Details of the Drug Combination

General Information of Drug Combination (ID: DCIHYRW)

• Drug Combination Name: Glibenclamide + Dapagliflozin
• Indication: Hypertension; Status: Phase 4 [1]
• Component Drugs:
  Glibenclamide (DM8JXPZ): Small molecular drug
  Dapagliflozin (DM28UJG): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Glibenclamide

Disease Entry	ICD 11	Status	REF
Diabetic complication	5A2Y	Approved	[2]
Non-insulin dependent diabetes	5A11	Approved	[3]
Stroke	8B20	Phase 3	[4]

Glibenclamide Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
ATP-binding cassette transporter C8 (ABCC8)	TTP835K	ABCC8_HUMAN	Modulator	[8]

Glibenclamide Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[9]
Multidrug resistance-associated protein 3 (ABCC3)	DTQ3ZHF	MRP3_HUMAN	Substrate	[10]
Organic anion transporting polypeptide 2B1 (SLCO2B1)	DTPFTEQ	SO2B1_HUMAN	Substrate	[11]

Glibenclamide Interacts with 6 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	[13]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[14]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[14]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[15]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[12]

Glibenclamide Interacts with 7 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[16]
Aldo-keto reductase family 1 member C3 (AKR1C3)	OTU2SXBA	AK1C3_HUMAN	Decreases Activity	[17]
Aldo-keto reductase family 1 member C2 (AKR1C2)	OTQ2XMO3	AK1C2_HUMAN	Decreases Activity	[17]
Aldo-keto reductase family 1 member C1 (AKR1C1)	OTQKR4CM	AK1C1_HUMAN	Decreases Activity	[17]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[18]
Calpain-2 catalytic subunit (CAPN2)	OTIAPE5J	CAN2_HUMAN	Increases Expression	[19]
ATP-sensitive inward rectifier potassium channel 8 (KCNJ8)	OTZ8G8FE	KCNJ8_HUMAN	Decreases Activity	[20]

Indication(s) of Dapagliflozin

Disease Entry	ICD 11	Status	REF
Non-insulin dependent diabetes	5A11	Approved	[5]
Type-2 diabetes	5A11	Approved	[6]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[7]

Dapagliflozin 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	[21]

Dapagliflozin Interacts with 7 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[22]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[22]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[22]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[22]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[22]
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[22]
UDP-glucuronosyltransferase 1A9 (UGT1A9)	DE85D2P	UD19_HUMAN	Metabolism	[22]

References

• [1] ClinicalTrials.gov (NCT03089333) Effects of SGLT2 Inhibitor on Hemodynamic Parameters in Resistant Hypertensive Subjects
• [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: 2414).
• [3] Spectroscopic interactions of non-insulin-dependent diabetes mellitus with levocetirizine. Pak J Pharm Sci. 2021 Jul;34(4(Supplementary)):1639-1644.
• [4] Antibodies and venom peptides: new modalities for ion channels. Nat Rev Drug Discov. 2019 May;18(5):339-357.
• [5] Dapagliflozin 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: 4594).
• [7] Dapagliflozin in Respiratory Failure in Patients With COVID-19 (DARE-19)
• [8] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [9] Glyburide transport across the human placenta. Obstet Gynecol. 2015 Mar;125(3):583-8.
• [10] Transport of glyburide by placental ABC transporters: implications in fetal drug exposure. Placenta. 2006 Nov-Dec;27(11-12):1096-102.
• [11] Citrus juices inhibit the function of human organic anion-transporting polypeptide OATP-B. Drug Metab Dispos. 2005 Apr;33(4):518-23.
• [12] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
• [13] Contribution of UDP-glucuronosyltransferases 1A9 and 2B7 to the glucuronidation of indomethacin in the human liver. Eur J Clin Pharmacol. 2007 Mar;63(3):289-96.
• [14] Identification of CYP3A7 for glyburide metabolism in human fetal livers. Biochem Pharmacol. 2014 Dec 15;92(4):690-700.
• [15] Contributions of human cytochrome P450 enzymes to glyburide metabolism. Biopharm Drug Dispos. 2010 May;31(4):228-42.
• [16] Potential cholestatic activity of various therapeutic agents assessed by bile canalicular membrane vesicles isolated from rats and humans. Drug Metab Pharmacokinet. 2003;18(1):16-22.
• [17] Initro inhibition of AKR1Cs by sulphonylureas and the structural basis. Chem Biol Interact. 2015 Oct 5;240:310-5.
• [18] Chromatographic studies of changes in binding of sulfonylurea drugs to human serum albumin due to glycation and fatty acids. J Chromatogr B Analyt Technol Biomed Life Sci. 2010 Nov 15;878(30):3193-7. doi: 10.1016/j.jchromb.2010.09.033. Epub 2010 Oct 23.
• [19] 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.
• [20] The intermediate conductance Ca2+-activated K+ channel inhibitor TRAM-34 stimulates proliferation of breast cancer cells via activation of oestrogen receptors. Br J Pharmacol. 2010 Feb 1;159(3):650-8. doi: 10.1111/j.1476-5381.2009.00557.x. Epub 2009 Dec 24.
• [21] 2014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.
• [22] Clinical pharmacokinetics and pharmacodynamics of dapagliflozin, a selective inhibitor of sodium-glucose co-transporter type 2. Clin Pharmacokinet. 2014 Jan;53(1):17-27.