Details of the Drug Combination

General Information of Drug Combination (ID: DCN174U)

• Drug Combination Name: Clopidogrel + Tamoxifen
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Clopidogrel (DMOL54H): Small molecular drug
  Tamoxifen (DMLB0EZ): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 0.65
  Bliss Independence Score: 0.65
  Loewe Additivity Score: 13.19
  LHighest Single Agent (HSA) Score: 13.19

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	[7]

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	[8]

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	[9]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[10]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[11]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[11]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[12]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[13]

Clopidogrel Interacts with 26 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[14]
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Increases Expression	[14]
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Increases Oxidation	[15]
Cytochrome P450 3A5 (CYP3A5)	OTSXFBXB	CP3A5_HUMAN	Affects Response To Substance	[16]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Expression	[8]
P2Y purinoceptor 12 (P2RY12)	OTX2W0WD	P2Y12_HUMAN	Affects Response To Substance	[17]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Increases ADR	[18]
Stearoyl-CoA desaturase (SCD)	OTB1073G	SCD_HUMAN	Decreases Expression	[14]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[19]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[20]
Thrombospondin-1 (THBS1)	OT0ECWK3	TSP1_HUMAN	Increases Expression	[19]
C-C motif chemokine 4 (CCL4)	OT6B8P25	CCL4_HUMAN	Increases Expression	[21]
C-C motif chemokine 5 (CCL5)	OTSCA5CK	CCL5_HUMAN	Increases Expression	[21]
Brain-derived neurotrophic factor (BDNF)	OTLGH7EW	BDNF_HUMAN	Decreases Secretion	[22]
Phosphoenolpyruvate carboxykinase, cytosolic (PCK1)	OTNWEJ5Y	PCKGC_HUMAN	Increases Expression	[14]
Glucose-6-phosphatase catalytic subunit 1 (G6PC1)	OTJ6FM9F	G6PC1_HUMAN	Decreases Expression	[14]
Tight junction protein ZO-1 (TJP1)	OTBDCUPK	ZO1_HUMAN	Decreases Expression	[23]
Nuclear receptor subfamily 1 group I member 3 (NR1I3)	OTS3SGH7	NR1I3_HUMAN	Affects Localization	[14]
Occludin (OCLN)	OTSUTVWL	OCLN_HUMAN	Decreases Expression	[23]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[20]
Thyroid hormone-inducible hepatic protein (THRSP)	OTKYE01L	THRSP_HUMAN	Increases Expression	[14]
Proteinase-activated receptor 1 (F2R)	OT4WVWBO	PAR1_HUMAN	Affects Response To Substance	[24]
Serum paraoxonase/arylesterase 1 (PON1)	OTD0Z2XO	PON1_HUMAN	Affects Response To Substance	[25]
Cytochrome P450 2C9 (CYP2C9)	OTGLBN29	CP2C9_HUMAN	Decreases Metabolism	[26]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Increases Response To Substance	[27]
Integrin beta-3 (ITGB3)	OTWCK1K6	ITB3_HUMAN	Decreases Response To Substance	[28]

Indication(s) of Tamoxifen

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Approved	[5]
Inflammatory breast cancer	2C62	Approved	[6]
Invasive ductal breast carcinoma	N.A.	Approved	[6]

Tamoxifen Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Estrogen receptor (ESR)	TTZAYWL	ESR1_HUMAN	Antagonist	[29]

Tamoxifen Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[30]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[31]
Multidrug resistance-associated protein 7 (ABCC10)	DTPS120	MRP7_HUMAN	Substrate	[32]

Tamoxifen Interacts with 16 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[33]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[34]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[35]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[36]
Cytochrome P450 1A1 (CYP1A1)	DE6OQ3W	CP1A1_HUMAN	Metabolism	[37]
Sulfotransferase 1A1 (SULT1A1)	DEYWLRK	ST1A1_HUMAN	Metabolism	[38]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[39]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[40]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[36]
Thiopurine methyltransferase (TPMT)	DEFQ8VO	TPMT_HUMAN	Metabolism	[41]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[42]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[43]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[44]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[45]
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[46]
UDP-glucuronosyltransferase 1A10 (UGT1A10)	DEL5N6Y	UD110_HUMAN	Metabolism	[47]

Tamoxifen Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Coagulation factor V (F5)	OTDMZ3LT	FA5_HUMAN	Increases ADR	[48]

