Details of the Drug

General Information of Drug (ID: DM3GO0J)

• Drug Name: Sodium taurocholate
• Synonyms: Sodium taurocholate (rectal gel, diabetes/ obesity)

Indication

Disease Entry	ICD 11	Status	REF
Type-2 diabetes	5A11	Phase 1/2	[1]

• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 1:
  Molecular Weight; 537.7
  Topological Polar Surface Area; Not Available
  Rotatable Bond Count; 7
  Hydrogen Bond Donor Count; 4
  Hydrogen Bond Acceptor Count; 7
• Chemical Identifiers:
  Formula: C26H44NNaO7S
  IUPAC Name: sodium;2-[[(4R)-4-[(3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]ethanesulfonate
  Canonical SMILES: C[C@H](CCC(=O)NCCS(=O)(=O)[O-])[C@H]1CC[C@@H]2[C@@]1([C@H](C[C@H]3[C@H]2[C@@H](C[C@H]4[C@@]3(CC[C@H](C4)O)C)O)O)C.[Na+]
  InChI: InChI=1S/C26H45NO7S.Na/c1-15(4-7-23(31)27-10-11-35(32,33)34)18-5-6-19-24-20(14-22(30)26(18,19)3)25(2)9-8-17(28)12-16(25)13-21(24)29;/h15-22,24,28-30H,4-14H2,1-3H3,(H,27,31)(H,32,33,34);/q;+1/p-1/t15-,16+,17-,18-,19+,20+,21-,22+,24+,25+,26-;/m1./s1
  InChIKey: JAJWGJBVLPIOOH-IZYKLYLVSA-M
• Cross-matching ID:
  PubChem CID: 23666345
  ChEBI ID: CHEBI:36276
  CAS Number: 145-42-6
  TTD ID: D03BZN
  VARIDT ID: DR00053

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
G-protein coupled bile acid receptor 1 (GPBAR1)	TTSDVTR	GPBAR_HUMAN	Modulator	[1]

Drug Transporter (DTP)

DTP Name	DTP ID	UniProt ID	MOA	REF
ATP-binding cassette sub-family A member 8 (ABCA8)	DT9NXMV	ABCA8_HUMAN	Substrate	[2]
Apical sodium-dependent bile acid transporter (SLC10A2)	DT7JELC	NTCP2_HUMAN	Substrate	[3]
Organic solute transporter subunit beta (SLC51B)	DT1V9AJ	OSTB_HUMAN	Substrate	[4]
Bile salt export pump (ABCB11)	DTJ0EW4	ABCBB_HUMAN	Substrate	[5]
Sodium/taurocholate cotransporting polypeptide (SLC10A1)	DT56EKP	NTCP_HUMAN	Substrate	[6]
Multidrug resistance-associated protein 3 (ABCC3)	DTQ3ZHF	MRP3_HUMAN	Substrate	[7]
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[2]
Organic anion transporting polypeptide 2B1 (SLCO2B1)	DTPFTEQ	SO2B1_HUMAN	Substrate	[8]
Organic anion transporting polypeptide 1A2 (SLCO1A2)	DTE2B1D	SO1A2_HUMAN	Substrate	[9]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[10]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[11]

Molecular Expression Atlas of This Drug

• The Studied Disease: Type-2 diabetes
• ICD Disease Classification: 5A11

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
G-protein coupled bile acid receptor 1 (GPBAR1)	DTT	GPBAR1	4.60E-01	0.02	0.09
Multidrug resistance-associated protein 3 (ABCC3)	DTP	MRP3	9.87E-01	-1.86E-01	-4.71E-01
Organic anion transporting polypeptide 2B1 (SLCO2B1)	DTP	OATP2B1	4.61E-01	-7.46E-02	-2.18E-01
Bile salt export pump (ABCB11)	DTP	BSEP	5.33E-01	-8.86E-02	-2.56E-01
Multidrug resistance-associated protein 2 (ABCC2)	DTP	MRP2	7.65E-01	-2.63E-02	-1.32E-01
Organic anion transporting polypeptide 1A2 (SLCO1A2)	DTP	OATP1A2	1.39E-01	-6.13E-01	-6.63E-01
ATP-binding cassette sub-family A member 8 (ABCA8)	DTP	ABCA8	3.75E-01	-2.33E-01	-4.33E-01
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DTP	OATP1B3	5.85E-01	1.81E-01	6.68E-01
Apical sodium-dependent bile acid transporter (SLC10A2)	DTP	ASBT	2.54E-01	-6.48E-02	-1.69E-01
Sodium/taurocholate cotransporting polypeptide (SLC10A1)	DTP	NTCP	2.93E-01	2.87E-02	1.38E-01
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DTP	OATP1B1	2.81E-01	3.67E-02	2.82E-01
Organic solute transporter subunit beta (SLC51B)	DTP	OSTbeta	4.32E-01	1.33E-01	1.00E+00

