statin class of medicines, where elevated blood concentrations due to inhibition of hepatic uptake can result in myopathy and rhabdomyolysis. Complex drug interactions involving OATP1B1, other uptake and efflux transporters, and drug-metabolizing enzymes (DMEs) have been described, as have clinically important genetic polymorphisms, resulting in label recommendations, dose adjustments, and product withdrawals. The FDA and EMA recommend in vitro testing of OATP1B1 interactions for drug candidates that are eliminated in part via the liver and/or will be co-administered with OATP1B1 substrates.
OATP1B1 is located to the sinusoidal (basolateral) membrane of hepatocytes, and is expressed uniformly throughout the lobules.
Function, physiology, and clinically significant polymorphisms
Despite its name, OATP1B1 has broad substrate selectivity that includes anionic, zwitterionic, and neutral lipophilic drugs. It also transports endogenous substances including bile acids, bilirubin, coproporphyrins I and III, glucuronide conjugates, and peptides [1, 2].
In common with many drug metabolizing enzymes, OATP1B1 expression is known to be regulated by the nuclear hormone receptors FXR, HNF1α, HNF3β and HNF4α. These also transcriptionally regulate other important OATPs such as OATP1B3 and OATP2B1 [3-6].
Rotor syndrome (OMIM #237450) is the simultaneous and complete deficiency of OATP1B1 and 1B3 which disrupts the hepatic reuptake of conjugated bilirubin and clinically presents as mild hyperbilirubinemia [7, 8]. Downregulation or pharmacologic inhibition of OATP1B transporters can also cause hyperbilirubinemia. Decreased expression of OATP1B1 and 1B3 in cholestatic diseases correlates with jaundice , and chronic treatment with fusidic acid, a widely used bacteriostatic that besides OATP1B1 also inhibits NTCP and BSEP, is often accompanied by cholestasis and conjugated hyperbilirubinemia .
Selective, complete or partial, loss of OATP1B1 function due to polymorphisms in the SLCO1B1 gene is associated with altered PK of substrate drugs. The OATP1B1 polymorphisms 521 T > C and 388A > G are clinically relevant and occur commonly in ethnically diverse populations, albeit with different frequencies across racial and ethnic groups . The frequency of the OATP1B1 c.388G allele (*1b) in Caucasians, Asians, and African-Americans is about 40%, 60%, and 75%, respectively, and the frequency of c.521C in codon 174 is approximately 15%, 15%, and 2%, respectively , resulting in ethnicity-dependent label warnings and dose adjustments. Despite some discrepancies in the reports, c.521T>C generally seems to decrease hepatic uptake activity, while c.388A>G tends to increase it slightly . These two SNPs together form four functionally distinct haplotypes. The OATP1B1*5 and OATP1B1*15 haplotypes correlate with increased systemic exposure to statins, increasing the potential for myopathy, rhabdomyolysis and hepatotoxicity.
OATP1B1 is an important transporter for the hepatic uptake of xenobiotics, particularly the widely prescribed statin class. DDI studies investigating the clearance mechanisms of a range of statins, the meglitinide-class antidiabetic repaglinide, and the endothelin receptor antagonist bosentan, implicate hepatic OATPs, alone or in conjunction with DMEs and other transporters, as sensitive clearance mechanisms [14, 15]. Therapeutically important drugs such as cyclosporine, gemfibrozil, some statins, antibiotics, and antiretroviral drugs are recognized clinical inhibitors of OATP1B1. For example, gemfibrozil caused an eightfold increase in the AUC of repaglinide (also a substrate of CYP2C8 and CYP3A4), and approximately 2-3-fold increase in the AUC of drugs that are not, or only partly, metabolized by CYP2C8, including pravastatin, rosuvastatin, and simvastatin . Co-administration of statins with fusidic acid in patients treated for methicillin-resistant Staphylococcus aureus infection poses the risk of myopathy and rhabdomyolysis due to potent inhibition of OATP1B1 and 1B3 by the antibiotic .
