Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTUGD21)

• DTT Name: Sodium-independent organic anion transporter (SLCO1A2)
• Synonyms: Solute carrier organic anion transporter family member 1A2; Solute carrier family 21 member 3; SLC21A3; Organic anion-transporting polypeptide 1; OATP1A2; OATP-A; OATP-1; OATP
• Gene Name: SLCO1A2
• DTT Type: Literature-reported target; [1]
• UniProt ID: SO1A2_HUMAN
• TTD ID: T00569
• Sequence:
  MGETEKRIETHRIRCLSKLKMFLLAITCAFVSKTLSGSYMNSMLTQIERQFNIPTSLVGF
  INGSFEIGNLLLIIFVSYFGTKLHRPIMIGIGCVVMGLGCFLKSLPHFLMNQYEYESTVS
  VSGNLSSNSFLCMENGTQILRPTQDPSECTKEVKSLMWVYVLVGNIVRGMGETPILPLGI
  SYIEDFAKFENSPLYIGLVETGAIIGPLIGLLLASFCANVYVDTGFVNTDDLIITPTDTR
  WVGAWWFGFLICAGVNVLTAIPFFFLPNTLPKEGLETNADIIKNENEDKQKEEVKKEKYG
  ITKDFLPFMKSLSCNPIYMLFILVSVIQFNAFVNMISFMPKYLEQQYGISSSDAIFLMGI
  YNLPPICIGYIIGGLIMKKFKITVKQAAHIGCWLSLLEYLLYFLSFLMTCENSSVVGINT
  SYEGIPQDLYVENDIFADCNVDCNCPSKIWDPVCGNNGLSYLSACLAGCETSIGTGINMV
  FQNCSCIQTSGNSSAVLGLCDKGPDCSLMLQYFLILSAMSSFIYSLAAIPGYMVLLRCMK
  SEEKSLGVGLHTFCTRVFAGIPAPIYFGALMDSTCLHWGTLKCGESGACRIYDSTTFRYI
  YLGLPAALRGSSFVPALIILILLRKCHLPGENASSGTELIETKVKGKENECKDIYQKSTV
  LKDDELKTKL
• Function: Mediates the Na(+)-independent transport of organic anions such as sulfobromophthalein (BSP) and conjugated (taurocholate) and unconjugated (cholate) bile acids (By similarity). Selectively inhibited by the grapefruit juice component naringin.
• Reactome Pathway:
  Transport of organic anions (R-HSA-879518)
  Recycling of bile acids and salts (R-HSA-159418)

Molecular Interaction Atlas (MIA) of This DTT

2 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Naringin	DM4DG1Y	Discovery agent	N.A.	Investigative	[1]
[3H]estrone-3-sulphate	DMGPF0N	Discovery agent	N.A.	Investigative	[2]

The Drug Transporter (DTP) Role of This DTT

• DTT DTP Name: Organic anion transporting polypeptide 1A2 (SLCO1A2) DTP Info
• Gene Name: SLCO1A2

