Details of the Drug Combination

General Information of Drug Combination (ID: DCAL6TJ)

• Drug Combination Name: Tamoxifen + Abacavir
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Tamoxifen (DMLB0EZ): Small molecular drug
  Abacavir (DMMN36E): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 1.83
  Bliss Independence Score: 1.83
  Loewe Additivity Score: 14.79
  LHighest Single Agent (HSA) Score: 14.79

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Tamoxifen

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Approved	[2]
Inflammatory breast cancer	2C62	Approved	[3]
Invasive ductal breast carcinoma	N.A.	Approved	[3]

Tamoxifen Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Estrogen receptor (ESR)	TTZAYWL	ESR1_HUMAN	Antagonist	[5]

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	[6]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[7]
Multidrug resistance-associated protein 7 (ABCC10)	DTPS120	MRP7_HUMAN	Substrate	[8]

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	[9]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[10]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[11]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[12]
Cytochrome P450 1A1 (CYP1A1)	DE6OQ3W	CP1A1_HUMAN	Metabolism	[13]
Sulfotransferase 1A1 (SULT1A1)	DEYWLRK	ST1A1_HUMAN	Metabolism	[14]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[15]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[16]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[12]
Thiopurine methyltransferase (TPMT)	DEFQ8VO	TPMT_HUMAN	Metabolism	[17]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[18]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[19]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[20]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[21]
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[22]
UDP-glucuronosyltransferase 1A10 (UGT1A10)	DEL5N6Y	UD110_HUMAN	Metabolism	[23]

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	[24]

Indication(s) of Abacavir

Disease Entry	ICD 11	Status	REF
Human immunodeficiency virus infection	1C62	Approved	[4]

Abacavir Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human immunodeficiency virus Reverse transcriptase (HIV RT)	TT84ETX	POL_HV1B1	Inhibitor	[27]

Abacavir Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[28]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[29]
Multidrug resistance-associated protein 4 (ABCC4)	DTCSGPB	MRP4_HUMAN	Substrate	[30]

Abacavir Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[31]
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[32]
Alcohol dehydrogenase class-V (ADH6)	DE017IC	ADH6_HUMAN	Metabolism	[31]

Abacavir Interacts with 26 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
HLA class I histocompatibility antigen, B alpha chain (HLA-B)	OTNXFWY2	HLAB_HUMAN	Increases Response To Substance	[33]
C-reactive protein (CRP)	OT0RFT8F	CRP_HUMAN	Increases Expression	[34]
Myeloperoxidase (MPO)	OTOOXLIN	PERM_HUMAN	Increases Expression	[34]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Increases Expression	[34]
Telomerase reverse transcriptase (TERT)	OT085VVA	TERT_HUMAN	Decreases Activity	[35]
Retinal dehydrogenase 2 (ALDH1A2)	OTJB560Z	AL1A2_HUMAN	Decreases Expression	[25]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[36]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[37]
Synaptophysin (SYP)	OTFJKMO4	SYPH_HUMAN	Increases Expression	[35]
Homeobox protein Hox-B7 (HOXB7)	OTC7WYU8	HXB7_HUMAN	Increases Expression	[25]
HLA class I histocompatibility antigen, C alpha chain (HLA-C)	OTV38BUJ	HLAC_HUMAN	Affects Binding	[38]
Glial fibrillary acidic protein (GFAP)	OTQ01ZAS	GFAP_HUMAN	Increases Expression	[35]
Homeobox protein Hox-B9 (HOXB9)	OTMVHQOU	HXB9_HUMAN	Increases Expression	[25]
Paired box protein Pax-3 (PAX3)	OTN5PJZV	PAX3_HUMAN	Decreases Expression	[25]
Paired box protein Pax-6 (PAX6)	OTOC9876	PAX6_HUMAN	Increases Expression	[25]
Homeobox protein MOX-1 (MEOX1)	OTJEMT2D	MEOX1_HUMAN	Decreases Expression	[25]
Fibroblast growth factor 8 (FGF8)	OTFU0IUW	FGF8_HUMAN	Increases Expression	[25]
Mesoderm posterior protein 2 (MESP2)	OT7H4LYA	MESP2_HUMAN	Decreases Expression	[25]
Transcription factor 15 (TCF15)	OTA6UCWC	TCF15_HUMAN	Decreases Expression	[25]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[37]
Oligodendrocyte transcription factor 3 (OLIG3)	OTU8XLAF	OLIG3_HUMAN	Increases Expression	[25]
Eyes absent homolog 1 (EYA1)	OTHU807A	EYA1_HUMAN	Decreases Expression	[25]
Forkhead box protein C2 (FOXC2)	OT83P1E0	FOXC2_HUMAN	Decreases Expression	[25]
Neurogenin-2 (NEUROG2)	OTAEMIGT	NGN2_HUMAN	Increases Expression	[25]
Interleukin-4 (IL4)	OTOXBWAU	IL4_HUMAN	Affects Response To Substance	[39]
HLA class I histocompatibility antigen protein P5 (HCP5)	OTV0YRI8	HCP5_HUMAN	Increases ADR	[40]

