Details of the Drug Combination

General Information of Drug Combination (ID: DC0F8SH)

• Drug Combination Name: Lactulose + Metronidazole
• Indication: Hepatic Encephalopathy; Status: Phase 2 [1]
• Component Drugs:
  Lactulose (DMSAOWQ): Small molecular drug
  Metronidazole (DMTIVEN): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Lactulose

Disease Entry	ICD 11	Status	REF
Constipation	DD91.1	Approved	[2]
Hepatic encephalopathy	DB99.5	Approved	[3]
Ornithine transcarbamylase deficiency	5C50.AY	Approved	[3]

Lactulose Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Beta-galactosidase (bgaB)	DEIEY19	BGAL_CROS8	Metabolism	[8]
Beta-glucosidase (bglA)	DE235K6	Q3Y0M8_ENTFD	Metabolism	[8]
Glycosyl hydrolase (glyH)	DEPB9C2	A0A379KQ43_PSEPU	Metabolism	[8]

Indication(s) of Metronidazole

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

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	[9]

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	[10]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[11]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[12]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[12]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[12]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[13]
Nitroreductase (NTR)	DE8R7QY	A0A482G3K9_GIAIN	Metabolism	[14]
Nitroreductase (NTR)	DE2VSMT	A2DZ34_TRIVA	Metabolism	[14]
Nitroreductase (NTR)	DEQGIMN	A4K8Z3_ENTHI	Metabolism	[14]
Nitroreductase (NTR)	DEP7ECA	B1R7B9_CLOPF	Metabolism	[15]
Nitroreductase (NTR)	DEAN5EW	NFSB_ENTCL	Metabolism	[16]
Nitroreductase (NTR)	DE3U2Y6	A0A377KR04_ENTCA	Metabolism	[17]
Nitroreductase (NTR)	DEUW4J0	A0A376H6M5_ENTGA	Metabolism	[17]
Nitroreductase (NTR)	DELAPDY	A0A1C0X0J8_BACFG	Metabolism	[18]

Metronidazole Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Proepiregulin (EREG)	OTRM4NQY	EREG_HUMAN	Increases Expression	[19]
HLA class II histocompatibility antigen, DRB1 beta chain (HLA-DRB1)	OTRGGIFP	DRB1_HUMAN	Affects Expression	[20]
HLA class II histocompatibility antigen, DQ beta 1 chain (HLA-DQB1)	OTVVI3UI	DQB1_HUMAN	Affects Expression	[20]
Interleukin-24 (IL24)	OT4VUWH1	IL24_HUMAN	Increases Expression	[19]

References

• [1] ClinicalTrials.gov (NCT02334163) The Effects of Nitazoxanide in Hepatic Encephalopathy
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] Lactulose FDA Label
• [4] Metronidazole FDA Label
• [5] FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 018517.
• [6] ClinicalTrials.gov (NCT00509639) Evaluation of Topical 10% Metronidazole Ointment for the Treatment of Active Perianal Crohn's Disease. U.S. National Institutes of Health.
• [7] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [8] In vitro fermentation of lactulose by human gut bacteria. J Agric Food Chem. 2014 Nov 12;62(45):10970-7.
• [9] DNA breakage due to metronidazole treatment. Mutat Res. 2001 Jul 1;478(1-2):153-8.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [14] Giardia, Entamoeba, and Trichomonas enzymes activate metronidazole (nitroreductases) and inactivate metronidazole (nitroimidazole reductases). Antimicrob Agents Chemother. 2009 Feb;53(2):458-64.
• [15] Acetamide--a metabolite of metronidazole formed by the intestinal flora. Biochem Pharmacol. 1979 Dec 15;28(24):3611-5.
• [16] Overexpression, isotopic labeling, and spectral characterization of Enterobacter cloacae nitroreductase. Protein Expr Purif. 1998 Jun;13(1):53-60.
• [17] 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.
• [18] 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
• [19] 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.
• [20] 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.