Details of the Drug Combination

General Information of Drug Combination (ID: DCEBFDN)

• Drug Combination Name: Losartan + Pentoxifylline
• Indication: Diabetic Nephropathies; Status: Phase 4 [1]
• Component Drugs:
  Losartan (DM72JXH): Small molecular drug
  Pentoxifylline (DMU3DNC): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Losartan

Disease Entry	ICD 11	Status	REF
Diabetic kidney disease	GB61.Z	Approved	[2]
Hypertension	BA00-BA04	Approved	[3]
Prediabetes syndrome	N.A.	Approved	[2]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[4]

Losartan Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Angiotensin II receptor type-1 (AGTR1)	TT8DBY3	AGTR1_HUMAN	Antagonist	[7]
HUMAN type-1 angiotensin II receptor (AGTR1)	TTPKMXQ	AGTR1_HUMAN	Blocker	[8]

Losartan Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[9]
Peptide transporter 1 (SLC15A1)	DT9G7XN	S15A1_HUMAN	Substrate	[10]

Losartan Interacts with 8 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[11]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[12]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[11]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[13]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[14]
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[14]
UDP-glucuronosyltransferase 1A3 (UGT1A3)	DEF2WXN	UD13_HUMAN	Metabolism	[14]
UDP-glucuronosyltransferase 1A10 (UGT1A10)	DEL5N6Y	UD110_HUMAN	Metabolism	[14]

Losartan Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C9 (CYP2C9)	OTGLBN29	CP2C9_HUMAN	Increases ADR	[15]
Interleukin-1 alpha (IL1A)	OTPSGILV	IL1A_HUMAN	Increases ADR	[15]

Indication(s) of Pentoxifylline

Disease Entry	ICD 11	Status	REF
Alcoholic hepatitis	DB94.1	Approved	[5]
Intermittent claudication	BD40.00	Approved	[6]
Type-1 diabetes	5A10	Approved	[5]
Peripheral vascular disease	BD4Z	Investigative	[5]

Pentoxifylline Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Tumor necrosis factor (TNF)	TTF8CQI	TNFA_HUMAN	.	[16]

Pentoxifylline Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[17]

Pentoxifylline Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Metalloproteinase inhibitor 1 (TIMP1)	OTOXC51H	TIMP1_HUMAN	Increases ADR	[15]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Increases ADR	[15]
Thrombomodulin (THBD)	OT8VHLKY	TRBM_HUMAN	Increases ADR	[15]
Matrix metalloproteinase-14 (MMP14)	OT9C197Z	MMP14_HUMAN	Increases ADR	[15]
Perforin-1 (PRF1)	OTFVXD7H	PERF_HUMAN	Increases ADR	[15]
Granzyme B (GZMB)	OTPPVIRS	GRAB_HUMAN	Increases ADR	[15]
Interleukin-1 alpha (IL1A)	OTPSGILV	IL1A_HUMAN	Increases ADR	[15]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Increases ADR	[15]

References

• [1] ClinicalTrials.gov (NCT03006952) Add-on Pentoxifylline to Losartan Versus Increasing Dose of Losartan on NT-PRO BNP in Type 2 Diabetics With Nephropathy
• [2] Losartan 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: 590).
• [4] ClinicalTrials.gov (NCT04343001) Coronavirus Response - Active Support for Hospitalised Covid-19 Patients. U.S. National Institutes of Health.
• [5] Pentoxifylline FDA Label
• [6] 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: 7095).
• [7] Radioligand binding assays: application of [(125)I]angiotensin II receptor binding. Methods Mol Biol. 2009;552:131-41.
• [8] Controversies of renin-angiotensin system inhibition during the COVID-19 pandemic. Nat Rev Nephrol. 2020 Apr 3.
• [9] Active transport of the angiotensin-II antagonist losartan and its main metabolite EXP 3174 across MDCK-MDR1 and caco-2 cell monolayers. Br J Pharmacol. 2000 Mar;129(6):1235-43.
• [10] High-affinity interaction of sartans with H+/peptide transporters. Drug Metab Dispos. 2009 Jan;37(1):143-9.
• [11] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [12] The human UDP-glucuronosyltransferase UGT1A3 is highly selective towards N2 in the tetrazole ring of losartan, candesartan, and zolarsartan. Biochem Pharmacol. 2008 Sep 15;76(6):763-72.
• [13] Drug-drug interaction between losartan and paclitaxel in human liver microsomes with different CYP2C8 genotypes. Basic Clin Pharmacol Toxicol. 2015 Jun;116(6):493-8.
• [14] 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.
• [15] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [16] Targeted therapies in myelodysplastic syndromes: ASH 2003 review. Semin Hematol. 2004 Apr;41(2 Suppl 4):13-20.
• [17] Cytochrome P450 isozymes involved in lisofylline metabolism to pentoxifylline in human liver microsomes. Drug Metab Dispos. 1997 Dec;25(12):1354-8.