Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTU86P0)

• DTT Name: Liver organic anion transporter 2 (SLCO1B3)
• Synonyms: Solute carrier organic anion transporter family member 1B3; Solute carrier family 21 member 8; SLC21A8; Organic anion-transporting polypeptide 8; Organic anion transporter 8; OATP8; OATP1B3; OATP-8; Liver-specific organic anion transporter 2; LST2; LST-2
• Gene Name: SLCO1B3
• DTT Type: Literature-reported target; [1]
• UniProt ID: SO1B3_HUMAN
• TTD ID: T02565
• Sequence:
  MDQHQHLNKTAESASSEKKKTRRCNGFKMFLAALSFSYIAKALGGIIMKISITQIERRFD
  ISSSLAGLIDGSFEIGNLLVIVFVSYFGSKLHRPKLIGIGCLLMGTGSILTSLPHFFMGY
  YRYSKETHINPSENSTSSLSTCLINQTLSFNGTSPEIVEKDCVKESGSHMWIYVFMGNML
  RGIGETPIVPLGISYIDDFAKEGHSSLYLGSLNAIGMIGPVIGFALGSLFAKMYVDIGYV
  DLSTIRITPKDSRWVGAWWLGFLVSGLFSIISSIPFFFLPKNPNKPQKERKISLSLHVLK
  TNDDRNQTANLTNQGKNVTKNVTGFFQSLKSILTNPLYVIFLLLTLLQVSSFIGSFTYVF
  KYMEQQYGQSASHANFLLGIITIPTVATGMFLGGFIIKKFKLSLVGIAKFSFLTSMISFL
  FQLLYFPLICESKSVAGLTLTYDGNNSVASHVDVPLSYCNSECNCDESQWEPVCGNNGIT
  YLSPCLAGCKSSSGIKKHTVFYNCSCVEVTGLQNRNYSAHLGECPRDNTCTRKFFIYVAI
  QVINSLFSATGGTTFILLTVKIVQPELKALAMGFQSMVIRTLGGILAPIYFGALIDKTCM
  KWSTNSCGAQGACRIYNSVFFGRVYLGLSIALRFPALVLYIVFIFAMKKKFQGKDTKASD
  NERKVMDEANLEFLNNGEHFVPSAGTDSKTCNLDMQDNAAAN
• Function: Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotrexate and sulfobromophthalein (BSP). Involved in the clearance of bile acids and organic anions from the liver.
• KEGG Pathway: Bile secretion (hsa04976)
• Reactome Pathway:
  Heme degradation (R-HSA-189483)
  Defective SLCO1B3 causes hyperbilirubinemia, Rotor type (HBLRR) (R-HSA-5619058)
  Transport of organic anions (R-HSA-879518)
  Atorvastatin ADME (R-HSA-9754706)
  Recycling of bile acids and salts (R-HSA-159418)

Molecular Interaction Atlas (MIA) of This DTT

1 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
[3H]estradiol-17beta-glucuronide	DM3KJ45	Discovery agent	N.A.	Investigative	[1]

The Drug Transporter (DTP) Role of This DTT

• DTT DTP Name: Organic anion transporting polypeptide 1B3 (SLCO1B3) DTP Info
• Gene Name: SLCO1B3