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] 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).
• [3] Tamoxifen FDA Label
• [4] Abacavir (marketed as Ziagen) and Abacavir-containing Medications. FDA. 2008.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Modulation of the ATPase and transport activities of broad-acting multidrug resistance factor ABCC10 (MRP7). Cancer Res. 2012 Dec 15;72(24):6457-67.
• [9] 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.
• [10] Endoxifen and other metabolites of tamoxifen inhibit human hydroxysteroid sulfotransferase 2A1 (hSULT2A1). Drug Metab Dispos. 2014 Nov;42(11):1843-50.
• [11] Functional significance of UDP-glucuronosyltransferase variants in the metabolism of active tamoxifen metabolites. Cancer Res. 2009 Mar 1;69(5):1892-900.
• [12] Genotoxicity of tamoxifen, tamoxifen epoxide and toremifene in human lymphoblastoid cells containing human cytochrome P450s. Carcinogenesis. 1994 Jan;15(1):5-9.
• [13] 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.
• [14] Tamoxifen-induced adduct formation and cell stress in human endometrial glands. Drug Metab Dispos. 2010 Jan;38(1):200-7.
• [15] CYP2D6 polymorphisms and tamoxifen metabolism: clinical relevance. Curr Oncol Rep. 2010 Jan;12(1):7-15.
• [16] 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.
• [17] Polymorphism of estrogen metabolism genes and cataract. Med Hypotheses. 2004;63(3):494-7.
• [18] Drug Interactions Flockhart Table
• [19] Tamoxifen inhibits cytochrome P450 2C9 activity in breast cancer patients. J Chemother. 2006 Aug;18(4):421-4.
• [20] Effect of tamoxifen on the enzymatic activity of human cytochrome CYP2B6. J Pharmacol Exp Ther. 2002 Jun;301(3):945-52.
• [21] Cytochrome P450 pharmacogenetics and cancer. Oncogene. 2006 Mar 13;25(11):1679-91.
• [22] Metabolism and transport of tamoxifen in relation to its effectiveness: new perspectives on an ongoing controversy. Future Oncol. 2014 Jan;10(1):107-22.
• [23] Glucuronidation of active tamoxifen metabolites by the human UDP glucuronosyltransferases. Drug Metab Dispos. 2007 Nov;35(11):2006-14.
• [24] 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.
• [25] Exposure-based assessment of chemical teratogenicity using morphogenetic aggregates of human embryonic stem cells. Reprod Toxicol. 2020 Jan;91:74-91. doi: 10.1016/j.reprotox.2019.10.004. Epub 2019 Nov 8.
• [26] Mitochondrial proliferation, DNA depletion and adipocyte differentiation in subcutaneous adipose tissue of HIV-positive HAART recipients. Antivir Ther. 2003 Aug;8(4):323-31.
• [27] Quadruple nucleos(t)ide reverse transcriptase inhibitors-only regimen of tenofovir plus zidovudine/lamivudine/abacavir in heavily pre-treated HIV-1 infected patients: salvage therapy or backbone only Curr HIV Res. 2009 May;7(3):320-6.
• [28] The transport of anti-HIV drugs across blood-CNS interfaces: summary of current knowledge and recommendations for further research. Antiviral Res. 2009 May;82(2):A99-109.
• [29] QSAR analysis and molecular modeling of ABCG2-specific inhibitors. Adv Drug Deliv Rev. 2009 Jan 31;61(1):34-46.
• [30] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [31] A review of the pharmacokinetics of abacavir. Clin Pharmacokinet. 2008;47(6):351-71.
• [32] Product characteristics of Triumeq.
• [33] Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet. 2002 Mar 30;359(9312):1121-2. doi: 10.1016/S0140-6736(02)08158-8.
• [34] Changes in biomarkers of cardiovascular risk after a switch to abacavir in HIV-1-infected individuals receiving combination antiretroviral therapy. HIV Med. 2009 Nov;10(10):627-33.
• [35] The antiretroviral nucleoside analogue Abacavir reduces cell growth and promotes differentiation of human medulloblastoma cells. Int J Cancer. 2009 Jul 1;125(1):235-43. doi: 10.1002/ijc.24331.
• [36] Binding of anti-HIV drugs to human serum albumin. IUBMB Life. 2004 Oct;56(10):609-14. doi: 10.1080/15216540400016286.
• [37] 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.
• [38] Harvesting candidate genes responsible for serious adverse drug reactions from a chemical-protein interactome. PLoS Comput Biol. 2009 Jul;5(7):e1000441. doi: 10.1371/journal.pcbi.1000441. Epub 2009 Jul 24.
• [39] Intracellular cytokines may model immunoregulation of abacavir hypersensitivity in HIV-infected subjects. J Allergy Clin Immunol. 2005 May;115(5):1081-7. doi: 10.1016/j.jaci.2004.12.1140.
• [40] The HCP5 single-nucleotide polymorphism: a simple screening tool for prediction of hypersensitivity reaction to abacavir. J Infect Dis. 2008 Sep 15;198(6):864-7. doi: 10.1086/591184.