Details of the Drug Combination

General Information of Drug Combination (ID: DCBU4FI)

• Drug Combination Name: Colesevelam + Chenodiol
• Indication: Severe Obesity; Status: Phase 4 [1]
• Component Drugs:
  Colesevelam (DMMUFKM): Small molecular drug
  Chenodiol (DMQ8JIK): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Colesevelam

Disease Entry	ICD 11	Status	REF
Hypercholesterolaemia	5C80.0	Approved	[2]

Indication(s) of Chenodiol

Disease Entry	ICD 11	Status	REF
Cholelithiasis	DC11	Approved	[2]

Chenodiol Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Farnesoid X-activated receptor (FXR)	TTS4UGC	NR1H4_HUMAN	Modulator	[11]

Chenodiol Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[12]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[5]
Cytochrome P450 8B1 (CYP8B1)	DETL4WB	CP8B1_HUMAN	Metabolism	[13]

Chenodiol Interacts with 39 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase (CYP8B1)	OTRI4UR1	CP8B1_HUMAN	Decreases Expression	[14]
Aldo-keto reductase family 1 member C2 (AKR1C2)	OTQ2XMO3	AK1C2_HUMAN	Decreases Activity	[15]
Gastrotropin (FABP6)	OTIRQWLW	FABP6_HUMAN	Increases Expression	[4]
ATP-binding cassette sub-family C member 3 (ABCC3)	OTC3IJV4	MRP3_HUMAN	Increases Expression	[16]
ATP-binding cassette sub-family C member 4 (ABCC4)	OTO27PAL	MRP4_HUMAN	Decreases Expression	[17]
Solute carrier family 22 member 1 (SLC22A1)	OT7817I4	S22A1_HUMAN	Decreases Expression	[3]
Fatty acid-binding protein, brain (FABP7)	OTRE2H4G	FABP7_HUMAN	Decreases Expression	[3]
Aflatoxin B1 aldehyde reductase member 3 (AKR7A3)	OTW3GO4Y	ARK73_HUMAN	Decreases Expression	[3]
Apolipoprotein M (APOM)	OTI3FQQC	APOM_HUMAN	Decreases Expression	[3]
Aldo-keto reductase family 1 member C4 (AKR1C4)	OTW2MMOF	AK1C4_HUMAN	Decreases Expression	[3]
Acetyl-CoA acetyltransferase, mitochondrial (ACAT1)	OTJC60Q7	THIL_HUMAN	Decreases Expression	[3]
Short/branched chain specific acyl-CoA dehydrogenase, mitochondrial (ACADSB)	OTDO6HBG	ACDSB_HUMAN	Decreases Expression	[3]
Hydroxymethylglutaryl-CoA synthase, mitochondrial (HMGCS2)	OTC3RUN9	HMCS2_HUMAN	Decreases Expression	[3]
Apolipoprotein C-IV (APOC4)	OTE8ZUXY	APOC4_HUMAN	Decreases Expression	[3]
Peroxisomal biogenesis factor 3 (PEX3)	OTGZ7ME2	PEX3_HUMAN	Decreases Expression	[3]
