Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTTQR47)

• DTT Name: Solute carrier family 22 member 8 (SLC22A8)
• Synonyms: hROAT1; hPAHT; hOAT1; Solute carrier family 22 member 6; SLC22A8; SLC22A6; Renal organic anion transporter 1; PAHT; PAH transporter; OAT1
• Gene Name: SLC22A8
• DTT Type: Successful target; [1]
• BioChemical Class: Major facilitator superfamily
• UniProt ID: S22A8_HUMAN
• TTD ID: T70680
• Sequence:
  MTFSEILDRVGSMGHFQFLHVAILGLPILNMANHNLLQIFTAATPVHHCRPPHNASTGPW
  VLPMGPNGKPERCLRFVHPPNASLPNDTQRAMEPCLDGWVYNSTKDSIVTEWDLVCNSNK
  LKEMAQSIFMAGILIGGLVLGDLSDRFGRRPILTCSYLLLAASGSGAAFSPTFPIYMVFR
  FLCGFGISGITLSTVILNVEWVPTRMRAIMSTALGYCYTFGQFILPGLAYAIPQWRWLQL
  TVSIPFFVFFLSSWWTPESIRWLVLSGKSSKALKILRRVAVFNGKKEEGERLSLEELKLN
  LQKEISLAKAKYTASDLFRIPMLRRMTFCLSLAWFATGFAYYSLAMGVEEFGVNLYILQI
  IFGGVDVPAKFITILSLSYLGRHTTQAAALLLAGGAILALTFVPLDLQTVRTVLAVFGKG
  CLSSSFSCLFLYTSELYPTVIRQTGMGVSNLWTRVGSMVSPLVKITGEVQPFIPNIIYGI
  TALLGGSAALFLPETLNQPLPETIEDLENWSLRAKKPKQEPEVEKASQRIPLQPHGPGLG
  SS
• Function: Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one molecule of endogenous dicarboxylic acid (glutarate, ketoglutarate, etc).
• KEGG Pathway: Bile secretion (hsa04976)
• Reactome Pathway: Organic anion transport (R-HSA-561048)

Molecular Interaction Atlas (MIA) of This DTT

2 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
FLUORESCEIN	DMQTFAO	Ocular disease	1F00.1Z	Approved	[2]
Probenecid	DMMFWOJ	Acute gonococcal cervicitis		Approved	[1]

5 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
3R14S-OCHRATOXIN A	DM2KEW6	Discovery agent	N.A.	Investigative	[2]
ADIPATE	DM2XI09	Discovery agent	N.A.	Investigative	[2]
AMINOHIPPURIC ACID	DMUN54G	Discovery agent	N.A.	Investigative	[2]
GLUTARATE	DMPUFDS	Discovery agent	N.A.	Investigative	[2]
HEPTANOATE	DMGEO8N	Discovery agent	N.A.	Investigative	[2]

The Drug Transporter (DTP) Role of This DTT

• DTT DTP Name: Organic anion transporter 3 (SLC22A8) DTP Info
• Gene Name: SLC22A8

