Details of the Drug Combination

General Information of Drug Combination (ID: DCRTDAX)

• Drug Combination Name: Metformin + Sitagliptin
• Indication: Type-2 diabetes; Status: Phase 1 [1]
• Component Drugs:
  Metformin (DM89QE1): Small molecular drug
  Sitagliptin (DMGDKXN): 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	[8]
Solute carrier family 47 member 1 (SLC47A1)	TTMHCGA	S47A1_HUMAN	Modulator	[9]
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	[10]
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[11]
Multidrug and toxin extrusion protein 1 (SLC47A1)	DTZGT0P	S47A1_HUMAN	Substrate	[12]
Organic cation transporter 3 (SLC22A3)	DT6201N	S22A3_HUMAN	Substrate	[13]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[11]
Multidrug and toxin extrusion protein 2 (SLC47A2)	DT3TX4H	S47A2_HUMAN	Substrate	[14]
Thiamine transporter 1 (SLC19A2)	DTLA4Q2	S19A2_HUMAN	Substrate	[15]
Thiamine transporter 2 (SLC19A3)	DT39CEA	S19A3_HUMAN	Substrate	[15]
Equilibrative nucleoside transporter 4 (SLC29A4)	DT3EAQP	S29A4_HUMAN	Substrate	[16]

Indication(s) of Sitagliptin

Disease Entry	ICD 11	Status	REF
Cystic fibrosis	CA25	Approved	[5]
Non-insulin dependent diabetes	5A11	Approved	[5]
Renal hypoplasia	N.A.	Approved	[5]
Type-2 diabetes	5A11	Approved	[6]
Peripheral arterial disease	BD4Z	Phase 1/2	[7]

Sitagliptin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Dipeptidyl peptidase 4 (DPP-4)	TTDIGC1	DPP4_HUMAN	Inhibitor	[17]

Sitagliptin Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[18]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[19]
Organic anion transporter 3 (SLC22A8)	DTVP67E	S22A8_HUMAN	Substrate	[20]

Sitagliptin Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[21]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[21]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Type 2 Diabetes Mellitus	DC3BI0L	N. A.	Phase 4	[22]
Type 2 Diabetes	DCDEZAK	N. A.	Phase 1	[23]
Type 2 Diabetes Mellitus	DCRRXIM	N. A.	Phase 1	[24]

References

• [1] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [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] Sitagliptin 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: 6286).
• [7] ClinicalTrials.gov (NCT01619332) Clinical Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of LEZ763. U.S. National Institutes of Health.
• [8] 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.
• [9] Molecular cloning, functional characterization and tissue distribution of rat H+/organic cation antiporter MATE1. Pharm Res. 2006 Aug;23(8):1696-701.
• [10] 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.
• [11] Metformin is a superior substrate for renal organic cation transporter OCT2 rather than hepatic OCT1. Drug Metab Pharmacokinet. 2005 Oct;20(5):379-86.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Metformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR-2 (SLC19A3). Mol Pharm. 2015 Dec 7;12(12):4301-10.
• [16] Metformin: from mechanisms of action to therapies. Cell Metab. 2014 Dec 2;20(6):953-66.
• [17] Novel therapeutics for type 2 diabetes: incretin hormone mimetics (glucagon-like peptide-1 receptor agonists) and dipeptidyl peptidase-4 inhibitors. Pharmacol Ther. 2009 Oct;124(1):113-38.
• [18] Tarascon Pocket Pharmacopoeia 2018 Classic Shirt-Pocket Edition.
• [19] 265 effect of dietary cholesterol on gallbladder bile lithogenicity and gene expression in the enterohepatic axis of non-obese gallstone and control women. Journal of Hepatology, 2009, 50(09):S105-S106.
• [20] 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.
• [21] Pharmacokinetics of dipeptidylpeptidase-4 inhibitors. Diabetes Obes Metab. 2010 Aug;12(8):648-58.
• [22] ClinicalTrials.gov (NCT01709305) A Study of the Safety and Efficacy of Glimepiride, Gliclazide, Repaglinide or Acarbose When Added to Sitagliptin + Metformin Combination Therapy in Chinese Participants With Diabetes (MK-0431-313)
• [23] ClinicalTrials.gov (NCT00961480) A Study to Demonstrate the Bioequivalence of Sitagliptin/Metformin Combination Tablets and Co-administration of Sitagliptin and Metformin as Individual Tablets (0431A-095)
• [24] ClinicalTrials.gov (NCT00420511) Beta-Cell Function and Sitagliptin Trial (BEST)