Details of the Drug Combination

General Information of Drug Combination (ID: DC50VO4)

• Drug Combination Name: Metronidazole + Lansoprazole
• Indication: Functional Dyspepsia; Status: Phase 4 [1]
• Component Drugs:
  Metronidazole (DMTIVEN): Small molecular drug
  Lansoprazole (DMXYLQ3): N.A.

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Metronidazole

Disease Entry	ICD 11	Status	REF
Abscess	N.A.	Approved	[2]
Amoebiasis	1A36	Approved	[3]
Anaerobic bacteria infectious disease	N.A.	Approved	[2]
Bacteremia	1A73	Approved	[2]
Bacterial vaginosis	MF3A	Approved	[2]
Bladder squamous cell carcinoma	N.A.	Approved	[2]
Endometritis	N.A.	Approved	[2]
Liver abscess (disease)	N.A.	Approved	[2]
Peritonitis	N.A.	Approved	[2]
Trichomoniasis	N.A.	Approved	[2]
Crohn disease	DD70	Phase 3	[4]
Perianal crohn disease	DD70.4	Phase 3	[5]
Giardiasis	N.A.	Investigative	[2]

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	[7]

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	[8]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[9]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[10]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[10]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[10]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[11]
Nitroreductase (NTR)	DE8R7QY	A0A482G3K9_GIAIN	Metabolism	[12]
Nitroreductase (NTR)	DE2VSMT	A2DZ34_TRIVA	Metabolism	[12]
Nitroreductase (NTR)	DEQGIMN	A4K8Z3_ENTHI	Metabolism	[12]
Nitroreductase (NTR)	DEP7ECA	B1R7B9_CLOPF	Metabolism	[13]
Nitroreductase (NTR)	DEAN5EW	NFSB_ENTCL	Metabolism	[14]
Nitroreductase (NTR)	DE3U2Y6	A0A377KR04_ENTCA	Metabolism	[15]
Nitroreductase (NTR)	DEUW4J0	A0A376H6M5_ENTGA	Metabolism	[15]
Nitroreductase (NTR)	DELAPDY	A0A1C0X0J8_BACFG	Metabolism	[16]

Metronidazole Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Proepiregulin (EREG)	OTRM4NQY	EREG_HUMAN	Increases Expression	[17]
HLA class II histocompatibility antigen, DQ beta 1 chain (HLA-DQB1)	OTVVI3UI	DQB1_HUMAN	Affects Expression	[18]

Indication(s) of Lansoprazole

Disease Entry	ICD 11	Status	REF
Gastric ulcer	DA60	Approved	[6]
Gastrinoma	2C10.1	Approved	[6]
Peptic ulcer	DA61	Approved	[6]

Lansoprazole Interacts with 5 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[19]
Cytochrome P450 2C18 (CYP2C18)	DEZMWRE	CP2CI_HUMAN	Metabolism	[20]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[21]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[22]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[23]

Lansoprazole Interacts with 6 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Affects Response To Substance	[24]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[25]
Phospholipid-transporting ATPase ABCA1 (ABCA1)	OT94G6BQ	ABCA1_HUMAN	Increases Expression	[26]
Pro-opiomelanocortin (POMC)	OTV41F7T	COLI_HUMAN	Increases Expression	[27]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Decreases Expression	[28]
Phosphoethanolamine/phosphocholine phosphatase (PHOSPHO1)	OT43A0JA	PHOP1_HUMAN	Decreases Activity	[29]

References

• [1] ClinicalTrials.gov (NCT01668927) Empirical Rescue Therapies of Helicobacter Pylori Infection
• [2] Metronidazole FDA Label
• [3] FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 018517.
• [4] ClinicalTrials.gov (NCT00509639) Evaluation of Topical 10% Metronidazole Ointment for the Treatment of Active Perianal Crohn's Disease. U.S. National Institutes of Health.
• [5] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [6] Lansoprazole FDA Label
• [7] DNA breakage due to metronidazole treatment. Mutat Res. 2001 Jul 1;478(1-2):153-8.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [12] Giardia, Entamoeba, and Trichomonas enzymes activate metronidazole (nitroreductases) and inactivate metronidazole (nitroimidazole reductases). Antimicrob Agents Chemother. 2009 Feb;53(2):458-64.
• [13] Acetamide--a metabolite of metronidazole formed by the intestinal flora. Biochem Pharmacol. 1979 Dec 15;28(24):3611-5.
• [14] Overexpression, isotopic labeling, and spectral characterization of Enterobacter cloacae nitroreductase. Protein Expr Purif. 1998 Jun;13(1):53-60.
• [15] 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.
• [16] 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
• [17] 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.
• [18] 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.
• [19] An evaluation of the cytochrome P450 induction potential of pantoprazole in primary human hepatocytes. Chem Biol Interact. 1998 Jul 3;114(1-2):1-13.
• [20] Oxidative metabolism of lansoprazole by human liver cytochromes P450. Mol Pharmacol. 1995 Feb;47(2):410-8.
• [21] Identification of the human P450 enzymes involved in lansoprazole metabolism. J Pharmacol Exp Ther. 1996 May;277(2):805-16.
• [22] 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.
• [23] Effects of clarithromycin on lansoprazole pharmacokinetics between CYP2C19 genotypes. Br J Clin Pharmacol. 2005 Mar;59(3):302-9.
• [24] Effect of MDR1 C3435T polymorphism on lansoprazole in healthy Japanese subjects. Eur J Clin Pharmacol. 2009 Jun;65(6):593-600. doi: 10.1007/s00228-009-0625-8. Epub 2009 Feb 24.
• [25] Screening of a chemical library reveals novel PXR-activating pharmacologic compounds. Toxicol Lett. 2015 Jan 5;232(1):193-202. doi: 10.1016/j.toxlet.2014.10.009. Epub 2014 Oct 16.
• [26] Proton pump inhibitor lansoprazole is a nuclear liver X receptor agonist. Biochem Pharmacol. 2010 May 1;79(9):1310-6. doi: 10.1016/j.bcp.2009.12.018. Epub 2010 Jan 8.
• [27] Comparison of the effects of proton pump inhibitors on human plasma adrenocorticotropic hormone and cortisol levels under the starved condition. Biomed Pharmacother. 2006 Apr;60(3):109-12. doi: 10.1016/j.biopha.2006.01.004. Epub 2006 Feb 21.
• [28] Enhanced expression of interleukin-8 and activation of nuclear factor kappa-B in endoscopy-negative gastroesophageal reflux disease. Am J Gastroenterol. 2004 Apr;99(4):589-97. doi: 10.1111/j.1572-0241.2004.04110.x.
• [29] Functional involvement of PHOSPHO1 in matrix vesicle-mediated skeletal mineralization. J Bone Miner Res. 2007 Apr;22(4):617-27. doi: 10.1359/jbmr.070108.