The use of endogenous biomarkers such as coproporphyrins is a new approach for predicting clinically relevant transporter-mediated drug-drug interactions (DDIs) [18, 19]. 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 .
The combined action of drug transporters and metabolic enzymes results in significant and complex drug interactions that are difficult to predict using in vitro systems. Interplay between the OATP1B1 transporter and drug-metabolizing enzymes is implicated in the drug disposition of e.g. fluvastatin (OATP1B1 / CYP2C9 / CYP3A4 / CYP2C8), repaglinide (OATP1B1 / MDR1 / CYP2C8 / CYP3A4), maraviroc (OATP1B1 / MDR1 / CYP3A4) and bosentan (OATP1B1 / OATP1B3 / CYP3A4 / CYP2C9) [23-26]. The CYP3A4 inhibitors clarithromycin and itraconazole increase the AUC of repaglinide by ~ 40% [16, 24], and as much as 8.1-fold when co-administered with gemfibrozil [16, 24]. OATP1B1-mediated hepatic uptake of repaglinide is important for its elimination by CYP-mediated reactions, as evidenced by the elevation of repaglinide plasma levels in subjects with the OATP1B1 521CC genotype. The large drug interaction with gemfibrozil and its glucuronide metabolite is explained by the simultaneous inhibition of both OATP1B1 and CYP2C8. Similarly, the potentially lethal interaction between cerivastatin and gemfibrozil which led to the withdrawal of cerivastatin from the market was attributed to concomitant inhibition of OATP1B1 and CYP2C8 by gemfibrozil glucuronide .
In addition to prescription medications, bioactive components of several widely used medicinal plants also show interaction with OATP1B1, in most cases along with OATP1B3 [28-30]. Deoxyschizandrin and schizandrin B from Radix ophiopogonis are substrates of the transporter, and were reported to promote the OATP1B-mediated uptake of statins in vitro . Although many of these studies indicate that herb-drug interactions (HDIs) may occur in case of co-administration with substrate drugs, the few in vivo experiments failed to demonstrate such significant interactions [32, 33].
OATP1B1 transports bile acids, with a preference for conjugated over non-conjugated forms , and non-functioning OATP1B1 variants have been associated with elevated serum bile acids in vivo, implying a potential involvement of this transporter in hepatotoxicity. OATP1B1 and 1B3 are also responsible for the hepatic uptake of the antimicrotubular chemotherapeutic docetaxel, thereby facilitating its systemic clearance [35, 36].
Genetic polymorphisms of OATP1B1 give rise to clinically relevant changes in drug exposure. There is an approximately 10-fold variation in the AUC of pravastatin between individuals, mainly due to genetic polymorphisms in OATP1B1 transporter , and significantly increased risk of statin-induced myopathy correlates with the c.521C polymorphism . The OATP1B1*15 haplotype is also associated with increased, occasionally life-threatening, toxicity of SN-38, an active metabolite of the anticancer drug irinotecan. A pharyngeal carcinoma patient who had the SLCO1B1*15/*15 genotype combined with poor glucuronyl conjugation capacity due to the UGT1A1*6/*28 haplotype experienced Grade 4 toxicities resulting from accumulation of SN-38 . The SLCO1B1 variants c.388A>G or c.521T>C are associated with lower methotrexate clearance and increased renal toxicity. In adult patients with impaired OATP1B1 function and hematological malignancies, high-dose methotrexate treatment resulted in the accumulation of endogenous OATP1B1 substrates in blood, which were subsequently over-excreted into urine and interfered with the transporters in charge of renal methotrexate elimination [40, 41].