Aldo-keto reductase family 1 member C1 (AKR1C1)	OTQKR4CM	AK1C1_HUMAN	Decreases Expression	[3]
Bile acid-CoA:amino acid N-acyltransferase (BAAT)	OTTMB3JY	BAAT_HUMAN	Decreases Expression	[3]
Nuclear receptor subfamily 1 group I member 3 (NR1I3)	OTS3SGH7	NR1I3_HUMAN	Decreases Expression	[3]
Acyl-CoA dehydrogenase family member 11 (ACAD11)	OT3T9HAX	ACD11_HUMAN	Decreases Expression	[3]
ATP-binding cassette sub-family G member 8 (ABCG8)	OTIJ76XW	ABCG8_HUMAN	Increases Expression	[3]
Solute carrier family 22 member 7 (SLC22A7)	OTKTNH1W	S22A7_HUMAN	Decreases Expression	[3]
Solute carrier organic anion transporter family member 1B1 (SLCO1B1)	OTNEN8QK	SO1B1_HUMAN	Decreases Expression	[3]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[18]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Increases Expression	[19]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[20]
C-C motif chemokine 5 (CCL5)	OTSCA5CK	CCL5_HUMAN	Increases Expression	[21]
Nuclear receptor subfamily 1 group D member 1 (NR1D1)	OTJ38PTB	NR1D1_HUMAN	Affects Expression	[22]
Phosphatidylcholine translocator ABCB4 (ABCB4)	OTE6PY83	MDR3_HUMAN	Increases Expression	[23]
Coronin-1A (CORO1A)	OTVAZOHC	COR1A_HUMAN	Decreases Expression	[24]
Cyclin-dependent kinase inhibitor 1B (CDKN1B)	OTNY5LLZ	CDN1B_HUMAN	Affects Localization	[25]
Hydroxymethylglutaryl-CoA synthase, cytoplasmic (HMGCS1)	OTCO26FV	HMCS1_HUMAN	Affects Expression	[22]
Hematopoietically-expressed homeobox protein HHEX (HHEX)	OTLIUVYX	HHEX_HUMAN	Increases Expression	[26]
Nuclear receptor subfamily 1 group D member 2 (NR1D2)	OT9CVF41	NR1D2_HUMAN	Affects Expression	[22]
Nuclear receptor subfamily 0 group B member 2 (NR0B2)	OT7UVICX	NR0B2_HUMAN	Increases Expression	[10]
Organic solute transporter subunit alpha (SLC51A)	OTDJRZ0P	OSTA_HUMAN	Increases Expression	[27]
Organic solute transporter subunit beta (SLC51B)	OT4WYPSR	OSTB_HUMAN	Increases Expression	[27]
Homeobox protein CDX-2 (CDX2)	OTCG4TSY	CDX2_HUMAN	Increases Expression	[25]
ATP-binding cassette sub-family G member 5 (ABCG5)	OT1OMY93	ABCG5_HUMAN	Increases Expression	[14]
Solute carrier organic anion transporter family member 1B3 (SLCO1B3)	OTOM3BUH	SO1B3_HUMAN	Increases Expression	[14]