40 Approved Drug(s) Transported by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Acebutolol	DM0TI4U	Hypertension	BA00-BA04	Approved	[3]
Acocantherin	DM7JT24	Atrial fibrillation	BC81.3	Approved	[4]
Atenolol	DMNKG1Z	Hypertension	BA00-BA04	Approved	[3]
Atorvastatin	DMF28YC	Cardiovascular disease	BA00-BE2Z	Approved	[5]
Celiprolol HCL	DMD5LBX	Hypertension	BA00-BA04	Approved	[6]
Chlorambucil	DMRKE63	Chronic lymphocytic leukaemia	2A82.0	Approved	[7]
Cholic acid	DM7OKQV	Peroxisomal disorder	5C57	Approved	[8]
Ciprofloxacin XR	DM2NLS9	Bacterial infection	1A00-1C4Z	Approved	[3]
Darunavir	DMN3GCH	Human immunodeficiency virus infection	1C62	Approved	[9]
Dehydroepiandrosterone sulfate	DM4Q80H	Dyspareunia	GA12	Approved	[10]
Dinoprostone	DMTYOPD	Medical abortion	JA00.1Z	Approved	[11]
Enalapril	DMNFUZR	Hypertension	BA00-BA04	Approved	[12]
Enoxacin	DMYTE6L	Urinary tract infection	GC08	Approved	[13]
Estrone sulfate	DMVBIZL	Menopausal and postmenopausal disorder	GA30	Approved	[14]
Fexofenadine	DM17ONX	Allergic rhinitis	CA08.0	Approved	[5]
Gatifloxacin	DMSL679	Respiratory tract infection	CA45	Approved	[13]
Grepafloxacin	DMGLX0T	Chronic bronchitis	CA20.1	Approved	[13]
Hydroxyurea	DMOQVU9	Chronic myelogenous leukaemia	2A20.0	Approved	[15]
Imatinib	DM7RJXL	Acute lymphoblastic leukaemia	2A85	Approved	[16]
Labetalol	DMK8U72	Hypertension	BA00-BA04	Approved	[6]
Levofloxacin	DMS60RB	Bacterial infection	1A00-1C4Z	Approved	[13]
Levothyroxine	DMHN027	Hypothyroidism	5A00	Approved	[17]
Lifitegrast	DM4WVC5	Dry eye disease	9E1Z	Approved	[18]
Liothyronine	DM6IR3P	Hypothyroidism	5A00	Approved	[17]
Lomefloxacin	DMVRH9C	Bacterial infection	1A00-1C4Z	Approved	[13]
Methotrexate	DM2TEOL	leukaemia	2A60-2B33	Approved	[19]
Montelukast	DMD157S	Asthma	CA23	Approved	[20]
Nadolol	DMW6GVL	High blood pressure	BA00	Approved	[6]
Norfloxacin	DMIZ6W2	Bacterial infection	1A00-1C4Z	Approved	[13]
Pitavastatin	DMJH792	Hyperlipidemia	5C80.Z	Approved	[21]
Pitavastatin calcium	DM1UJO0	Dyslipidemia	5C80-5C81	Approved	[21]
Probenecid	DMMFWOJ	Gout	FA25	Approved	[22]
Quinolones	DM5GVHU	Bacterial infection	1A00-1C4Z	Approved	[23]
Rocuronium	DMY9BMK	Muscle spasm	MB47.3	Approved	[24]
Rosuvastatin	DMMIQ7G	Hypercholesterolaemia	5C80.0	Approved	[25]
Saquinavir	DMG814N	Human immunodeficiency virus infection	1C62	Approved	[26]
Sotalol	DML60TN	Sinus rhythm disorder	BC9Y	Approved	[6]
Telmisartan	DMS3GX2	Hypertension	BA00-BA04	Approved	[27]
Trospium chloride	DM32XZT	Discovery agent	N.A.	Approved	[28]
Urea	DMUK75B	Dermatological disease	DA24.Y	Approved	[15]

4 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	[29]
BQ-123	DM0MO8I	Pulmonary arterial hypertension	BB01.0	Phase 2	[30]
Sodium taurocholate	DM3GO0J	Type-2 diabetes	5A11	Phase 1/2	[8]
Taurocholic acid	DM2LZ8F	Type-2 diabetes	5A11	Phase 1/2	[31]

2 Discontinued Drug(s) Transported by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Rhodamine-123	DMQAK6T	Prostate cancer	2C82.0	Discontinued in Phase 1	[32]
Tr-14035	DMWD39E	Multiple sclerosis	8A40	Discontinued in Phase 1	[33]

6 Investigative Drug(s) Transported by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Aminohippuric acid	DMUN54G	Discovery agent	N.A.	Investigative	[34]
Bromsulphthalein	DM9W2ZV	N. A.	N. A.	Investigative	[30]
Glycocholic acid	DM0SXNM	Discovery agent	N.A.	Investigative	[30]
Talinolol	DMRTD16	Discovery agent	N.A.	Investigative	[35]
Tauroursodeoxycholic acid	DMFKRQE	Discovery agent	N.A.	Investigative	[8]
[3H]estradiol-17beta-glucuronide	DM3KJ45	Discovery agent	N.A.	Investigative	[36]

