Details of the Drug Combination

General Information of Drug Combination (ID: DCE4W6M)

• Drug Combination Name: Erythromycin + Voriconazole
• Indication: B-Cell Chronic Lymphocytic Leukemia; Status: Phase 1 [1]
• Component Drugs:
  Erythromycin (DM4K7GQ): Small molecular drug
  Voriconazole (DMAOL2S): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Erythromycin

Disease Entry	ICD 11	Status	REF
Acne vulgaris	ED80	Approved	[2]
Acute gonococcal cervicitis	N.A.	Approved	[2]
Acute otitis media	AB00	Approved	[2]
Bacteremia	1A73	Approved	[2]
Bacterial infection	1A00-1C4Z	Approved	[3]
Cholangitis	N.A.	Approved	[2]
Gastroparesis	DA41.00	Approved	[2]
Hepatic coma	N.A.	Approved	[2]
Inclusion conjunctivitis	N.A.	Approved	[2]
Legionnaires' disease	N.A.	Approved	[2]
Listeriosis	N.A.	Approved	[2]
Mycoplasma pneumoniae pneumonia	N.A.	Approved	[2]
Preterm premature rupture of the membranes	N.A.	Approved	[2]
Staphylococcus aureus infection	N.A.	Approved	[2]
Streptococcal pneumonia	N.A.	Approved	[2]
Syphilis	N.A.	Approved	[2]
Urinary tract infection	GC08	Approved	[2]
Erythema	ME64.0	Investigative	[2]
Pneumonia caused by chlamydia	N.A.	Investigative	[2]

Erythromycin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bacterial 50S ribosomal RNA (Bact 50S rRNA)	TTUWYEA	NOUNIPROTAC	Binder	[8]

Erythromycin Interacts with 5 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[9]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[10]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[11]
Organic anion transporter 2 (SLC22A7)	DT0OC1Q	S22A7_HUMAN	Substrate	[12]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[13]

Erythromycin Interacts with 8 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[14]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[15]
Cytochrome P450 1A1 (CYP1A1)	DE6OQ3W	CP1A1_HUMAN	Metabolism	[16]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[17]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[18]
Cytochrome P450 1B1 (CYP1B1)	DE9QHP6	CP1B1_HUMAN	Metabolism	[16]
Docosahexaenoic acid omega-hydroxylase (CYP4F11)	DEIZLTN	CP4FB_HUMAN	Metabolism	[19]
Beta-glucuronidase (uidA)	DE7IQ34	A0A2A5L2J1_LACRH	Metabolism	[20]

Erythromycin Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Nuclear protein 1 (NUPR1)	OT4FU8C0	NUPR1_HUMAN	Decreases Expression	[6]
Inhibin beta E chain (INHBE)	OTOI2NYG	INHBE_HUMAN	Increases Expression	[6]
Acid ceramidase (ASAH1)	OT1DNGXL	ASAH1_HUMAN	Increases Expression	[6]
Fibronectin type III domain-containing protein 4 (FNDC4)	OTOQK0WK	FNDC4_HUMAN	Decreases Expression	[6]
Protein DEPP1 (DEPP1)	OTB36PHJ	DEPP1_HUMAN	Increases Expression	[6]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[21]
Protein c-Fos (FOS)	OTJBUVWS	FOS_HUMAN	Increases Expression	[22]
HLA class I histocompatibility antigen, alpha chain G (HLA-G)	OTMLK1KN	HLAG_HUMAN	Affects Expression	[23]
Misshapen-like kinase 1 (MINK1)	OTKB0RA8	MINK1_HUMAN	Increases ADR	[24]

Indication(s) of Voriconazole

Disease Entry	ICD 11	Status	REF
Aspergillosis	1F20	Approved	[4]
Candidiasis	1F23	Approved	[4]
Fusariosis	N.A.	Approved	[4]
Invasive aspergillosis	1F20.0	Approved	[5]
Invasive candidiasis	1F23	Approved	[4]
Neuroaspergillosis	N.A.	Approved	[4]
Candidemia	1F23.3Y	Investigative	[4]
Esophageal candidiasis	N.A.	Investigative	[4]

Voriconazole Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Candida Cytochrome P450 51 (Candi ERG11)	TTTSOUD	CP51_CANAL	Modulator	[25]

Voriconazole Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[26]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[27]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[27]
Prostaglandin G/H synthase 1 (COX-1)	DE073H6	PGH1_HUMAN	Metabolism	[28]

Voriconazole Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Decreases Activity	[29]

References

• [1] ClinicalTrials.gov (NCT02381080) Interaction Study of Ibrutinib and Cytochrome P450 (CYP) 3A Inhibitors in Participants With B-cell Malignancy
• [2] Erythromycin 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: 1456).
• [4] Voriconazole FDA Label
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• [14] Effect of the CYP3A4 inhibitor erythromycin on the pharmacokinetics of lignocaine and its pharmacologically active metabolites in subjects with normal and impaired liver function. Br J Clin Pharmacol. 2003 Jan;55(1):86-93.
• [15] Comparative studies of in vitro inhibition of cytochrome P450 3A4-dependent testosterone 6beta-hydroxylation by roxithromycin and its metabolites, troleandomycin, and erythromycin. Drug Metab Dispos. 1998 Nov;26(11):1053-7.
• [16] Cytochromes P450 in crustacea. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol. 1998 Nov;121(1-3):157-72.
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• [18] Helices F-G are important for the substrate specificities of CYP3A7. Drug Metab Dispos. 2007 Mar;35(3):484-92.
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• [22] Liver toxicity of macrolide antibiotics in zebrafish. Toxicology. 2020 Aug;441:152501. doi: 10.1016/j.tox.2020.152501. Epub 2020 May 23.
• [23] Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
• [24] 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.
• [25] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [26] Roles of CYP3A4 and CYP2C19 in methyl hydroxylated and N-oxidized metabolite formation from voriconazole, a new anti-fungal agent, in human liver microsomes. Biochem Pharmacol. 2007 Jun 15;73(12):2020-6.
• [27] Effect of voriconazole on the pharmacokinetics of diclofenac. Fundam Clin Pharmacol. 2007 Dec;21(6):651-6.
• [28] 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.
• [29] The novel azole R126638 is a selective inhibitor of ergosterol synthesis in Candida albicans, Trichophyton spp., and Microsporum canis. Antimicrob Agents Chemother. 2004 Sep;48(9):3272-8.