References

• [1] ClinicalTrials.gov (NCT02952963) Effect of Bile Acids and Bile Acid Sequstrants on GLP-1 Secretion After Roux-en-Y Gastric Bypass
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] Chenodeoxycholic acid significantly impacts the expression of miRNAs and genes involved in lipid, bile acid and drug metabolism in human hepatocytes. Life Sci. 2016 Jul 1;156:47-56.
• [4] Lithocholic acid decreases expression of UGT2B7 in Caco-2 cells: a potential role for a negative farnesoid X receptor response element. Drug Metab Dispos. 2005 Jul;33(7):937-46.
• [5] Human UDP-glucuronosyltransferase (UGT)1A3 enzyme conjugates chenodeoxycholic acid in the liver. Hepatology. 2006 Nov;44(5):1158-70.
• [6] Regulation of the human bile acid UDP-glucuronosyltransferase 1A3 by the farnesoid X receptor and bile acids. J Hepatol. 2010 Apr;52(4):570-8.
• [7] Activation of nuclear factor (erythroid-2 like) factor 2 by toxic bile acids provokes adaptive defense responses to enhance cell survival at the emergence of oxidative stress. Mol Pharmacol. 2007 Nov;72(5):1380-90. doi: 10.1124/mol.107.039370. Epub 2007 Aug 27.
• [8] Regulation of VDR expression in rat and human intestine and liver--consequences for CYP3A expression. Toxicol In Vitro. 2010 Apr;24(3):822-9. doi: 10.1016/j.tiv.2009.12.011. Epub 2009 Dec 13.
• [9] Bile acids induce adhesion molecule expression in endothelial cells through activation of reactive oxygen species, NF-kappaB, and p38. Am J Physiol Heart Circ Physiol. 2006 Aug;291(2):H741-7. doi: 10.1152/ajpheart.01182.2005. Epub 2006 Mar 31.
• [10] VPAC1 expression is regulated by FXR agonists in the human gallbladder epithelium. Hepatology. 2005 Sep;42(3):549-57. doi: 10.1002/hep.20806.
• [11] Lithocholic acid decreases expression of bile salt export pump through farnesoid X receptor antagonist activity. J Biol Chem. 2002 Aug 30;277(35):31441-7.
• [12] Identification of human hepatic cytochrome p450 enzymes involved in the biotransformation of cholic and chenodeoxycholic acid. Drug Metab Dispos. 2008 Oct;36(10):1983-91.
• [13] Conversion of chenodeoxycholic acid to cholic acid by human CYP8B1. Biol Chem. 2019 Apr 24;400(5):625-628.
• [14] Potency of individual bile acids to regulate bile acid synthesis and transport genes in primary human hepatocyte cultures. Toxicol Sci. 2014 Oct;141(2):538-46. doi: 10.1093/toxsci/kfu151. Epub 2014 Jul 23.
• [15] Relationship of human liver dihydrodiol dehydrogenases to hepatic bile-acid-binding protein and an oxidoreductase of human colon cells. Biochem J. 1996 Jan 15;313 ( Pt 2)(Pt 2):373-6.
• [16] The role of lithocholic acid in the regulation of bile acid detoxication, synthesis, and transport proteins in rat and human intestine and liver slices. Toxicol In Vitro. 2011 Feb;25(1):80-90.
• [17] Discovery that theonellasterol a marine sponge sterol is a highly selective FXR antagonist that protects against liver injury in cholestasis. PLoS One. 2012;7(1):e30443.
• [18] Acetylated deoxycholic (DCA) and cholic (CA) acids are potent ligands of pregnane X (PXR) receptor. Toxicol Lett. 2017 Jan 4;265:86-96.
• [19] Retinoid X receptor (RXR) agonist-induced antagonism of farnesoid X receptor (FXR) activity due to absence of coactivator recruitment and decreased DNA binding. J Biol Chem. 2003 Mar 21;278(12):10028-32. doi: 10.1074/jbc.M208312200. Epub 2003 Jan 7.
• [20] Role of mitochondrial dysfunction in combined bile acid-induced cytotoxicity: the switch between apoptosis and necrosis. Toxicol Sci. 2004 May;79(1):196-204. doi: 10.1093/toxsci/kfh078. Epub 2004 Feb 19.
• [21] Fibrates suppress chenodeoxycholic acid-induced RANTES expression through inhibition of NF-kappaB activation. Eur J Pharmacol. 2002 Jul 12;448(1):19-26. doi: 10.1016/s0014-2999(02)01902-7.
• [22] System analysis of cross-talk between nuclear receptors reveals an opposite regulation of the cell cycle by LXR and FXR in human HepaRG liver cells. PLoS One. 2019 Aug 22;14(8):e0220894. doi: 10.1371/journal.pone.0220894. eCollection 2019.
• [23] Farnesoid X receptor activates transcription of the phospholipid pump MDR3. J Biol Chem. 2003 Dec 19;278(51):51085-90. doi: 10.1074/jbc.M308321200. Epub 2003 Oct 2.
• [24] Downregulation of TACO gene transcription restricts mycobacterial entry/survival within human macrophages. FEMS Microbiol Lett. 2005 Sep 1;250(1):137-44. doi: 10.1016/j.femsle.2005.06.056.
• [25] Inflammatory mediators of esophagitis alter p27 Kip1 expression in esophageal epithelial cells. J Pediatr Gastroenterol Nutr. 2010 Nov;51(5):556-62. doi: 10.1097/MPG.0b013e3181ecd65d.
• [26] Hematopoietically expressed homeobox is a target gene of farnesoid X receptor in chenodeoxycholic acid-induced liver hypertrophy. Hepatology. 2009 Mar;49(3):979-88. doi: 10.1002/hep.22712.
• [27] Upregulation of a basolateral FXR-dependent bile acid efflux transporter OSTalpha-OSTbeta in cholestasis in humans and rodents. Am J Physiol Gastrointest Liver Physiol. 2006 Jun;290(6):G1124-30. doi: 10.1152/ajpgi.00539.2005. Epub 2006 Jan 19.