Details of the Drug Combination

General Information of Drug Combination (ID: DCHI8O8)

Drug Combination Name

Glimepiride TAK-875

Indication

Disease Entry	Status	REF
Diabetes Mellitus, Type 2	Phase 3	[1]

Component Drugs

Glimepiride DM5FSJA

TAK-875 DMIM5AP

Small molecular drug

2D MOL

3D MOL

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)

Indication(s) of Glimepiride

Disease Entry	ICD 11	Status	REF
Diabetic complication	5A2Y	Approved	[2]

Glimepiride Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
ATP-binding cassette transporter C9 (ABCC9)	TTEF5MJ	ABCC9_HUMAN	Blocker	[4]
ATP-binding cassette transporter C8 (ABCC8)	TTP835K	ABCC8_HUMAN	Blocker	[4]
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Glimepiride Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Bile salt export pump (ABCB11)	DTJ0EW4	ABCBB_HUMAN	Substrate	[5]
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Glimepiride Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[6]
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Glimepiride Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[7]
Aldo-keto reductase family 1 member C3 (AKR1C3)	OTU2SXBA	AK1C3_HUMAN	Decreases Activity	[8]
Aldo-keto reductase family 1 member C1 (AKR1C1)	OTQKR4CM	AK1C1_HUMAN	Decreases Activity	[8]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[9]
Insulin (INS)	OTZ85PDU	INS_HUMAN	Decreases Expression	[10]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[11]
Calpain-1 catalytic subunit (CAPN1)	OTK6OQZR	CAN1_HUMAN	Increases Expression	[11]
Calpain-2 catalytic subunit (CAPN2)	OTIAPE5J	CAN2_HUMAN	Increases Expression	[11]
HLA class I histocompatibility antigen, alpha chain G (HLA-G)	OTMLK1KN	HLAG_HUMAN	Affects Expression	[12]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Expression	[11]
Calpain-10 (CAPN10)	OTS9LJW4	CAN10_HUMAN	Increases Expression	[11]
ATP-binding cassette sub-family C member 8 (ABCC8)	OTCWQ54I	ABCC8_HUMAN	Increases ADR	[13]
ATP-binding cassette sub-family C member 9 (ABCC9)	OTGAXLQN	ABCC9_HUMAN	Increases ADR	[13]
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⏷ Show the Full List of 13 DOT(s)

Indication(s) of TAK-875

Disease Entry	ICD 11	Status	REF
Type-2 diabetes	5A11	Phase 3	[3]

TAK-875 Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Free fatty acid receptor 1 (GPR40)	TTB8FUC	FFAR1_HUMAN	Modulator	[14]
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TAK-875 Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[15]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[15]
UDP-glucuronosyltransferase 1A3 (UGT1A3)	DEF2WXN	UD13_HUMAN	Metabolism	[15]
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TAK-875 Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-binding cassette sub-family C member 3 (ABCC3)	OTC3IJV4	MRP3_HUMAN	Decreases Activity	[16]
ATP-binding cassette sub-family C member 4 (ABCC4)	OTO27PAL	MRP4_HUMAN	Decreases Activity	[16]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[16]
Hepatic sodium/bile acid cotransporter (SLC10A1)	OTUJVMCL	NTCP_HUMAN	Decreases Activity	[17]
ATP-binding cassette sub-family C member 2 (ABCC2)	OTJSIGV5	MRP2_HUMAN	Decreases Activity	[17]
Solute carrier organic anion transporter family member 1B3 (SLCO1B3)	OTOM3BUH	SO1B3_HUMAN	Decreases Activity	[18]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Decreases Activity	[18]
Solute carrier organic anion transporter family member 1B1 (SLCO1B1)	OTNEN8QK	SO1B1_HUMAN	Decreases Activity	[18]
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⏷ Show the Full List of 8 DOT(s)

References

1	ClinicalTrials.gov (NCT01829477) Comparison of TAK-875 to Placebo as an Add-on to Glimepiride in Patients With Type 2 Diabetes
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. (Ligand id: 6820).
3	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. (Ligand id: 6484).
4	Mechanism of disopyramide-induced hypoglycaemia in a patient with Type 2 diabetes. Diabet Med. 2009 Jan;26(1):76-8.
5	Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013 Dec;136(2):328-43.
6	Effect of CYP2C9 genetic polymorphisms on the efficacy and pharmacokinetics of glimepiride in subjects with type 2 diabetes. Diabetes Res Clin Pract. 2006 May;72(2):148-54.
7	Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. Toxicol Sci. 2010 Dec; 118(2):485-500.
8	Initro inhibition of AKR1Cs by sulphonylureas and the structural basis. Chem Biol Interact. 2015 Oct 5;240:310-5.
9	Screening of a chemical library reveals novel PXR-activating pharmacologic compounds. Toxicol Lett. 2015 Jan 5;232(1):193-202. doi: 10.1016/j.toxlet.2014.10.009. Epub 2014 Oct 16.
10	Effects of prolonged in vitro exposure to sulphonylureas on the function and survival of human islets. J Diabetes Complications. 2005 Jan-Feb;19(1):60-4. doi: 10.1016/j.jdiacomp.2004.05.001.
11	A potential role of calpains in sulfonylureas (SUs) -mediated death of human pancreatic cancer cells (1.2B4). Toxicol In Vitro. 2021 Jun;73:105128. doi: 10.1016/j.tiv.2021.105128. Epub 2021 Feb 27.
12	Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
13	ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
14	Efficacy and safety of fasiglifam (TAK-875), a G protein-coupled receptor 40 agonist, in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise: a randomized, double-blind, placebo-controlled, phase III trial. Diabetes Obes Metab. 2015 Jul;17(7):675-81.
15	Disposition and metabolism of the G protein-coupled receptor 40 agonist TAK-875 (fasiglifam) in rats, dogs, and humans. Xenobiotica. 2019 Apr;49(4):433-445.
16	Fasiglifam (TAK-875): Mechanistic Investigation and Retrospective Identification of Hazards for Drug Induced Liver Injury. Toxicol Sci. 2018 Jun 1;163(2):374-384. doi: 10.1093/toxsci/kfx040.
17	Fasiglifam (TAK-875) Alters Bile Acid Homeostasis in Rats and Dogs: A Potential Cause of Drug Induced Liver Injury. Toxicol Sci. 2017 May 1;157(1):50-61. doi: 10.1093/toxsci/kfx018.
18	Mechanistic investigations of the liver toxicity of the free fatty acid receptor 1 agonist fasiglifam (TAK875) and its primary metabolites. J Biochem Mol Toxicol. 2019 Aug;33(8):e22345. doi: 10.1002/jbt.22345. Epub 2019 May 8.