Details of the Drug Combination

General Information of Drug Combination (ID: DCJ7WVH)

• Drug Combination Name: Doxycycline + Metronidazole
• Indication: Papulopustular Rosacea; Status: Phase 1 [1]
• Component Drugs:
  Doxycycline (DM7ICNU): Small molecular drug
  Metronidazole (DMTIVEN): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Doxycycline

Disease Entry	ICD 11	Status	REF
Acne vulgaris	ED80	Approved	[2]
Actinomycosis	N.A.	Approved	[2]
Acute gonococcal cervicitis	N.A.	Approved	[2]
Acute gonococcal epididymo-orchitis	N.A.	Approved	[2]
Advanced gum disease	DA0D	Approved	[3]
Anthrax	1B97	Approved	[2]
Bartonellosis	N.A.	Approved	[2]
Boutonneuse fever	N.A.	Approved	[2]
Brill-Zinsser disease	N.A.	Approved	[2]
Bronchitis	CA20	Approved	[2]
Brucellosis	N.A.	Approved	[2]
Chancroid	N.A.	Approved	[2]
Chlamydiaceae infections	N.A.	Approved	[2]
Chronic periodontitis	DA0C.Y	Approved	[3]
Colorectal carcinoma	N.A.	Approved	[2]
Cutaneous anthrax	N.A.	Approved	[2]
Endemic typhus	N.A.	Approved	[2]
Epidemic louse-borne typhus	N.A.	Approved	[2]
Gastrointestinal anthrax	N.A.	Approved	[2]
Inhalational anthrax	N.A.	Approved	[2]
Listeriosis	N.A.	Approved	[2]
Lymphogranuloma venereum	N.A.	Approved	[2]
Mycoplasma pneumoniae pneumonia	N.A.	Approved	[2]
Ornithosis	N.A.	Approved	[2]
Q fever	N.A.	Approved	[2]
Relapsing fever	N.A.	Approved	[2]
Rickettsialpox	N.A.	Approved	[2]
Rickettsiosis	N.A.	Approved	[2]
Rocky mountain spotted fever	N.A.	Approved	[2]
Syphilis	N.A.	Approved	[2]
Trachoma	N.A.	Approved	[2]
Tularemia	1B94	Approved	[2]
Typhus	N.A.	Approved	[2]
Yaws	N.A.	Approved	[2]
Diabetic foot ulcer	BD54	Phase 2	[4]
Sinusitis	CA0A.Z	Investigative	[2]
Vibrio cholerae infection	1A00	Investigative	[2]

Doxycycline Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bacterial 30S ribosomal RNA (Bact 30S rRNA)	TTOVFH2	NOUNIPROTAC	Modulator	[10]

Doxycycline Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[11]

Doxycycline Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[12]

Doxycycline Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Expression	[13]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Increases Expression	[9]
Aryl hydrocarbon receptor (AHR)	OTFE4EYE	AHR_HUMAN	Increases Expression	[9]
HLA class I histocompatibility antigen, B alpha chain (HLA-B)	OTNXFWY2	HLAB_HUMAN	Affects Expression	[14]
72 kDa type IV collagenase (MMP2)	OT5NIWA2	MMP2_HUMAN	Decreases Activity	[15]
Stromelysin-1 (MMP3)	OTGBI74Z	MMP3_HUMAN	Decreases Activity	[15]
Neutrophil collagenase (MMP8)	OTZXH19L	MMP8_HUMAN	Decreases Activity	[15]
Collagenase 3 (MMP13)	OTY8BZIE	MMP13_HUMAN	Increases Expression	[16]
TAR DNA-binding protein 43 (TARDBP)	OTVOSFWW	TADBP_HUMAN	Decreases Expression	[17]

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	[18]