51 Approved Drug(s) Transported by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Acocantherin	DM7JT24	Atrial fibrillation	BC81.3	Approved	[2]
Atorvastatin	DMF28YC	Acute coronary syndrome	BA41	Approved	[3]
Bosentan	DMIOGBU	Pulmonary arterial hypertension	BB01.0	Approved	[4]
Cefmetazole	DM42W1B	Bacterial infection	1A00-1C4Z	Approved	[5]
Cefoperazone	DM53PV8	Bacterial infection	1A00-1C4Z	Approved	[5]
Ceftriaxone	DMCEW64	Acute gonococcal cervicitis		Approved	[5]
Cerivastatin	DMXCM7H	Hyperlipidaemia	5C80	Approved	[3]
Cilostazol	DMZMSCT	Intermittent claudication	BD40.00	Approved	[6]
Crizotinib	DM4F29C	Non-small-cell lung cancer	2C25.Y	Approved	[7]
Dasatinib	DMJV2EK	Blast phase chronic myelogenous leukemia, BCR-ABL1 positive		Approved	[7]
Dehydroepiandrosterone sulfate	DM4Q80H	N. A.	N. A.	Approved	[8]
Diclofenac	DMPIHLS	Chronic renal failure	GB61.Z	Approved	[9]
Digoxin	DMQCTIH	Arrhythmia	BC9Z	Approved	[2]
Docetaxel	DMDI269	Advanced cancer	2A00-2F9Z	Approved	[10]
Enalapril	DMNFUZR	Congestive heart failure	BD10	Approved	[11]
Erythromycin	DM4K7GQ	Acne vulgaris	ED80	Approved	[12]
Estrone sulfate	DMVBIZL	Atrophic vaginitis	GA30.2	Approved	[13]
Etoposide	DMNH3PG	Acute myelogenous leukaemia	2A41	Approved	[13]
Fexofenadine	DM17ONX	Allergic rhinitis	CA08.0	Approved	[14]
FLUORESCEIN	DMQTFAO	Ocular disease	1F00.1Z	Approved	[15]
Fluvastatin	DM4MDJY	Arteriosclerosis	BD40	Approved	[16]
Gadobenate Dimeglumine	DM4VAOG	Schizophrenia	6A20	Approved	[17]
Gefitinib	DM15F0X	Colon adenocarcinoma		Approved	[7]
Glutathione	DMAHMT9	Human immunodeficiency virus infection	1C62	Approved	[18]
Hydroxyurea	DMOQVU9	Chronic myelogenous leukaemia	2A20.0	Approved	[19]
Imatinib	DM7RJXL	Acute lymphoblastic leukaemia	2A85	Approved	[7]
Indocyanine green	DM2NQUY	Gastrointestinal disease	DE2Z	Approved	[20]
Liothyronine	DM6IR3P	Congenital hypothyroidism		Approved	[8]
Mesalazine	DMOL5IU	Diverticulitis		Approved	[21]
Methotrexate	DM2TEOL	Anterior urethra cancer		Approved	[8]
Mycophenolate mofetil	DMPQAGE	Hepatosplenic T-cell lymphoma		Approved	[22]
Nateglinide	DMLK2QH	Diabetic complication	5A2Y	Approved	[3]
Nilotinib	DM7HXWT	Chronic myelogenous leukaemia	2A20.0	Approved	[7]
Olmesartan medoxomil	DMWBHRY	High blood pressure	BA00	Approved	[23]
Paclitaxel	DMLB81S	Breast carcinoma		Approved	[24]
Pitavastatin	DMJH792	Hypercholesterolaemia	5C80.0	Approved	[12]
PITAVASTATIN CALCIUM	DM1UJO0	Dyslipidemia	5C80-5C81	Approved	[25]
Pravastatin	DM6A0X7	Adult acute monocytic leukemia		Approved	[26]
Rifampin	DMA8J1G	Tuberculosis	1B10-1B1Z	Approved	[27]
Romidepsin	DMT5GNL	Cutaneous T-cell lymphoma	2B01	Approved	[28]
Rosuvastatin	DMMIQ7G	Arteriosclerosis	BD40	Approved	[29]
Sorafenib	DMS8IFC	Adenocarcinoma	2D40	Approved	[7]
Sunitinib	DMCBJSR	Acute undifferentiated leukemia		Approved	[7]
Technetium (99MTC) mebrofenin	DMUEWM3	N. A.	N. A.	Approved	[30]
Telmisartan	DMS3GX2	Hypertension	BA00-BA04	Approved	[31]
Testosterone	DM7HUNW	Hot flushes	GA30	Approved	[32]
Valsartan	DMREUQ6	Chronic heart failure	BD1Z	Approved	[33]
Vandetanib	DMRICNP	Solid tumour/cancer	2A00-2F9Z	Approved	[7]
Vemurafenib	DM62UG5	Melanoma	2C30	Approved	[7]
Warfarin	DMJYCVW	Atrial fibrillation	BC81.3	Approved	[4]
Primovist	DM37FKA	N. A.	N. A.	Phase 4	[34]