OATP1B1, along with OATP1B3, 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. Since OATP1B1 has clinically relevant gene polymorphisms, clinical trials may require inclusion of subjects with specific OATP1B1 haplotypes.
|Location||Endogenous substrates||In vitro substrates used experimentally||Substrate drugs||Inhibitors|
|liver: hepatocyte basolateral membrane||bile acids, bilirubin, steroid hormones, thyroid hormones, steroid sulfates, glucuronide conjugates and peptides, prostaglandin E2, thyroxine (T4) and triiodothyronine (T3)||bromosulfophthalein, coproporphyrin I, coproporphyrin III, estrone-3-sulfate, estradiol-17β-glucuronide, dehydroepiandrosterone-3-sulfate, statins||sstatins, repaglinide, olmesartan, enalapril, temocaprilat, valsartan, phalloidin, docetaxel,
beraprost sodium, para-aminosalicylic acid
rifampicin, rifamycin SV,
fusidic acid, clarithromycin, erythromycin, roxithromycin, telithromycin cyclosporine, gemfibrozil,
numerous HIV and hepatitis C antivirals
1. Kullak-Ublick, G., et al., Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology, 2001. 120(2): p. 525-33.
2. Hsiang, B., et al., A novel human hepatic organic anion transporting polypeptide (OATP2). Identification of a liver-specific human organic anion transporting polypeptide and identification of rat and human hydroxymethylglutaryl-CoA reductase inhibitor transporters. J Biol Chem, 1999. 274(52): p. 37161-8.
3. 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.
4. 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.
5. 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.
6. 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.
7. Dhumeaux, D. and S. Erlinger, Hereditary conjugated hyperbilirubinaemia: 37 years later. J Hepatol, 2013. 58(2): p. 388-90.
8. van de Steeg, E., et al., Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. J Clin Invest, 2012. 122(2): p. 519-28.
9. Sticova, E., et al., Down-regulation of OATP1B proteins correlates with hyperbilirubinemia in advanced cholestasis. Int J Clin Exp Pathol, 2015. 8(5): p. 5252-62.
10. Lapham, K., et al., Inhibition of Hepatobiliary Transport Activity by the Antibacterial Agent Fusidic Acid: Insights into Factors Contributing to Conjugated Hyperbilirubinemia/Cholestasis. Chem Res Toxicol, 2016.
11. Lee, H.H. and R.H. Ho, Interindividual and interethnic variability in drug disposition: polymorphisms in organic anion transporting polypeptide 1B1 (OATP1B1; SLCO1B1). Br J Clin Pharmacol, 2016.
12. Giacomini, K.M., et al., Membrane transporters in drug development. Nat Rev Drug Discov, 2010. 9(3): p. 215-36.
13. Maeda, K., Organic anion transporting polypeptide (OATP)1B1 and OATP1B3 as important regulators of the pharmacokinetics of substrate drugs. Biol Pharm Bull, 2015. 38(2): p. 155-68.
14. Neuvonen, P.J., M. Niemi, and J.T. Backman, Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther, 2006. 80(6): p. 565-81.
15. Goosen, T.C., et al., Atorvastatin glucuronidation is minimally and nonselectively inhibited by the fibrates gemfibrozil, fenofibrate, and fenofibric acid. Drug Metab Dispos, 2007. 35(8): p. 1315-24.
16. Niemi, M., et al., Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide. Diabetologia, 2003. 46(3): p. 347-51.
17. Eng, H., et al., The Antimicrobial Agent Fusidic Acid Inhibits Organic Anion Transporting Polypeptide-Mediated Hepatic Clearance and May Potentiate Statin-Induced Myopathy. Drug Metab Dispos, 2016. 44(5): p. 692-9.
18. 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.
19. Rodrigues, A.D., et al., Endogenous Probes for Drug Transporters: Balancing Vision With Reality. Clin Pharmacol Ther, 2018. 103(3): p. 434-448.
20. 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.
21. 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.
22. 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.
23. Niemi, M., et al., Polymorphic organic anion transporting polypeptide 1B1 is a major determinant of repaglinide pharmacokinetics. Clin Pharmacol Ther, 2005. 77(6): p. 468-78.
24. Niemi, M., P.J. Neuvonen, and K.T. Kivisto, The cytochrome P4503A4 inhibitor clarithromycin increases the plasma concentrations and effects of repaglinide. Clin Pharmacol Ther, 2001. 70(1): p. 58-65.
