Details of the Drug Combination

General Information of Drug Combination (ID: DC0AQOM)

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

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

Atazanavir Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human immunodeficiency virus Protease (HIV PR)	TT5FNQT	POL_HV1B1	Modulator	[15]

Atazanavir Interacts with 5 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[16]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[17]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[16]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[16]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[18]

Atazanavir Interacts with 30 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[19]
ATP-binding cassette sub-family C member 3 (ABCC3)	OTC3IJV4	MRP3_HUMAN	Decreases Expression	[14]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Decreases Expression	[14]
Phosphatidylinositol 3-kinase C2 domain-containing subunit gamma (PIK3C2G)	OTW3LY1C	P3C2G_HUMAN	Decreases Expression	[14]
Aflatoxin B1 aldehyde reductase member 3 (AKR7A3)	OTW3GO4Y	ARK73_HUMAN	Decreases Expression	[14]
Ubiquitin-like modifier-activating enzyme ATG7 (ATG7)	OTVT4YA1	ATG7_HUMAN	Increases Expression	[14]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[20]
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Increases Expression	[14]
Plasminogen activator inhibitor 1 (SERPINE1)	OTT0MPQ3	PAI1_HUMAN	Increases Expression	[14]
C-C motif chemokine 3 (CCL3)	OTW2H3ND	CCL3_HUMAN	Increases Expression	[21]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Expression	[21]
Glutathione peroxidase 2 (GPX2)	OTXI2NTI	GPX2_HUMAN	Decreases Expression	[14]
Cyclic AMP-dependent transcription factor ATF-4 (ATF4)	OTRFV19J	ATF4_HUMAN	Increases Expression	[14]
Cyclic AMP-dependent transcription factor ATF-6 alpha (ATF6)	OTAFHAVI	ATF6A_HUMAN	Increases Expression	[14]
Phosphatidylinositol 3-kinase regulatory subunit alpha (PIK3R1)	OT5BZ1J9	P85A_HUMAN	Decreases Expression	[14]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[14]
Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6)	OTK13JKC	MP2K6_HUMAN	Decreases Expression	[14]
Flavin-containing monooxygenase 1 (FMO1)	OTTHSQKP	FMO1_HUMAN	Decreases Expression	[14]
Peptidyl-prolyl cis-trans isomerase FKBP5 (FKBP5)	OT404F9K	FKBP5_HUMAN	Decreases Expression	[14]
Nuclear receptor subfamily 1 group I member 3 (NR1I3)	OTS3SGH7	NR1I3_HUMAN	Decreases Expression	[14]
DnaJ homolog subfamily C member 10 (DNAJC10)	OTD2EG0R	DJC10_HUMAN	Increases Expression	[14]
Mixed lineage kinase domain-like protein (MLKL)	OTDSLC81	MLKL_HUMAN	Increases Expression	[14]
DnaJ homolog subfamily C member 9 (DNAJC9)	OTDBQBNZ	DNJC9_HUMAN	Increases Expression	[14]
Bile acid receptor (NR1H4)	OTWZLPTB	NR1H4_HUMAN	Decreases Expression	[14]
Microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B)	OTUYHB84	MLP3B_HUMAN	Increases Expression	[14]
Ubiquitin carboxyl-terminal hydrolase CYLD (CYLD)	OT37FKH0	CYLD_HUMAN	Increases Expression	[14]
Transcription factor MafF (MAFF)	OT9B7MX0	MAFF_HUMAN	Increases Expression	[14]
Endophilin-B1 (SH3GLB1)	OTAZ5OP8	SHLB1_HUMAN	Increases Expression	[14]
Solute carrier organic anion transporter family member 1B1 (SLCO1B1)	OTNEN8QK	SO1B1_HUMAN	Decreases Expression	[14]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Transport	[22]

References

• [1] ClinicalTrials.gov (NCT01384734) HIV Attachment Inhibitor to Treat Human Immunodeficiency Virus 1 (HIV-1) Infections
• [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] Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
• [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] Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for UGT1A1 and Atazanavir Prescribing. Clin Pharmacol Ther. 2016 Apr;99(4):363-9. doi: 10.1002/cpt.269. Epub 2015 Nov 9.
• [14] Robustness testing and optimization of an adverse outcome pathway on cholestatic liver injury. Arch Toxicol. 2020 Apr;94(4):1151-1172. doi: 10.1007/s00204-020-02691-9. Epub 2020 Mar 10.
• [15] Hollow-fiber unit evaluation of a new human immunodeficiency virus type 1 protease inhibitor, BMS-232632, for determination of the linked pharmacod... J Infect Dis. 2001 Apr 1;183(7):1126-9.
• [16] Atazanavir: effects on P-glycoprotein transport and CYP3A metabolism in vitro. Drug Metab Dispos. 2005 Jun;33(6):764-70.
• [17] In vitro inhibition of UDP glucuronosyltransferases by atazanavir and other HIV protease inhibitors and the relationship of this property to in vivo bilirubin glucuronidation. Drug Metab Dispos. 2005 Nov;33(11):1729-39.
• [18] Atazanavir for the treatment of human immunodeficiency virus infection. Pharmacotherapy. 2004 Dec;24(12):1732-47.
• [19] Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013 Dec;136(2):328-43.
• [20] Binding of anti-HIV drugs to human serum albumin. IUBMB Life. 2004 Oct;56(10):609-14. doi: 10.1080/15216540400016286.
• [21] Some HIV antiretrovirals increase oxidative stress and alter chemokine, cytokine or adiponectin production in human adipocytes and macrophages. Antivir Ther. 2007;12(4):489-500.
• [22] Interactions of protease inhibitors atazanavir and ritonavir with ABCB1, ABCG2, and ABCC2 transporters: Effect on transplacental disposition in rats. Reprod Toxicol. 2018 Aug;79:57-65. doi: 10.1016/j.reprotox.2018.05.008. Epub 2018 May 30.