7 Clinical Trial Drug(s) Transported by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Atrasentan	DMM74PK	Diabetic nephropathy	GB61.Z	Phase 3	[35]
Benzylpenicillin	DMS9503	Actinomycosis		Phase 3	[36]
BQ-123	DM0MO8I	Pulmonary arterial hypertension	BB01.0	Phase 2	[2]
Danoprevir	DM20MDU	Hepatitis C virus infection	1E51.1	Phase 2	[3]
LE-SN38	DMW50NF	Colorectal cancer	2B91.Z	Phase 2	[10]
Sodium taurocholate	DM3GO0J	Type-2 diabetes	5A11	Phase 1/2	[8]
Taurocholic Acid	DM2LZ8F	Type-2 diabetes	5A11	Phase 1/2	[13]

7 Investigative Drug(s) Transported by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
amanitin	DM59IT4	Discovery agent	N.A.	Investigative	[36]
bilirubin	DMI0V4O	Discovery agent	N.A.	Investigative	[37]
bromsulphthalein	DM9W2ZV	N. A.	N. A.	Investigative	[2]
CCK-8	DMN0J4W	N. A.	N. A.	Investigative	[38]
Fluo-3	DMLO9FU	N. A.	N. A.	Investigative	[13]
glycocholic acid	DM0SXNM	Discovery agent	N.A.	Investigative	[2]
[3H]estradiol-17beta-glucuronide	DM3KJ45	Discovery agent	N.A.	Investigative	[39]

