Details of the Drug Combination

General Information of Drug Combination (ID: DC9K90S)

• Drug Combination Name: Clarithromycin + Metronidazole
• Indication: Peptic Ulcer; Status: Phase 4 [1]
• Component Drugs:
  Clarithromycin (DM4M1SG): Small molecular drug
  Metronidazole (DMTIVEN): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Clarithromycin

Disease Entry	ICD 11	Status	REF
Acute maxillary sinusitis	N.A.	Approved	[2]
Acute otitis media	AB00	Approved	[2]
Bacterial infection	1A00-1C4Z	Approved	[3]
Mycoplasma pneumoniae pneumonia	N.A.	Approved	[2]
Staphylococcus aureus infection	N.A.	Approved	[2]
Streptococcal pneumonia	N.A.	Approved	[2]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[4]
Pneumonia caused by chlamydia	N.A.	Investigative	[2]

Clarithromycin 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	[9]

Clarithromycin Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[10]

Clarithromycin Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[11]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[12]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[13]

Clarithromycin Interacts with 15 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Expression	[14]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[15]
Phytanoyl-CoA dioxygenase, peroxisomal (PHYH)	OTUG4BWA	PAHX_HUMAN	Decreases Expression	[16]
Lanosterol synthase (LSS)	OT9W2SFH	LSS_HUMAN	Decreases Expression	[16]
Inhibin beta E chain (INHBE)	OTOI2NYG	INHBE_HUMAN	Increases Expression	[16]
Acid ceramidase (ASAH1)	OT1DNGXL	ASAH1_HUMAN	Increases Expression	[16]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[17]
Cytochrome c oxidase subunit 2 (COX2)	OTTMVBJJ	COX2_HUMAN	Decreases Expression	[18]
Protein c-Fos (FOS)	OTJBUVWS	FOS_HUMAN	Increases Expression	[19]
Interleukin-4 (IL4)	OTOXBWAU	IL4_HUMAN	Decreases Expression	[20]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[21]
Integrin beta-4 (ITGB4)	OT28UK84	ITB4_HUMAN	Decreases Expression	[22]
Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1)	OT8SPJNX	KCNQ1_HUMAN	Increases ADR	[23]
Translation initiation factor IF-2, mitochondrial (MTIF2)	OTAIOZ0J	IF2M_HUMAN	Decreases Response To Substance	[18]
Misshapen-like kinase 1 (MINK1)	OTKB0RA8	MINK1_HUMAN	Increases ADR	[23]

Indication(s) of Metronidazole

Disease Entry	ICD 11	Status	REF
Abscess	N.A.	Approved	[5]
Amoebiasis	1A36	Approved	[6]
Anaerobic bacteria infectious disease	N.A.	Approved	[5]
Bacteremia	1A73	Approved	[5]
Bacterial vaginosis	MF3A	Approved	[5]
Bladder squamous cell carcinoma	N.A.	Approved	[5]
Endometritis	N.A.	Approved	[5]
Liver abscess (disease)	N.A.	Approved	[5]
Peritonitis	N.A.	Approved	[5]
Trichomoniasis	N.A.	Approved	[5]
Crohn disease	DD70	Phase 3	[7]
Perianal crohn disease	DD70.4	Phase 3	[8]
Giardiasis	N.A.	Investigative	[5]

Metronidazole Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bacterial Deoxyribonucleic acid (Bact DNA)	TTS1W4A	NOUNIPROTAC	Modulator	[24]

Metronidazole Interacts with 14 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[25]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[26]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[27]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[27]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[27]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[28]
Nitroreductase (NTR)	DE8R7QY	A0A482G3K9_GIAIN	Metabolism	[29]
Nitroreductase (NTR)	DE2VSMT	A2DZ34_TRIVA	Metabolism	[29]
Nitroreductase (NTR)	DEQGIMN	A4K8Z3_ENTHI	Metabolism	[29]
Nitroreductase (NTR)	DEP7ECA	B1R7B9_CLOPF	Metabolism	[30]
Nitroreductase (NTR)	DEAN5EW	NFSB_ENTCL	Metabolism	[31]
Nitroreductase (NTR)	DE3U2Y6	A0A377KR04_ENTCA	Metabolism	[32]
Nitroreductase (NTR)	DEUW4J0	A0A376H6M5_ENTGA	Metabolism	[32]
Nitroreductase (NTR)	DELAPDY	A0A1C0X0J8_BACFG	Metabolism	[33]

Metronidazole Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Proepiregulin (EREG)	OTRM4NQY	EREG_HUMAN	Increases Expression	[34]
HLA class II histocompatibility antigen, DRB1 beta chain (HLA-DRB1)	OTRGGIFP	DRB1_HUMAN	Affects Expression	[35]
HLA class II histocompatibility antigen, DQ beta 1 chain (HLA-DQB1)	OTVVI3UI	DQB1_HUMAN	Affects Expression	[35]
Interleukin-24 (IL24)	OT4VUWH1	IL24_HUMAN	Increases Expression	[34]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Helicobacter Pylori Infection	DCBVAFA	N. A.	Phase 4	[36]
Helicobacter Pylori Infection	DCEORIT	N. A.	Phase 4	[36]
Helicobacter Pylori Infection	DC7FL3I	N. A.	Phase 1	[37]

