Details of the Drug Combination

General Information of Drug Combination (ID: DCTL991)

• Drug Combination Name: Tenofovir + Dolutegravir
• Indication: HIV Infections; Status: Phase 2 [1]
• Component Drugs:
  Tenofovir (DM1IS6U): Small molecular drug
  Dolutegravir (DMCZGRE): 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	[5]

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	[6]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[7]
Multidrug resistance-associated protein 4 (ABCC4)	DTCSGPB	MRP4_HUMAN	Substrate	[8]
Organic anion transporter 1 (SLC22A6)	DTQ23VB	S22A6_HUMAN	Substrate	[9]
Organic anion transporter 3 (SLC22A8)	DTVP67E	S22A8_HUMAN	Substrate	[10]
Multidrug resistance-associated protein 7 (ABCC10)	DTPS120	MRP7_HUMAN	Substrate	[11]
Multidrug resistance-associated protein 8 (ABCC11)	DTWN7FC	ABCCB_HUMAN	Substrate	[12]

Indication(s) of Dolutegravir

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

Dolutegravir Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human immunodeficiency virus Integrase (HIV IN)	TT5FH9Y	POL_HV1B1	Modulator	[13]

Dolutegravir Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[14]

Dolutegravir Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[15]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[15]

Dolutegravir Interacts with 5 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 26A1 (CYP26A1)	OTL1DFWV	CP26A_HUMAN	Decreases Expression	[16]
T-box transcription factor TBX6 (TBX6)	OTW1Q8RM	TBX6_HUMAN	Increases Expression	[16]
Homeobox protein Hox-B1 (HOXB1)	OTGC0EKI	HXB1_HUMAN	Increases Expression	[16]
Fibroblast growth factor 8 (FGF8)	OTFU0IUW	FGF8_HUMAN	Increases Expression	[16]
Homeobox protein MIXL1 (MIXL1)	OT584VOQ	MIXL1_HUMAN	Increases Expression	[16]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Human Immunodeficiency Virus	DCFVOSL	N. A.	Phase 3	[17]
AIDS	DCVH2RE	N. A.	Phase 1	[18]

References

• [1] ClinicalTrials.gov (NCT02386098) Strategy-confirming Study of BMS-955176 to Treat HIV-1 Infected Treatment-experienced Adults
• [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] 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: 7365).
• [5] Antiviral drugs in current clinical use. J Clin Virol. 2004 Jun;30(2):115-33.
• [6] KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res. 2017 Jan 4;45(D1):D353-D361. (dg:DG01665)
• [7] KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res. 2017 Jan 4;45(D1):D353-D361. (dg:DG01913)
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Genetic variants of ABCC10, a novel tenofovir transporter, are associated with kidney tubular dysfunction. J Infect Dis. 2011 Jul 1;204(1):145-53.
• [12] 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.
• [13] Radium 223 dichloride for prostate cancer treatment. Drug Des Devel Ther. 2017 Sep 6;11:2643-2651.
• [14] Tarascon Pocket Pharmacopoeia 2018 Classic Shirt-Pocket Edition.
• [15] Mechanisms of action, pharmacology and interactions of dolutegravir. Enferm Infecc Microbiol Clin. 2015 Mar;33 Suppl 1:2-8.
• [16] Dolutegravir Impairs Stem Cell-Based 3D Morphogenesis Models in a Manner Dependent on Dose and Timing of Exposure: An Implication for Its Developmental Toxicity. Toxicol Sci. 2021 Nov 24;184(2):191-203. doi: 10.1093/toxsci/kfab112.
• [17] ClinicalTrials.gov (NCT03988452) Nucleosides And Darunavir/Dolutegravir In Africa
• [18] ClinicalTrials.gov (NCT03782142) Effect on HIV Medications on EPC Cells