References

• [1] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1221).
• [2] Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology. 2001 Feb;120(2):525-33.
• [3] FDA Drug Development and Drug Interactions
• [4] 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 Aug;35(8):1400-7.
• [5] Screening of antibiotics that interact with organic anion-transporting polypeptides 1B1 and 1B3 using fluorescent probes. Biol Pharm Bull. 2011;34(3):389-95.
• [6] Organic Anion-Transporting Polypeptide and Efflux Transporter-Mediated Hepatic Uptake and Biliary Excretion of Cilostazol and Its Metabolites in Rats and Humans. J Pharm Sci. 2017 Sep;106(9):2515-2523.
• [7] Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res. 2013 Mar 15;19(6):1458-66.
• [8] LST-2, a human liver-specific organic anion transporter, determines methotrexate sensitivity in gastrointestinal cancers. Gastroenterology. 2001 Jun;120(7):1689-99.
• [9] Influence of non-steroidal anti-inflammatory drugs on organic anion transporting polypeptide (OATP) 1B1- and OATP1B3-mediated drug transport. Drug Metab Dispos. 2011 Jun;39(6):1047-53.
• [10] Rapid screening of antineoplastic candidates for the human organic anion transporter OATP1B3 substrates using fluorescent probes. Cancer Lett. 2008 Feb 18;260(1-2):163-9.
• [11] Vectorial transport of enalapril by Oatp1a1/Mrp2 and OATP1B1 and OATP1B3/MRP2 in rat and human livers. J Pharmacol Exp Ther. 2006 Jul;318(1):395-402.
• [12] Impact of OATP transporters on pharmacokinetics. Br J Pharmacol. 2009 Oct;158(3):693-705.
• [13] Effect of pregnane X receptor ligands on transport mediated by human OATP1B1 and OATP1B3. Eur J Pharmacol. 2008 Apr 14;584(1):57-65.
• [14] Contribution of OATP (organic anion-transporting polypeptide) family transporters to the hepatic uptake of fexofenadine in humans. Drug Metab Dispos. 2005 Oct;33(10):1477-81.
• [15] Development of a cell-based high-throughput assay to screen for inhibitors of organic anion transporting polypeptides 1B1 and 1B3. Curr Chem Genomics. 2010 Mar 1;4:1-8.
• [16] Substrate-dependent drug-drug interactions between gemfibrozil, fluvastatin and other organic anion-transporting peptide (OATP) substrates on OATP1B1, OATP2B1, and OATP1B3. Drug Metab Dispos. 2007 Aug;35(8):1308-14.
• [17] Liver Perfusion Modifies Gd-DTPA and Gd-BOPTA Hepatocyte Concentrations Through Transfer Clearances Across Sinusoidal Membranes. Eur J Drug Metab Pharmacokinet. 2017 Aug;42(4):657-667.
• [18] Regulation of Organic Anion Transporting Polypeptides (OATP) 1B1- and OATP1B3-Mediated Transport: An Updated Review in the Context of OATP-Mediated Drug-Drug Interactions. Int J Mol Sci. 2018 Mar 14;19(3). pii: E855.
• [19] Transcellular movement of hydroxyurea is mediated by specific solute carrier transporters. Exp Hematol. 2011 Apr;39(4):446-56.
• [20] Primovist, Eovist: what to expect? J Hepatol. 2012 Aug;57(2):421-9.
• [21] Role of organic anion-transporting polypeptides for cellular mesalazine (5-aminosalicylic acid) uptake. Drug Metab Dispos. 2011 Jun;39(6):1097-102.
• [22] Influence of SLCO1B1, 1B3, 2B1 and ABCC2 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients. Eur J Clin Pharmacol. 2007 Dec;63(12):1161-9.
• [23] Multiple human isoforms of drug transporters contribute to the hepatic and renal transport of olmesartan, a selective antagonist of the angiotensin II AT1-receptor. Drug Metab Dispos. 2007 Dec;35(12):2166-76.
• [24] Identification of OATP1B3 as a high-affinity hepatocellular transporter of paclitaxel. Cancer Biol Ther. 2005 Aug;4(8):815-8.
• [25] Contribution of OATP2 (OATP1B1) and OATP8 (OATP1B3) to the hepatic uptake of pitavastatin in humans. J Pharmacol Exp Ther. 2004 Oct;311(1):139-46.
• [26] Relevance of conserved lysine and arginine residues in transmembrane helices for the transport activity of organic anion transporting polypeptide 1B3. Br J Pharmacol. 2010 Feb 1;159(3):698-708.
• [27] Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver. Hepatology. 2002 Jul;36(1):164-72.
• [28] Population pharmacokinetics of romidepsin in patients with cutaneous T-cell lymphoma and relapsed peripheral T-cell lymphoma. Clin Cancer Res. 2009 Feb 15;15(4):1496-503.
• [29] Involvement of multiple transporters in the hepatobiliary transport of rosuvastatin. Drug Metab Dispos. 2008 Oct;36(10):2014-23.
• [30] Transporters involved in the hepatic uptake of (99m)Tc-mebrofenin and indocyanine green. J Hepatol. 2011 Apr;54(4):738-45.
• [31] Predominant contribution of OATP1B3 to the hepatic uptake of telmisartan, an angiotensin II receptor antagonist, in humans. Drug Metab Dispos. 2006 Jul;34(7):1109-15.
• [32] Effect of SLCO1B3 haplotype on testosterone transport and clinical outcome in caucasian patients with androgen-independent prostatic cancer. Clin Cancer Res. 2008 Jun 1;14(11):3312-8.
• [33] Involvement of transporters in the hepatic uptake and biliary excretion of valsartan, a selective antagonist of the angiotensin II AT1-receptor, in humans. Drug Metab Dispos. 2006 Jul;34(7):1247-54.
• [34] Hepatic uptake of the magnetic resonance imaging contrast agent Gd-EOB-DTPA: role of human organic anion transporters. Drug Metab Dispos. 2010 Jul;38(7):1024-8.
• [35] Organic anion transporting polypeptide 1B1 activity classified by SLCO1B1 genotype influences atrasentan pharmacokinetics. Clin Pharmacol Ther. 2006 Mar;79(3):186-96.
• [36] Molecular characterization and inhibition of amanitin uptake into human hepatocytes. Toxicol Sci. 2006 May;91(1):140-9.
• [37] Role of organic anion-transporting polypeptides, OATP-A, OATP-C and OATP-8, in the human placenta-maternal liver tandem excretory pathway for foetal bilirubin. Biochem J. 2003 May 1;371(Pt 3):897-905.
• [38] Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions. J Med Chem. 2012 May 24;55(10):4740-63.
• [39] Interactions of green tea catechins with organic anion-transporting polypeptides. Drug Metab Dispos. 2011 May;39(5):920-6.