Details of the Drug Combination

General Information of Drug Combination (ID: DCFN2J8)

• Drug Combination Name: Clopidogrel + Ramipril
• Indication: Diabetes Type 2; Status: Phase 1 [1]
• Component Drugs:
  Clopidogrel (DMOL54H): Small molecular drug
  Ramipril (DM2R68E): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Clopidogrel

Disease Entry	ICD 11	Status	REF
Acute coronary syndrome	BA41	Approved	[2]
Atherosclerosis	BD40	Approved	[2]
Myocardial infarction	BA41-BA43	Approved	[2]
Thrombosis	DB61-GB90	Approved	[3]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[4]
Intracranial embolism	8B22.1	Investigative	[2]

Clopidogrel Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
P2Y purinoceptor 12 (P2RY12)	TTZ1DT0	P2Y12_HUMAN	Antagonist	[9]

Clopidogrel Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[10]

Clopidogrel Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[11]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[12]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[13]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[13]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[14]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[15]

Clopidogrel Interacts with 11 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Expression	[10]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Increases ADR	[16]
Stearoyl-CoA desaturase (SCD)	OTB1073G	SCD_HUMAN	Decreases Expression	[17]
C-C motif chemokine 4 (CCL4)	OT6B8P25	CCL4_HUMAN	Increases Expression	[18]
C-C motif chemokine 5 (CCL5)	OTSCA5CK	CCL5_HUMAN	Increases Expression	[18]
Phosphoenolpyruvate carboxykinase, cytosolic (PCK1)	OTNWEJ5Y	PCKGC_HUMAN	Increases Expression	[17]
Glucose-6-phosphatase catalytic subunit 1 (G6PC1)	OTJ6FM9F	G6PC1_HUMAN	Decreases Expression	[17]
Tight junction protein ZO-1 (TJP1)	OTBDCUPK	ZO1_HUMAN	Decreases Expression	[19]
Nuclear receptor subfamily 1 group I member 3 (NR1I3)	OTS3SGH7	NR1I3_HUMAN	Affects Localization	[17]
Occludin (OCLN)	OTSUTVWL	OCLN_HUMAN	Decreases Expression	[19]
Thyroid hormone-inducible hepatic protein (THRSP)	OTKYE01L	THRSP_HUMAN	Increases Expression	[17]

Indication(s) of Ramipril

Disease Entry	ICD 11	Status	REF
Acute heart failure	BD10-BD13	Approved	[5]
Chronic heart failure	BD1Z	Approved	[6]
Congestive heart failure	BD10	Approved	[7]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[8]
Stroke	8B20	Investigative	[6]

Ramipril Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Angiotensin-converting enzyme (ACE)	TTL69WB	ACE_HUMAN	Inhibitor	[20]
HUMAN angiotensin-converting enzyme (ACE)	TTGFNPD	ACE_HUMAN	Inhibitor	[21]

Ramipril Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Peptide transporter 1 (SLC15A1)	DT9G7XN	S15A1_HUMAN	Substrate	[22]
Peptide transporter 2 (SLC15A2)	DT8QKNP	S15A2_HUMAN	Substrate	[22]

Ramipril Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Activity	[23]

References

• [1] ClinicalTrials.gov (NCT01743014) Ramipril and Clopidogrel in Oxidative Stress, Vascular Inflammation and Endothelial Dysfunction in Type 2 Diabetes and Diabetic Nephropathy
• [2] Clopidogrel FDA Label
• [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: 7150).
• [4] Preventing Cardiac Complication of COVID-19 Disease With Early Acute Coronary Syndrome Therapy: A Randomised Controlled Trial. (C-19-ACS)
• [5] FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (ANDA) 202392.
• [6] Ramipril FDA Label
• [7] 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: 6339).
• [8] ClinicalTrials.gov (NCT04366050) Ramipril for the Treatment of COVID-19. U.S. National Institutes of Health.
• [9] P2Y12, a new platelet ADP receptor, target of clopidogrel. Semin Vasc Med. 2003 May;3(2):113-22.
• [10] Impact of P-glycoprotein on clopidogrel absorption. Clin Pharmacol Ther. 2006 Nov;80(5):486-501.
• [11] 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.
• [12] Clinical pharmacokinetics and pharmacodynamics of clopidogrel. Clin Pharmacokinet. 2015 Feb;54(2):147-66.
• [13] Cytochrome P450 3A inhibition by ketoconazole affects prasugrel and clopidogrel pharmacokinetics and pharmacodynamics differently. Clin Pharmacol Ther. 2007 May;81(5):735-41.
• [14] Clopidogrel pathway. Pharmacogenet Genomics. 2010 Jul;20(7):463-5.
• [15] Impact of the CYP2C19 gene polymorphism on clopidogrel personalized drug regimen and the clinical outcomes. Clin Lab. 2016 Sep 1;62(9):1773-1780.
• [16] Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther. 2013 Sep;94(3):317-23. doi: 10.1038/clpt.2013.105. Epub 2013 May 22.
• [17] Identification of novel agonists by high-throughput screening and molecular modelling of human constitutive androstane receptor isoform 3. Arch Toxicol. 2019 Aug;93(8):2247-2264. doi: 10.1007/s00204-019-02495-6. Epub 2019 Jul 16.
• [18] Clopidogrel increases expression of chemokines in peripheral blood mononuclear cells in patients with coronary artery disease: results of a double-blind placebo-controlled study. J Thromb Haemost. 2006 Oct;4(10):2140-7. doi: 10.1111/j.1538-7836.2006.02131.x. Epub 2006 Jul 17.
• [19] Attenuated expression of the tight junction proteins is involved in clopidogrel-induced gastric injury through p38 MAPK activation. Toxicology. 2013 Feb 8;304:41-8. doi: 10.1016/j.tox.2012.11.020. Epub 2012 Dec 7.
• [20] Knockouts model the 100 best-selling drugs--will they model the next 100 Nat Rev Drug Discov. 2003 Jan;2(1):38-51.
• [21] Outcomes in Patients with COVID-19 Infection Taking ACEI/ARB. Curr Cardiol Rep. 2020 Apr 14;22(5):31.
• [22] Transport of angiotensin-converting enzyme inhibitors by H+/peptide transporters revisited. J Pharmacol Exp Ther. 2008 Nov;327(2):432-41.
• [23] Effects of an angiotensin converting enzyme inhibitor, ramipril, on intracranial circulation in healthy volunteers. off. Br J Clin Pharmacol. 1992 Sep;34(3):224-30. doi: 10.1111/j.1365-2125.1992.tb04128.x.