References

• [1] Bile acids and sphingosine-1-phosphate receptor 2 in hepatic lipid metabolism.Acta Pharmaceutica Sinica B Volume 5, Issue 2, March 2015, Pages 151-157.
• [2] Functional analysis of ABCA8, a new drug transporter. Biochem Biophys Res Commun. 2002 Oct 18;298(1):41-5.
• [3] Identification of a region of the ileal-type sodium/bile acid cotransporter interacting with a competitive bile acid transport inhibitor. Biochemistry. 2002 Dec 17;41(50):14916-24.
• [4] OSTalpha-OSTbeta: a major basolateral bile acid and steroid transporter in human intestinal, renal, and biliary epithelia. Hepatology. 2005 Dec;42(6):1270-9.
• [5] Bile salt export pump (BSEP/ABCB11) can transport a nonbile acid substrate, pravastatin. J Pharmacol Exp Ther. 2005 Aug;314(2):876-82.
• [6] Differential inhibition of rat and human Na+-dependent taurocholate cotransporting polypeptide (NTCP/SLC10A1)by bosentan: a mechanism for species differences in hepatotoxicity. J Pharmacol Exp Ther. 2007 Jun;321(3):1170-8.
• [7] Characterization of the role of polar amino acid residues within predicted transmembrane helix 17 in determining the substrate specificity of multidrug resistance protein 3. Biochemistry. 2003 Aug 26;42(33):9989-10000.
• [8] Functional characterization of pH-sensitive organic anion transporting polypeptide OATP-B in human. J Pharmacol Exp Ther. 2004 Feb;308(2):438-45.
• [9] Molecular and functional characterization of an organic anion transporting polypeptide cloned from human liver. Gastroenterology. 1995 Oct;109(4):1274-82.
• [10] 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.
• [11] LST-2, a human liver-specific organic anion transporter, determines methotrexate sensitivity in gastrointestinal cancers. Gastroenterology. 2001 Jun;120(7):1689-99.
• [12] Involvement of the drug transporters p glycoprotein and multidrug resistance-associated protein Mrp2 in telithromycin transport. Antimicrob Agents Chemother. 2006 Jan;50(1):80-7.
• [13] Dose-dependent disposition of methotrexate in Abcc2 and Abcc3 gene knockout murine models. Drug Metab Dispos. 2011 Nov;39(11):2155-61.
• [14] Mammalian multidrug-resistance proteins (MRPs). Essays Biochem. 2011 Sep 7;50(1):179-207.
• [15] Enhancing chemosensitivity in oral squamous cell carcinoma by lentivirus vector-mediated RNA interference targeting EGFR and MRP2. Oncol Lett. 2016 Sep;12(3):2107-2114.
• [16] Multidrug resistance associated protein 2 mediates transport of prostaglandin E2. Liver Int. 2006 Apr;26(3):362-8.
• [17] Lentivirus-mediated RNAi silencing targeting ABCC2 increasing the sensitivity of a human nasopharyngeal carcinoma cell line against cisplatin. J Transl Med. 2008 Oct 4;6:55.
• [18] Effect of acetaminophen on expression and activity of rat liver multidrug resistance-associated protein 2 and P-glycoprotein. Biochem Pharmacol. 2004 Aug 15;68(4):791-8.
• [19] Small intestinal efflux mediated by MRP2 and BCRP shifts sulfasalazine intestinal permeability from high to low, enabling its colonic targeting. Am J Physiol Gastrointest Liver Physiol. 2009 Aug;297(2):G371-7.
• [20] Delineating the contribution of secretory transporters in the efflux of etoposide using Madin-Darby canine kidney (MDCK) cells overexpressing P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP1), and canalicular multispecific organic anion transporter (cMOAT). Drug Metab Dispos. 2002 Apr;30(4):457-63.
• [21] Multidrug Resistance-Associated Protein 2 (MRP2) Mediated Transport of Oxaliplatin-Derived Platinum in Membrane Vesicles. PLoS One. 2015 Jul 1;10(7):e0130727.