38 Approved Drug(s) Transported by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Aciclovir	DMYLOVR	Genital herpes	1A94	Approved	[3]
Adefovir	DMM278X	N. A.	N. A.	Approved	[4]
Allopurinol	DMLPAOB	Gout	FA25	Approved	[5]
Bumetanide	DMRV7H0	Congestive heart failure	BD10	Approved	[6]
Cefaclor	DMJXDGC	Bacterial infection	1A00-1C4Z	Approved	[7]
Cefazolin	DMPDYFR	Bacteremia	1A73	Approved	[8]
Cefdinir	DMJ7A0H	Bacterial infection	1A00-1C4Z	Approved	[7]
Cefotiam	DMF5HU6	Respiratory tract infection	CA45	Approved	[9]
Ceftizoxime	DM3VOGS	Acute gonococcal cervicitis		Approved	[7]
Chlorothiazide	DMLHESP	Chronic heart failure	BD1Z	Approved	[10]
Cidofovir	DMA13GD	Cytomegalovirus infection	1D82	Approved	[11]
Cilostazol	DMZMSCT	Intermittent claudication	BD40.00	Approved	[12]
Cimetidine	DMH61ZB	Acid-reflux disorder	DA22	Approved	[13]
Ciprofloxacin XR	DM2NLS9	Acute gonococcal cervicitis		Approved	[14]
Dinoprostone	DMTYOPD	Medical abortion	JA00.1Z	Approved	[15]
Estrone sulfate	DMVBIZL	Atrophic vaginitis	GA30.2	Approved	[16]
Famotidine	DMRL3AB	Gastric ulcer	DA60	Approved	[17]
Furosemide	DMMQ8ZG	Congestive heart failure	BD10	Approved	[6]
Ganciclovir	DM1MBYQ	Cytomegalovirus infection	1D82	Approved	[4]
L-Tryptophan	DMIBH7M	Depression	6A70-6A7Z	Approved	[18]
MCI-186	DM8ZHP1	Amyotrophic lateral sclerosis	8B60.0	Approved	[19]
Mercaptopurine	DMTM2IK	Acute lymphoblastic leukaemia	2A85	Approved	[20]
Methotrexate	DM2TEOL	Anterior urethra cancer		Approved	[21]
Olmesartan medoxomil	DMWBHRY	High blood pressure	BA00	Approved	[22]
Oseltamivir	DMGO72P	Influenza	1E30-1E32	Approved	[4]
PITAVASTATIN CALCIUM	DM1UJO0	Dyslipidemia	5C80-5C81	Approved	[23]
Prasterone	DM67VKL	Chronic obstructive pulmonary disease	CA22	Approved	[24]
Pravastatin	DM6A0X7	Adult acute monocytic leukemia		Approved	[25]
Ranitidine	DM0GUSX	Gastric ulcer	DA60	Approved	[17]
Rosuvastatin	DMMIQ7G	Arteriosclerosis	BD40	Approved	[26]
Saxagliptin	DMGXENV	Type-2 diabetes	5A11	Approved	[27]
Sitagliptin	DMGDKXN	Cystic fibrosis	CA25	Approved	[13]
Tenofovir	DM1IS6U	Chronic hepatitis B virus infection		Approved	[28]
Tetracycline	DMZA017	Acne vulgaris	ED80	Approved	[29]
Trichlormethiazide	DMHAQCO	Hypertension	BA00-BA04	Approved	[25]
Valaciclovir	DMHKS94	Genital herpes	1A94	Approved	[30]
Valsartan	DMREUQ6	Chronic heart failure	BD1Z	Approved	[25]
Zidovudine	DM4KI7O	Human immunodeficiency virus infection	1C62	Approved	[30]

3 Clinical Trial Drug(s) Transported by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Benzylpenicillin	DMS9503	Actinomycosis		Phase 3	[25]
Dimesna	DMU4T9Y	Diabetic nephropathy	GB61.Z	Phase 3	[31]
PGF2alpha	DM4XAU7	Solid tumour/cancer	2A00-2F9Z	Clinical trial	[15]

1 Discontinued Drug(s) Transported by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Cephaloridine	DM4Y95F	Gram-positive bacterial infection	1B74-1G40	Withdrawn from market	[7]

4 Investigative Drug(s) Transported by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
3R14S-OCHRATOXIN A	DM2KEW6	Discovery agent	N.A.	Investigative	[32]
AMINOHIPPURIC ACID	DMUN54G	Discovery agent	N.A.	Investigative	[24]
Phenolsulfonphthalein	DMCTUAD	N. A.	N. A.	Investigative	[8]
uric acid	DMA1MKT	Discovery agent	N.A.	Investigative	[33]

