Details of the Drug Combination

General Information of Drug Combination (ID: DC2KNZU)

• Drug Combination Name: Tenofovir + Emtricitabine
• Indication: Infection, Human Immunodeficiency Virus; Status: Phase 2 [1]
• Component Drugs:
  Tenofovir (DM1IS6U): Small molecular drug
  Emtricitabine (DMBMUWZ): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Tenofovir

Disease Entry	ICD 11	Status	REF
Chronic hepatitis B virus infection	N.A.	Approved	[2]
Hepatitis B virus infection	1E51.0	Approved	[2]
Human immunodeficiency virus infection	1C62	Approved	[3]

Tenofovir 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	[6]

Tenofovir Interacts with 7 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[7]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[8]
Multidrug resistance-associated protein 4 (ABCC4)	DTCSGPB	MRP4_HUMAN	Substrate	[9]
Organic anion transporter 1 (SLC22A6)	DTQ23VB	S22A6_HUMAN	Substrate	[10]
Organic anion transporter 3 (SLC22A8)	DTVP67E	S22A8_HUMAN	Substrate	[11]
Multidrug resistance-associated protein 7 (ABCC10)	DTPS120	MRP7_HUMAN	Substrate	[12]
Multidrug resistance-associated protein 8 (ABCC11)	DTWN7FC	ABCCB_HUMAN	Substrate	[13]

Indication(s) of Emtricitabine

Disease Entry	ICD 11	Status	REF
Hepatitis virus infection	1E50-1E51	Approved	[4]
Human immunodeficiency virus infection	1C62	Approved	[4]
Hepatitis B virus infection	1E51.0	Phase 3	[5]

Emtricitabine 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	Modulator	[4]

Emtricitabine Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug and toxin extrusion protein 1 (SLC47A1)	DTZGT0P	S47A1_HUMAN	Substrate	[14]

Emtricitabine Interacts with 3 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
E3 ubiquitin-protein ligase parkin (PRKN)	OTJBN41W	PRKN_HUMAN	Decreases Expression	[15]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[16]
Deoxycytidine kinase (DCK)	OTW8HLZC	DCK_HUMAN	Affects Binding	[17]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
HIV-1-infection	DC0E91Q	N. A.	Phase 4	[18]
HIV	DCSIUUP	N. A.	Phase 4	[19]
Acute HIV Infection	DC4VA0W	N. A.	Phase 1	[20]
HIV/AIDS	DC21DGG	N. A.	Phase 1	[21]

References

• [1] ClinicalTrials.gov (NCT01803074) Study to Evaluate a HIV Drug for the Treatment of HIV Infection
• [2] Tenofovir FDA Label
• [3] Anti-hepatitis B virus activity in vitro of combinations of tenofovir with nucleoside/nucleotide analogues. Antivir Chem Chemother. 2009;19(4):165-76.
• [4] Nat Rev Drug Discov. 2013 Feb;12(2):87-90.
• [5] Clinical pipeline report, company report or official report of Gilead (2011).
• [6] Antiviral drugs in current clinical use. J Clin Virol. 2004 Jun;30(2):115-33.
• [7] KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res. 2017 Jan 4;45(D1):D353-D361. (dg:DG01665)
• [8] KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res. 2017 Jan 4;45(D1):D353-D361. (dg:DG01913)
• [9] Functional involvement of multidrug resistance-associated protein 4 (MRP4/ABCC4) in the renal elimination of the antiviral drugs adefovir and tenofovir. Mol Pharmacol. 2007 Feb;71(2):619-27.
• [10] Human renal organic anion transporter 1 (hOAT1) and its role in the nephrotoxicity of antiviral nucleotide analogs. Nucleosides Nucleotides Nucleic Acids. 2001 Apr-Jul;20(4-7):641-8.
• [11] Tenofovir alafenamide is not a substrate for renal organic anion transporters (OATs) and does not exhibit OAT-dependent cytotoxicity. Antivir Ther. 2014;19(7):687-92.
• [12] Genetic variants of ABCC10, a novel tenofovir transporter, are associated with kidney tubular dysfunction. J Infect Dis. 2011 Jul 1;204(1):145-53.
• [13] Tenofovir Disoproxil Fumarate Is a New Substrate of ATP-Binding Cassette Subfamily C Member 11. Antimicrob Agents Chemother. 2017 Mar 24;61(4). pii: e01725-16.
• [14] Emtricitabine is a substrate of MATE1 but not of OCT1, OCT2, P-gp, BCRP or MRP2 transporters. Xenobiotica. 2017 Jan;47(1):77-85.
• [15] Chronic Nucleoside Reverse Transcriptase Inhibitors Disrupt Mitochondrial Homeostasis and Promote Premature Endothelial Senescence. Toxicol Sci. 2019 Dec 1;172(2):445-456. doi: 10.1093/toxsci/kfz203.
• [16] Binding of anti-HIV drugs to human serum albumin. IUBMB Life. 2004 Oct;56(10):609-14. doi: 10.1080/15216540400016286.
• [17] Nonenantioselectivity property of human deoxycytidine kinase explained by structures of the enzyme in complex with L- and D-nucleosides. J Med Chem. 2007 Jun 28;50(13):3004-14. doi: 10.1021/jm0700215. Epub 2007 May 27.
• [18] ClinicalTrials.gov (NCT03360682) Clinical Trial to Evaluate the Efficacy, Pharmacokinetics (PK) Interactions and Safety of Dolutegravir Plus 2 Nucleoside Reverse Transcriptase Inhibitors (NRTIs) in HIV-1-Infected Solid Organ Transplant Patients
• [19] ClinicalTrials.gov (NCT01335620) The Safety, Pharmacokinetic Profile and Efficacy of Raltegravir in HIV-infected Patients at Least 60 Years of Age
• [20] ClinicalTrials.gov (NCT02475915) Efficacy of VHM After Treatment Interruption in Subjects Initiating ART During Acute HIV Infection
• [21] ClinicalTrials.gov (NCT03917420) Quantification of Estradiol's Impact on Nucleotides in Cellular Populations of the Lower GI Tract