• [22] Preclinical Mouse Models To Study Human OATP1B1- and OATP1B3-Mediated Drug-Drug Interactions in Vivo. Mol Pharm. 2015 Dec 7;12(12):4259-69.
• [23] Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev. 2011 Mar;63(1):157-81.
• [24] Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res. 2013 Mar 15;19(6):1458-66.
• [25] Identification of drugs and drug metabolites as substrates of multidrug resistance protein 2 (MRP2) using triple-transfected MDCK-OATP1B1-UGT1A1-MRP2 cells. Br J Pharmacol. 2012 Mar;165(6):1836-1847.
• [26] The effect of SLCO1B1*15 on the disposition of pravastatin and pitavastatin is substrate dependent: the contribution of transporting activity changes by SLCO1B1*15. Pharmacogenet Genomics. 2008 May;18(5):424-33.
• [27] 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.
• [28] Rifampicin alters atorvastatin plasma concentration on the basis of SLCO1B1 521T>C polymorphism. Clin Chim Acta. 2009 Jul;405(1-2):49-52.
• [29] FDA Drug Development and Drug Interactions
• [30] Multidrug resistance protein (MRP) 1 and MRP3 attenuate cytotoxic and transactivating effects of the cyclopentenone prostaglandin, 15-deoxy-Delta(12,14)prostaglandin J2 in MCF7 breast cancer cells. Biochemistry. 2003 May 13;42(18):5429-37.
• [31] Transport of methotrexate (MTX) and folates by multidrug resistance protein (MRP) 3 and MRP1: effect of polyglutamylation on MTX transport. Cancer Res. 2001 Oct 1;61(19):7225-32.
• [32] ATP-binding cassette C transporters in human pancreatic carcinoma cell lines. Upregulation in 5-fluorouracil-resistant cells. Pancreatology. 2009;9(1-2):136-44.
• [33] Functional reconstitution of human ABCC3 into proteoliposomes reveals a transport mechanism with positive cooperativity. Biochemistry. 2009 May 26;48(20):4423-30.
• [34] Complex pharmacokinetic behavior of ezetimibe depends on abcc2, abcc3, and abcg2. Drug Metab Dispos. 2009 Aug;37(8):1698-702.
• [35] Transport of glyburide by placental ABC transporters: implications in fetal drug exposure. Placenta. 2006 Nov-Dec;27(11-12):1096-102.
• [36] Multidrug resistance-associated proteins 3, 4, and 5. Pflugers Arch. 2007 Feb;453(5):661-73.
• [37] Oral availability of cefadroxil depends on ABCC3 and ABCC4. Drug Metab Dispos. 2012 Mar;40(3):515-21.
• [38] Characterization of drug transport by the human multidrug resistance protein 3 (ABCC3). J Biol Chem. 2001 Dec 7;276(49):46400-7.
• [39] Involvement of multiple efflux transporters in hepatic disposition of fexofenadine. Mol Pharmacol. 2008 May;73(5):1474-83.
• [40] Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013 Dec;136(2):328-43.
• [41] Inhibition of transport across the hepatocyte canalicular membrane by the antibiotic fusidate. Biochem Pharmacol. 2002 Jul 1;64(1):151-8.
• [42] Differential effect of genetic variants of Na(+)-taurocholate co-transporting polypeptide (NTCP) and organic anion-transporting polypeptide 1B1 (OATP1B1) on the uptake of HMG-CoA reductase inhibitors. Xenobiotica. 2011 Jan;41(1):24-34.
• [43] Transporter-mediated influx and efflux mechanisms of pitavastatin, a new inhibitor of HMG-CoA reductase. J Pharm Pharmacol. 2005 Oct;57(10):1305-11.
• [44] Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics. Gastroenterology. 2006 May;130(6):1793-806.
• [45] Identification of thyroid hormone transporters. Biochem Biophys Res Commun. 1999 Jan 19;254(2):497-501.
• [46] Ethnicity-dependent polymorphism in Na+-taurocholate cotransporting polypeptide (SLC10A1) reveals a domain critical for bile acid substrate recognition. J Biol Chem. 2004 Feb 20;279(8):7213-22.
