Details of the Drug Combination

General Information of Drug Combination (ID: DCDZWCY)

• Drug Combination Name: Metformin + Canagliflozin
• Indication: Type-2 diabetes; Status: Phase 1 [1]
• Component Drugs:
  Metformin (DM89QE1): Small molecular drug
  Canagliflozin (DMFRM1I): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Metformin

Disease Entry	ICD 11	Status	REF
Colorectal carcinoma	N.A.	Approved	[2]
Non-insulin dependent diabetes	5A11	Approved	[2]
Ovarian serous cystadenocarcinoma	N.A.	Approved	[2]
Prostate carcinoma	N.A.	Approved	[2]
Type-2 diabetes	5A11	Approved	[3]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Investigative	[4]

Metformin Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Acetyl-CoA carboxylase 2 (ACACB)	TTY84UG	ACACB_HUMAN	Activator	[9]
Solute carrier family 47 member 1 (SLC47A1)	TTMHCGA	S47A1_HUMAN	Modulator	[10]
HUMAN mannose receptor (MRC1)	TTKV8W5	MRC1_HUMAN	Inhibitor	[4]

Metformin Interacts with 9 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[11]
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[12]
Multidrug and toxin extrusion protein 1 (SLC47A1)	DTZGT0P	S47A1_HUMAN	Substrate	[13]
Organic cation transporter 3 (SLC22A3)	DT6201N	S22A3_HUMAN	Substrate	[14]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[12]
Multidrug and toxin extrusion protein 2 (SLC47A2)	DT3TX4H	S47A2_HUMAN	Substrate	[15]
Thiamine transporter 1 (SLC19A2)	DTLA4Q2	S19A2_HUMAN	Substrate	[16]
Thiamine transporter 2 (SLC19A3)	DT39CEA	S19A3_HUMAN	Substrate	[16]
Equilibrative nucleoside transporter 4 (SLC29A4)	DT3EAQP	S29A4_HUMAN	Substrate	[17]

Indication(s) of Canagliflozin

Disease Entry	ICD 11	Status	REF
Non-insulin dependent diabetes	5A11	Approved	[5]
Type-2 diabetes	5A11	Approved	[6]
Diabetic nephropathy	GB61.Z	Phase 3	[7]
Type-1 diabetes	5A10	Phase 2	[8]

Canagliflozin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Sodium/glucose cotransporter 2 (SGLT2)	TTLWPVF	SC5A2_HUMAN	Modulator	[19]

Canagliflozin Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[20]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[20]

Canagliflozin Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[21]
UDP-glucuronosyltransferase 1A9 (UGT1A9)	DE85D2P	UD19_HUMAN	Metabolism	[22]
UDP-glucuronosyltransferase 2B4 (UGT2B4)	DENUPDX	UD2B4_HUMAN	Metabolism	[22]

Canagliflozin Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Sodium/glucose cotransporter 2 (SLC5A2)	OT93UUDI	SC5A2_HUMAN	Decreases Activity	[23]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Polycystic Ovary Syndrome	DCRY3FB	N. A.	Phase 4	[24]

References

• [1] ClinicalTrials.gov (NCT01508182) A Study of Canagliflozin and Metformin Immediate Release (150 mg/500 mg) FDC Tablets in Healthy Volunteers. U.S. National Institutes of Health.
• [2] Metformin FDA Label
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [4] A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing. March 2020
• [5] Canagliflozin FDA Label
• [6] 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: 4582).
• [7] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [8] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [9] AMP-activated protein kinase-dependent and -independent mechanisms underlying in vitro antiglioma action of compound C. Biochem Pharmacol. 2009 Jun 1;77(11):1684-93.
• [10] Molecular cloning, functional characterization and tissue distribution of rat H+/organic cation antiporter MATE1. Pharm Res. 2006 Aug;23(8):1696-701.
• [11] Role of human placental apical membrane transporters in the efflux of glyburide, rosiglitazone, and metformin. Am J Obstet Gynecol. 2010 Apr;202(4):383.e1-7.
• [12] Metformin is a superior substrate for renal organic cation transporter OCT2 rather than hepatic OCT1. Drug Metab Pharmacokinet. 2005 Oct;20(5):379-86.
• [13] Human multidrug and toxin extrusion 1 (MATE1/SLC47A1) transporter: functional characterization, interaction with OCT2 (SLC22A2), and single nucleotide polymorphisms. Am J Physiol Renal Physiol. 2010 Apr;298(4):F997-F1005.
• [14] Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver. Hepatology. 2009 Oct;50(4):1227-40.
• [15] Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H(+)-organic cation antiporters. Biochem Pharmacol. 2007 Jul 15;74(2):359-71.
• [16] Metformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR-2 (SLC19A3). Mol Pharm. 2015 Dec 7;12(12):4301-10.
• [17] Metformin: from mechanisms of action to therapies. Cell Metab. 2014 Dec 2;20(6):953-66.
• [18] Evaluation of inhibitors of intestinal UDP-glucuronosyltransferases 1A8 and 1A10 using raloxifene as a substrate in Caco-2 cells: Studies with four flavonoids of Scutellaria baicalensis. Toxicol In Vitro. 2021 Apr;72:105087. doi: 10.1016/j.tiv.2021.105087. Epub 2021 Jan 10.
• [19] Radium 223 dichloride for prostate cancer treatment. Drug Des Devel Ther. 2017 Sep 6;11:2643-2651.
• [20] In vitro and physiologically-based pharmacokinetic based assessment of drug-drug interaction potential of canagliflozin. Br J Clin Pharmacol. 2017 May;83(5):1082-1096.
• [21] Sodium-glucose linked transporter 2 (SGLT2) inhibitors in the management of type-2 diabetes: a drug class overview. P T. 2015 Jul;40(7):451-62.
• [22] Effects of rifampin, cyclosporine A, and probenecid on the pharmacokinetic profile of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in healthy participants. Int J Clin Pharmacol Ther. 2015 Feb;53(2):115-28.
• [23] Discovery of novel N--D-xylosylindole derivatives as sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the management of hyperglycemia in diabetes. J Med Chem. 2011 Jan 13;54(1):166-78. doi: 10.1021/jm101072y. Epub 2010 Dec 3.
• [24] ClinicalTrials.gov (NCT06256289) Efficacy of Canagliflozin Versus Metformin in Women With Polycystic Ovary Syndrome