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	[19]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[20]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[21]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[21]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[21]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[22]
Nitroreductase (NTR)	DE8R7QY	A0A482G3K9_GIAIN	Metabolism	[23]
Nitroreductase (NTR)	DE2VSMT	A2DZ34_TRIVA	Metabolism	[23]
Nitroreductase (NTR)	DEQGIMN	A4K8Z3_ENTHI	Metabolism	[23]
Nitroreductase (NTR)	DEP7ECA	B1R7B9_CLOPF	Metabolism	[24]
Nitroreductase (NTR)	DEAN5EW	NFSB_ENTCL	Metabolism	[25]
Nitroreductase (NTR)	DE3U2Y6	A0A377KR04_ENTCA	Metabolism	[26]
Nitroreductase (NTR)	DEUW4J0	A0A376H6M5_ENTGA	Metabolism	[26]
Nitroreductase (NTR)	DELAPDY	A0A1C0X0J8_BACFG	Metabolism	[27]

Metronidazole Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Proepiregulin (EREG)	OTRM4NQY	EREG_HUMAN	Increases Expression	[28]
HLA class II histocompatibility antigen, DRB1 beta chain (HLA-DRB1)	OTRGGIFP	DRB1_HUMAN	Affects Expression	[14]
HLA class II histocompatibility antigen, DQ beta 1 chain (HLA-DQB1)	OTVVI3UI	DQB1_HUMAN	Affects Expression	[14]
Interleukin-24 (IL24)	OT4VUWH1	IL24_HUMAN	Increases Expression	[28]

References

• [1] ClinicalTrials.gov (NCT00855595) Efficacy of Topical Azelaic Acid 15% Gel Plus Anti-inflammatory Dose Doxycycline or Metronidazole Gel 1% Plus Anti-inflammatory Dose Doxycycline in Moderate Papulopustular Rosacea
• [2] Doxycycline 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: 6464).
• [4] ClinicalTrials.gov (NCT00764361) Safety Study of Topical Doxycycline Gel for Adult Diabetic Lower Extremity Ulcers. U.S. National Institutes of Health.
• [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] Aryl hydrocarbon receptor protects lung adenocarcinoma cells against cigarette sidestream smoke particulates-induced oxidative stress. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):293-301.
• [10] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [11] 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.
• [12] A further interaction study of quinine with clinically important drugs by human liver microsomes: determinations of inhibition constant (Ki) and type of inhibition. Eur J Drug Metab Pharmacokinet. 1999 Jul-Sep;24(3):272-8.
• [13] Functional and histochemical analysis of MDR3 P-glycoprotein in a tetracycline-controlled gene expression system. Eur J Med Res. 2000 Dec 29;5(12):517-22.
• [14] 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.
• [15] Synthesis and in vitro evaluation of targeted tetracycline derivatives: effects on inhibition of matrix metalloproteinases. Bioorg Med Chem. 2007 Mar 15;15(6):2368-74. doi: 10.1016/j.bmc.2007.01.026. Epub 2007 Jan 19.
• [16] Chloramphenicol causes mitochondrial stress, decreases ATP biosynthesis, induces matrix metalloproteinase-13 expression, and solid-tumor cell invasion. Toxicol Sci. 2010 Jul;116(1):140-50. doi: 10.1093/toxsci/kfq085. Epub 2010 Mar 25.
• [17] A high-content screen identifies novel compounds that inhibit stress-induced TDP-43 cellular aggregation and associated cytotoxicity. J Biomol Screen. 2014 Jan;19(1):44-56. doi: 10.1177/1087057113501553. Epub 2013 Sep 9.
• [18] DNA breakage due to metronidazole treatment. Mutat Res. 2001 Jul 1;478(1-2):153-8.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [23] Giardia, Entamoeba, and Trichomonas enzymes activate metronidazole (nitroreductases) and inactivate metronidazole (nitroimidazole reductases). Antimicrob Agents Chemother. 2009 Feb;53(2):458-64.
• [24] Acetamide--a metabolite of metronidazole formed by the intestinal flora. Biochem Pharmacol. 1979 Dec 15;28(24):3611-5.
• [25] Overexpression, isotopic labeling, and spectral characterization of Enterobacter cloacae nitroreductase. Protein Expr Purif. 1998 Jun;13(1):53-60.
• [26] 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.
• [27] 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
• [28] 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.