References

• [1] Transport of organic anions across the basolateral membrane of proximal tubule cells. Rev Physiol Biochem Pharmacol. 2003;146:95-158.
• [2] Structural variation governs substrate specificity for organic anion transporter (OAT) homologs. Potential remote sensing by OAT family members. J Biol Chem. 2007 Aug 17;282(33):23841-53.
• [3] Expression of organic anion transporter 2 in the human kidney and its potential role in the tubular secretion of guanine-containing antiviral drugs. Drug Metab Dispos. 2012 Mar;40(3):617-24.
• [4] FDA Drug Development and Drug Interactions
• [5] Renal transport of organic compounds mediated by mouse organic anion transporter 3 (mOat3): further substrate specificity of mOat3. Drug Metab Dispos. 2004 May;32(5):479-83.
• [6] Interactions of human organic anion transporters with diuretics. J Pharmacol Exp Ther. 2004 Mar;308(3):1021-9.
• [7] Human organic anion transporter hOAT3 is a potent transporter of cephalosporin antibiotics, in comparison with hOAT1. Biochem Pharmacol. 2005 Oct 1;70(7):1104-13.
• [8] Expression levels of renal organic anion transporters (OATs) and their correlation with anionic drug excretion in patients with renal diseases. Pharm Res. 2004 Jan;21(1):61-7.
• [9] Adaptive responses of renal organic anion transporter 3 (OAT3) during cholestasis. Am J Physiol Renal Physiol. 2008 Jul;295(1):F247-52.
• [10] Overlapping in vitro and in vivo specificities of the organic anion transporters OAT1 and OAT3 for loop and thiazide diuretics. Am J Physiol Renal Physiol. 2008 Apr;294(4):F867-73.
• [11] Renal transport of adefovir, cidofovir, and tenofovir by SLC22A family members (hOAT1, hOAT3, and hOCT2). Pharm Res. 2007 Apr;24(4):811-5.
• [12] Aspirin and probenecid inhibit organic anion transporter 3-mediated renal uptake of cilostazol and probenecid induces metabolism of cilostazol in the rat. Drug Metab Dispos. 2014 Jun;42(6):996-1007.
• [13] Transport of the dipeptidyl peptidase-4 inhibitor sitagliptin by human organic anion transporter 3, organic anion transporting polypeptide 4C1, and multidrug resistance P-glycoprotein. J Pharmacol Exp Ther. 2007 May;321(2):673-83.
• [14] Organic anion transporter 3 (oat3/slc22a8) interacts with carboxyfluoroquinolones, and deletion increases systemic exposure to ciprofloxacin. Mol Pharmacol. 2008 Jul;74(1):122-31.
• [15] Human organic anion transporters and human organic cation transporters mediate renal transport of prostaglandins. J Pharmacol Exp Ther. 2002 Apr;301(1):293-8.
• [16] Involvement of tyrosine kinase and PI3K in the regulation of OAT3-mediated estrone sulfate transport in isolated rabbit renal proximal tubules. Am J Physiol Renal Physiol. 2005 Nov;289(5):F1057-64.
• [17] A species difference in the transport activities of H2 receptor antagonists by rat and human renal organic anion and cation transporters. J Pharmacol Exp Ther. 2005 Oct;315(1):337-45.
• [18] Murine renal organic anion transporters mOAT1 and mOAT3 facilitate the transport of neuroactive tryptophan metabolites. Am J Physiol Cell Physiol. 2005 Nov;289(5):C1075-84.
• [19] Human organic anion transporters 1 (hOAT1/SLC22A6) and 3 (hOAT3/SLC22A8) transport edaravone (MCI-186; 3-methyl-1-phenyl-2-pyrazolin-5-one) and its sulfate conjugate. Drug Metab Dispos. 2007 Aug;35(8):1429-34.
• [20] Organic anion transporter 3 is involved in the brain-to-blood efflux transport of thiopurine nucleobase analogs. J Neurochem. 2004 Aug;90(4):931-41.
• [21] Methotrexate-loxoprofen interaction: involvement of human organic anion transporters hOAT1 and hOAT3. Drug Metab Pharmacokinet. 2004 Oct;19(5):369-74.
• [22] 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.
• [23] Transporter-mediated influx and efflux mechanisms of pitavastatin, a new inhibitor of HMG-CoA reductase. J Pharm Pharmacol. 2005 Oct;57(10):1305-11.
• [24] Identification and characterization of human organic anion transporter 3 expressing predominantly in the kidney. Mol Pharmacol. 2001 May;59(5):1277-86.
• [25] Prediction of the overall renal tubular secretion and hepatic clearance of anionic drugs and a renal drug-drug interaction involving organic anion transporter 3 in humans by in vitro uptake experiments. Drug Metab Dispos. 2011 Jun;39(6):1031-8.
• [26] The contribution of organic anion transporters OAT1 and OAT3 to the renal uptake of rosuvastatin. J Pharmacol Exp Ther. 2007 Sep;322(3):1221-7.
• [27] Comparative clinical pharmacokinetics of dipeptidyl peptidase-4 inhibitors. Clin Pharmacokinet. 2012 Aug 1;51(8):501-14.
• [28] Tenofovir alafenamide is not a substrate for renal organic anion transporters (OATs) and does not exhibit OAT-dependent cytotoxicity. Antivir Ther. 2014;19(7):687-92.
• [29] Human organic anion transporters mediate the transport of tetracycline. Jpn J Pharmacol. 2002 Jan;88(1):69-76.
• [30] Human organic anion transporters and human organic cation transporters mediate renal antiviral transport. J Pharmacol Exp Ther. 2002 Mar;300(3):918-24.
• [31] In vitro and in vivo assessment of renal drug transporters in the disposition of mesna and dimesna. J Clin Pharmacol. 2012 Apr;52(4):530-42.
• [32] Characterization of ochratoxin A transport by human organic anion transporters. Life Sci. 2001 Sep 21;69(18):2123-35.
• [33] Involvement of uric acid transporters in alteration of serum uric acid level by angiotensin II receptor blockers. Pharm Res. 2008 Mar;25(3):639-46.