References

• [1] ClinicalTrials.gov (NCT02648659) The Pilot Study on Tailored Eradication Therapy According to Clarithromycin Resistance in H.Pylori Patients
• [2] Clarithromycin FDA Label
• [3] Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
• [4] Anti-inflammatory Clarithromycin for Improving COVID-19 Infection Early (ACHIEVE)
• [5] Metronidazole FDA Label
• [6] FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 018517.
• [7] ClinicalTrials.gov (NCT00509639) Evaluation of Topical 10% Metronidazole Ointment for the Treatment of Active Perianal Crohn's Disease. U.S. National Institutes of Health.
• [8] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [9] Structural basis for the interaction of antibiotics with the peptidyl transferase centre in eubacteria. Nature. 2001 Oct 25;413(6858):814-21.
• [10] Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016 Jan 1;370(1):153-64.
• [11] Pharmacokinetic variability of clarithromycin and differences in CYP3A4 activity in patients with cystic fibrosis. J Cyst Fibros. 2014 Mar;13(2):179-85.
• [12] Drug Interactions Flockhart Table
• [13] Influence of CYP2C19 polymorphism and Helicobacter pylori genotype determined from gastric tissue samples on response to triple therapy for H pylori infection. Clin Gastroenterol Hepatol. 2005 Jun;3(6):564-73.
• [14] Use of immortalized human hepatocytes to predict the magnitude of clinical drug-drug interactions caused by CYP3A4 induction. Drug Metab Dispos. 2006 Oct;34(10):1742-8.
• [15] Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model. Toxicol Sci. 2013 Dec;136(2):581-94. doi: 10.1093/toxsci/kft205. Epub 2013 Sep 19.
• [16] A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system. Toxicol Sci. 2005 Feb;83(2):282-92.
• [17] Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013 Dec;136(2):328-43.
• [18] A genome-wide analysis of targets of macrolide antibiotics in mammalian cells. J Biol Chem. 2020 Feb 14;295(7):2057-2067. doi: 10.1074/jbc.RA119.010770. Epub 2020 Jan 8.
• [19] Liver toxicity of macrolide antibiotics in zebrafish. Toxicology. 2020 Aug;441:152501. doi: 10.1016/j.tox.2020.152501. Epub 2020 May 23.
• [20] Differential effects of three antibiotics on T helper cell cytokine expression. J Antimicrob Chemother. 2005 Sep;56(3):502-6. doi: 10.1093/jac/dki251. Epub 2005 Jul 8.
• [21] T-cell involvement in drug-induced acute generalized exanthematous pustulosis. J Clin Invest. 2001 Jun;107(11):1433-41. doi: 10.1172/JCI12118.
• [22] Effects of eight antibacterial agents on cell survival and expression of epithelial-cell- or cell-adhesion-related genes in human gingival epithelial cells. J Periodontal Res. 2004 Feb;39(1):50-8. doi: 10.1111/j.1600-0765.2004.00704.x.
• [23] 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.
• [24] DNA breakage due to metronidazole treatment. Mutat Res. 2001 Jul 1;478(1-2):153-8.
• [25] Does metronidazole interact with CYP3A substrates by inhibiting their metabolism through this metabolic pathway? Or should other mechanisms be considered? Ann Pharmacother. 2007 Apr;41(4):653-8.
• [26] Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos. 2004 Nov;32(11):1201-8.
• [27] The role of human cytochrome P450 enzymes in the formation of 2-hydroxymetronidazole: CYP2A6 is the high affinity (low Km) catalyst. Drug Metab Dispos. 2013 Sep;41(9):1686-94.
• [28] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [29] Giardia, Entamoeba, and Trichomonas enzymes activate metronidazole (nitroreductases) and inactivate metronidazole (nitroimidazole reductases). Antimicrob Agents Chemother. 2009 Feb;53(2):458-64.
• [30] Acetamide--a metabolite of metronidazole formed by the intestinal flora. Biochem Pharmacol. 1979 Dec 15;28(24):3611-5.
• [31] Overexpression, isotopic labeling, and spectral characterization of Enterobacter cloacae nitroreductase. Protein Expr Purif. 1998 Jun;13(1):53-60.
• [32] Mechanism of metronidazole-resistance by isolates of nitroreductase-producing Enterococcus gallinarum and Enterococcus casseliflavus from the human intestinal tract. FEMS Microbiol Lett. 2003 Aug 29;225(2):195-200.
• [33] Isolation of metronidazole-resistant Bacteroides fragilis carrying the nimA nitroreductase gene from a patient in Washington State. J Clin Microbiol. 2004 Sep;42(9):4127-9. Case Reports
• [34] An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury. Arch Toxicol. 2021 Jan;95(1):149-168. doi: 10.1007/s00204-020-02882-4. Epub 2020 Aug 20.
• [35] 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.
• [36] ClinicalTrials.gov (NCT03130452) Helicobacter Pylori Eradication Study
• [37] ClinicalTrials.gov (NCT05926804) A "Screen and Treat" Helicobacter Pylori Eradication Trial in Adolescents in Three Regions of Chile