25. Treiber, A., et al., Bosentan is a substrate of human OATP1B1 and OATP1B3: inhibition of hepatic uptake as the common mechanism of its interactions with cyclosporin A, rifampicin, and sildenafil. Drug Metab Dispos, 2007. 35(8): p. 1400-7.
26. Kimoto, E., et al., Mechanistic Evaluation of the Complex Drug-Drug Interactions of Maraviroc: Contribution of Cytochrome P450 3A, P-Glycoprotein and Organic Anion Transporting Polypeptide 1B1. Drug Metab Dispos, 2019. 47(5): p. 493-503.
27. Shitara, Y., et al., Gemfibrozil and its glucuronide inhibit the organic anion transporting polypeptide 2 (OATP2/OATP1B1:SLC21A6)-mediated hepatic uptake and CYP2C8-mediated metabolism of cerivastatin: analysis of the mechanism of the clinically relevant drug-drug interaction between cerivastatin and gemfibrozil. J Pharmacol Exp Ther, 2004. 311(1): p. 228-36.
28. Mandery, K., et al., Inhibition of hepatic uptake transporters by flavonoids. Eur J Pharm Sci, 2012. 46(1-2): p. 79-85.
29. Jaerapong, N., et al., Organic aniontransporting polypeptides contribute to the uptake of curcumin and its main metabolites by human breast cancer cells: Impact on antitumor activity. Oncol Rep, 2019. 41(4): p. 2558-2566.
30. Oh, Y., et al., Inhibition of Organic Anion Transporting Polypeptide 1B1 and 1B3 by Betulinic Acid: Effects of Preincubation and Albumin in the Media. J Pharm Sci, 2018. 107(6): p. 1713-1723.
31. Chen, L., et al., Modulation of transporter activity of OATP1B1 and OATP1B3 by the major active components of Radix Ophiopogonis. Xenobiotica, 2019. 49(10): p. 1221-1228.
32. Seong, S.J., et al., A Comprehensive In Vivo and In Vitro Assessment of the Drug Interaction Potential of Red Ginseng. Clin Ther, 2018. 40(8): p. 1322-1337.
33. Li, J., et al., High degree of pharmacokinetic compatibility exists between the five-herb medicine XueBiJing and antibiotics comedicated in sepsis care. Acta Pharm Sin B, 2019. 9(5): p. 1035-1049.
34. Suga, T., et al., Preference of Conjugated Bile Acids over Unconjugated Bile Acids as Substrates for OATP1B1 and OATP1B3. PLoS One, 2017. 12(1): p. e0169719.
35. Iusuf, D., et al., Human OATP1B1, OATP1B3 and OATP1A2 can mediate the in vivo uptake and clearance of docetaxel. Int J Cancer, 2015. 136(1): p. 225-33.
36. Lee, H.H., et al., Contribution of hepatic organic anion-transporting polypeptides to docetaxel uptake and clearance. Mol Cancer Ther, 2015. 14(4): p. 994-1003.
37. Neuvonen, P.J., T. Kantola, and K.T. Kivisto, Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole. Clin Pharmacol Ther, 1998. 63(3): p. 332-41.
38. Link, E., et al., SLCO1B1 variants and statin-induced myopathy--a genomewide study. N Engl J Med, 2008. 359(8): p. 789-99.
39. Takane, H., et al., Life-threatening toxicities in a patient with UGT1A1*6/*28 and SLCO1B1*15/*15 genotypes after irinotecan-based chemotherapy. Cancer Chemother Pharmacol, 2009. 63(6): p. 1165-9.
40. Trevino, L.R., et al., Germline genetic variation in an organic anion transporter polypeptide associated with methotrexate pharmacokinetics and clinical effects. J Clin Oncol, 2009. 27(35): p. 5972-8.
41. Martinez, D., et al., Endogenous Metabolites-Mediated Communication Between OAT1/OAT3 and OATP1B1 May Explain the Association Between SLCO1B1 SNPs and Methotrexate Toxicity. Clin Pharmacol Ther, 2018. 104(4): p. 687-698.