• [47] Modulation by drugs of human hepatic sodium-dependent bile acid transporter (sodium taurocholate cotransporting polypeptide) activity. J Pharmacol Exp Ther. 1999 Dec;291(3):1204-9.
• [48] Expression and transport properties of the human ileal and renal sodium-dependent bile acid transporter. Am J Physiol. 1998 Jan;274(1):G157-69.
• [49] Functional nanoparticles exploit the bile acid pathway to overcome multiple barriers of the intestinal epithelium for oral insulin delivery. Biomaterials. 2018 Jan;151:13-23.
• [50] Interaction of methotrexate with organic-anion transporting polypeptide 1A2 and its genetic variants. J Pharmacol Exp Ther. 2006 Aug;318(2):521-9.
• [51] 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.
• [52] Environmental and genetic factors affecting transport of imatinib by OATP1A2. Clin Pharmacol Ther. 2011 Jun;89(6):816-20.
• [53] 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.
• [54] 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.
• [55] 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.
• [56] Identification of thyroid hormone transporters in humans: different molecules are involved in a tissue-specific manner. Endocrinology. 2001 May;142(5):2005-12.
• [57] Effect of pregnane X receptor ligands on transport mediated by human OATP1B1 and OATP1B3. Eur J Pharmacol. 2008 Apr 14;584(1):57-65.
• [58] 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.
• [59] 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.
• [60] Impact of OATP transporters on pharmacokinetics. Br J Pharmacol. 2009 Oct;158(3):693-705.
• [61] Molecular identification and characterization of novel members of the human organic anion transporter (OATP) family. Biochem Biophys Res Commun. 2000 Jun 24;273(1):251-60.
• [62] The Transporter Classification Database (TCDB): recent advances. Nucleic Acids Res. 2016 Jan 4;44(D1):D372-9. (ID: 2.A.60.1.20)
• [63] Small-Dosing Clinical Study: Pharmacokinetic, Pharmacogenomic (SLCO2B1 and ABCG2), and Interaction (Atorvastatin and Grapefruit Juice) Profiles of 5 Probes for OATP2B1 and BCRP. J Pharm Sci. 2017 Sep;106(9):2688-2694.
• [64] Human platelets express organic anion-transporting peptide 2B1, an uptake transporter for atorvastatin. Drug Metab Dispos. 2009 May;37(5):1129-37.
• [65] pH-sensitive interaction of HMG-CoA reductase inhibitors (statins) with organic anion transporting polypeptide 2B1. Mol Pharm. 2011 Aug 1;8(4):1303-13.
• [66] Drug-drug interaction between pitavastatin and various drugs via OATP1B1. Drug Metab Dispos. 2006 Jul;34(7):1229-36.
• [67] Drug Interactions in Infectious Diseases.
• [68] Involvement of multiple transporters in the hepatobiliary transport of rosuvastatin. Drug Metab Dispos. 2008 Oct;36(10):2014-23.
• [69] Functional complementation between a novel mammalian polygenic transport complex and an evolutionarily ancient organic solute transporter, OSTalpha-OSTbeta. J Biol Chem. 2003 Jul 25;278(30):27473-82.
• [70] Farnesoid X receptor modulators 2014-present: a patent review.Expert Opin Ther Pat. 2018 May;28(5):351-364.
• [71] FXR/TGR5 Dual Agonist Prevents Progression of Nephropathy in Diabetes and Obesity. J Am Soc Nephrol. 2018 Jan;29(1):118-137.
• [72] Clinical pipeline report, company report or official report of Exelixis (2011).
• [73] 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: 37).
• [74] Synthesis and SAR of 2-aryl-3-aminomethylquinolines as agonists of the bile acid receptor TGR5. Bioorg Med Chem Lett. 2010 Oct 1;20(19):5718-21.