References

• [1] Naringin is a major and selective clinical inhibitor of organic anion-transporting polypeptide 1A2 (OATP1A2) in grapefruit juice. Clin Pharmacol Ther. 2007 Apr;81(4):495-502.
• [2] 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: 1219).
• [3] Fruit juice inhibition of uptake transport: a new type of food-drug interaction. Br J Clin Pharmacol. 2010 Nov;70(5):645-55.
• [4] Molecular cloning and functional characterization of the mouse organic-anion-transporting polypeptide 1 (Oatp1) and mapping of the gene to chromosome X. Biochem J. 2000 Jan 1;345 Pt 1:115-20.
• [5] Influence of the flavonoids apigenin, kaempferol, and quercetin on the function of organic anion transporting polypeptides 1A2 and 2B1. Biochem Pharmacol. 2010 Dec 1;80(11):1746-53.
• [6] Involvement of influx and efflux transport systems in gastrointestinal absorption of celiprolol. J Pharm Sci. 2009 Jul;98(7):2529-39.
• [7] Transporters and renal drug elimination. Annu Rev Pharmacol Toxicol. 2004;44:137-66.
• [8] Molecular and functional characterization of an organic anion transporting polypeptide cloned from human liver. Gastroenterology. 1995 Oct;109(4):1274-82.
• [9] P-glycoprotein mediates efflux transport of darunavir in human intestinal Caco-2 and ABCB1 gene-transfected renal LLC-PK1 cell lines. Biol Pharm Bull. 2009 Sep;32(9):1588-93.
• [10] Membrane transporters in drug development. Nat Rev Drug Discov. 2010 Mar;9(3):215-36.
• [11] Localization of organic anion transporting polypeptide 4 (Oatp4) in rat liver and comparison of its substrate specificity with Oatp1, Oatp2 and Oatp3. Pflugers Arch. 2001 Nov;443(2):188-95.
• [12] Uptake of enalapril and expression of organic anion transporting polypeptide 1 in zonal, isolated rat hepatocytes. Drug Metab Dispos. 2000 Jul;28(7):801-6.
• [13] Identification of influx transporter for the quinolone antibacterial agent levofloxacin. Mol Pharm. 2007 Jan-Feb;4(1):85-94.
• [14] Determination of OATP-, NTCP- and OCT-mediated substrate uptake activities in individual and pooled batches of cryopreserved human hepatocytes. Eur J Pharm Sci. 2011 Jul 17;43(4):297-307.
• [15] Transcellular movement of hydroxyurea is mediated by specific solute carrier transporters. Exp Hematol. 2011 Apr;39(4):446-56.
• [16] Environmental and genetic factors affecting transport of imatinib by OATP1A2. Clin Pharmacol Ther. 2011 Jun;89(6):816-20.
• [17] Identification of thyroid hormone transporters in humans: different molecules are involved in a tissue-specific manner. Endocrinology. 2001 May;142(5):2005-12.
• [18] Clinical Pharmacology and Biopharmaceutics review(s)
• [19] Interaction of methotrexate with organic-anion transporting polypeptide 1A2 and its genetic variants. J Pharmacol Exp Ther. 2006 Aug;318(2):521-9.
• [20] Effect of citrus juice and SLCO2B1 genotype on the pharmacokinetics of montelukast. J Clin Pharmacol. 2011 May;51(5):751-60.
• [21] Transporter-mediated influx and efflux mechanisms of pitavastatin, a new inhibitor of HMG-CoA reductase. J Pharm Pharmacol. 2005 Oct;57(10):1305-11.
• [22] Characterization of the efflux transport of 17beta-estradiol-D-17beta-glucuronide from the brain across the blood-brain barrier. J Pharmacol Exp Ther. 2001 Jul;298(1):316-22.
• [23] The Transporter Classification Database (TCDB): recent advances. Nucleic Acids Res. 2016 Jan 4;44(D1):D372-9. (ID: 2.A.60.1.14)
• [24] Polyspecific organic anion transporting polypeptides mediate hepatic uptake of amphipathic type II organic cations. J Pharmacol Exp Ther. 1999 Oct;291(1):147-52.
• [25] Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics. Gastroenterology. 2006 May;130(6):1793-806.
• [26] Human organic anion-transporting polypeptide OATP-A (SLC21A3) acts in concert with P-glycoprotein and multidrug resistance protein 2 in the vectorial transport of Saquinavir in Hep G2 cells. Mol Pharm. 2004 Jan 12;1(1):49-56.
• [27] 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.
• [28] Expression of drug transporters and drug metabolizing enzymes in the bladder urothelium in man and affinity of the bladder spasmolytic trospium chloride to transporters likely involved in its pharmacokinetics. Mol Pharm. 2015 Jan 5;12(1):171-8.
• [29] Organic anion transporting polypeptide 1B1 activity classified by SLCO1B1 genotype influences atrasentan pharmacokinetics. Clin Pharmacol Ther. 2006 Mar;79(3):186-96.
• [30] 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.
• [31] Identification of multiple binding sites for substrate transport in bovine organic anion transporting polypeptide 1a2. Drug Metab Dispos. 2013 Mar;41(3):602-7.
• [32] Characterization of rhodamine-123 as a tracer dye for use in in vitro drug transport assays. PLoS One. 2012;7(3):e33253.
• [33] Characterization of hepatobiliary transport systems of a novel alpha4beta1/alpha4beta7 dual antagonist, TR-14035. Pharm Res. 2006 Nov;23(11):2646-56.
• [34] Characterization and identification of steroid sulfate transporters of human placenta. Am J Physiol Endocrinol Metab. 2003 Feb;284(2):E390-8.
• [35] Concentration-dependent effect of naringin on intestinal absorption of beta(1)-adrenoceptor antagonist talinolol mediated by p-glycoprotein and organic anion transporting polypeptide (Oatp). Pharm Res. 2009 Mar;26(3):560-7.
• [36] Regulation of renal oatp mRNA expression by testosterone. Am J Physiol. 1996 Feb;270(2 Pt 2):F332-7.