References

• [1] Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
• [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] 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: 1016).
• [6] Tamoxifen FDA Label
• [7] P2Y12, a new platelet ADP receptor, target of clopidogrel. Semin Vasc Med. 2003 May;3(2):113-22.
• [8] Impact of P-glycoprotein on clopidogrel absorption. Clin Pharmacol Ther. 2006 Nov;80(5):486-501.
• [9] 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.
• [10] Clinical pharmacokinetics and pharmacodynamics of clopidogrel. Clin Pharmacokinet. 2015 Feb;54(2):147-66.
• [11] Cytochrome P450 3A inhibition by ketoconazole affects prasugrel and clopidogrel pharmacokinetics and pharmacodynamics differently. Clin Pharmacol Ther. 2007 May;81(5):735-41.
• [12] Clopidogrel pathway. Pharmacogenet Genomics. 2010 Jul;20(7):463-5.
• [13] Impact of the CYP2C19 gene polymorphism on clopidogrel personalized drug regimen and the clinical outcomes. Clin Lab. 2016 Sep 1;62(9):1773-1780.
• [14] 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.
• [15] Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos. 2010 Jan;38(1):92-9. doi: 10.1124/dmd.109.029132.
• [16] Increased risk of atherothrombotic events associated with cytochrome P450 3A5 polymorphism in patients taking clopidogrel. CMAJ. 2006 Jun 6;174(12):1715-22. doi: 10.1503/cmaj.060664.
• [17] Platelet reactivity and clopidogrel resistance are associated with the H2 haplotype of the P2Y12-ADP receptor gene. Int J Cardiol. 2009 Apr 17;133(3):341-5. doi: 10.1016/j.ijcard.2007.12.118. Epub 2008 May 15.
• [18] 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.
• [19] Angiogenesis inhibitor SR 25989 upregulates thrombospondin-1 expression in human vascular endothelial cells and foreskin fibroblasts. Biol Cell. 1997 Jul;89(4):295-307.
• [20] Association of CYP1A1 and CYP1B1 inhibition in in vitro assays with drug-induced liver injury. J Toxicol Sci. 2021;46(4):167-176. doi: 10.2131/jts.46.167.
• [21] 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.
• [22] Differential effect of clopidogrel and aspirin on the release of BDNF from platelets. J Neuroimmunol. 2011 Sep 15;238(1-2):104-6. doi: 10.1016/j.jneuroim.2011.06.015. Epub 2011 Jul 31.
• [23] 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.
• [24] PAR-1 genotype influences platelet aggregation and procoagulant responses in patients with coronary artery disease prior to and during clopidogrel therapy. Platelets. 2005 Sep;16(6):340-5. doi: 10.1080/00207230500120294.
• [25] Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nat Med. 2011 Jan;17(1):110-6. doi: 10.1038/nm.2281. Epub 2010 Dec 19.
• [26] Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost. 2007 Dec;5(12):2429-36. doi: 10.1111/j.1538-7836.2007.02775.x. Epub 2007 Sep 26.
• [27] Interleukin-6 alters the cellular responsiveness to clopidogrel, irinotecan, and oseltamivir by suppressing the expression of carboxylesterases HCE1 and HCE2. Mol Pharmacol. 2007 Sep;72(3):686-94. doi: 10.1124/mol.107.036889. Epub 2007 May 30.
• [28] High loading dose of clopidogrel is unable to satisfactorily inhibit platelet reactivity in patients with glycoprotein IIIA gene polymorphism: a genetic substudy of PRAGUE-8 trial. Blood Coagul Fibrinolysis. 2009 Jun;20(4):257-62. doi: 10.1097/mbc.0b013e328325455b.
• [29] Modulators of vascular sex hormone receptors and their effects in estrogen-deficiency states associated with menopause. Recent Pat Cardiovasc Drug Discov. 2008 Nov;3(3):165-86.
• [30] Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016 Jan 1;370(1):153-64.
• [31] The phytoestrogen genistein enhances multidrug resistance in breast cancer cell lines by translational regulation of ABC transporters. Cancer Lett. 2016 Jun 28;376(1):165-72.
• [32] Modulation of the ATPase and transport activities of broad-acting multidrug resistance factor ABCC10 (MRP7). Cancer Res. 2012 Dec 15;72(24):6457-67.
• [33] Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther. 2004 Sep;310(3):1062-75.
• [34] Endoxifen and other metabolites of tamoxifen inhibit human hydroxysteroid sulfotransferase 2A1 (hSULT2A1). Drug Metab Dispos. 2014 Nov;42(11):1843-50.
• [35] Functional significance of UDP-glucuronosyltransferase variants in the metabolism of active tamoxifen metabolites. Cancer Res. 2009 Mar 1;69(5):1892-900.
• [36] Genotoxicity of tamoxifen, tamoxifen epoxide and toremifene in human lymphoblastoid cells containing human cytochrome P450s. Carcinogenesis. 1994 Jan;15(1):5-9.
• [37] Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes: formation of the 4-hydroxy, 4'-hydroxy and N-desmethyl metabolites and isomerization of trans-4-hydroxytamoxifen. Drug Metab Dispos. 2002 Aug;30(8):869-74.
• [38] Tamoxifen-induced adduct formation and cell stress in human endometrial glands. Drug Metab Dispos. 2010 Jan;38(1):200-7.
• [39] CYP2D6 polymorphisms and tamoxifen metabolism: clinical relevance. Curr Oncol Rep. 2010 Jan;12(1):7-15.
• [40] Polymorphisms in cytochrome P4503A5 (CYP3A5) may be associated with race and tumor characteristics, but not metabolism and side effects of tamoxifen in breast cancer patients. Cancer Lett. 2005 Jan 10;217(1):61-72.
• [41] Polymorphism of estrogen metabolism genes and cataract. Med Hypotheses. 2004;63(3):494-7.
• [42] Drug Interactions Flockhart Table
• [43] Tamoxifen inhibits cytochrome P450 2C9 activity in breast cancer patients. J Chemother. 2006 Aug;18(4):421-4.
• [44] Effect of tamoxifen on the enzymatic activity of human cytochrome CYP2B6. J Pharmacol Exp Ther. 2002 Jun;301(3):945-52.
• [45] Cytochrome P450 pharmacogenetics and cancer. Oncogene. 2006 Mar 13;25(11):1679-91.
• [46] Metabolism and transport of tamoxifen in relation to its effectiveness: new perspectives on an ongoing controversy. Future Oncol. 2014 Jan;10(1):107-22.
• [47] Glucuronidation of active tamoxifen metabolites by the human UDP glucuronosyltransferases. Drug Metab Dispos. 2007 Nov;35(11):2006-14.
• [48] Factor V Leiden mutation and thromboembolism risk in women receiving adjuvant tamoxifen for breast cancer. J Natl Cancer Inst. 2010 Jul 7;102(13):942-9. doi: 10.1093/jnci/djq211. Epub 2010 Jun 16.