Details of the Drug Combination

General Information of Drug Combination (ID: DCB15R3)

• Drug Combination Name: Nitrofurantoin + Cephalexin
• Indication: Bacteriuria (Asymptomatic) in Pregnancy; Status: Phase 1 [1]
• Component Drugs:
  Nitrofurantoin (DM7PQIK): Small molecular drug
  Cephalexin (DMD5JU8): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Nitrofurantoin

Disease Entry	ICD 11	Status	REF
Urinary tract infection	GC08	Approved	[2]

Nitrofurantoin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bacterial Deoxyribonucleic acid (Bact DNA)	TTS1W4A	NOUNIPROTAC	Breaker	[5]

Nitrofurantoin Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[6]

Nitrofurantoin Interacts with 10 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
NADPH-cytochrome P450 reductase (CPR)	DE3N2FM	NCPR_HUMAN	Metabolism	[7]
Nitroreductase (NTR)	DEAVXGM	A0A412R9E4_9FIRM	Metabolism	[8]
NADPH-dependent oxidoreductase (nfrA)	DE82GV7	NRFA_STAA8	Metabolism	[9]
NADPH-dependent nitroreductase (nfrA1)	DE21PLI	NFRA1_BACSU	Metabolism	[10]
Nitroreductase (NTR)	DE7XBKW	A0A174SJF2_9CLOT	Metabolism	[8]
Nitroreductase (NTR)	DEP7ECA	B1R7B9_CLOPF	Metabolism	[8]
Nitroreductase (NTR)	DEH3ABM	A0A351QTB1_CLOSP	Metabolism	[8]
Nitroreductase (NTR)	DE3U2Y6	A0A377KR04_ENTCA	Metabolism	[11]
Nitroreductase (NTR)	DEUW4J0	A0A376H6M5_ENTGA	Metabolism	[11]
Nitroreductase (NTR)	DE5LYXF	A0A2X3BKF5_CLOSG	Metabolism	[12]

Nitrofurantoin Interacts with 7 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Increases Transport	[13]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[14]
Transmembrane protease serine 2 (TMPRSS2)	OTN44YQ5	TMPS2_HUMAN	Increases Expression	[15]
Phosphatidylcholine translocator ABCB4 (ABCB4)	OTE6PY83	MDR3_HUMAN	Decreases Activity	[16]
Glutamate--cysteine ligase catalytic subunit (GCLC)	OTESDI4D	GSH1_HUMAN	Increases Expression	[17]
Heat shock factor protein 1 (HSF1)	OTYNJ4KP	HSF1_HUMAN	Increases Activity	[18]
NAD(P)H dehydrogenase 1 (NQO1)	OTZGGIVK	NQO1_HUMAN	Increases Response To Substance	[19]

Indication(s) of Cephalexin

Disease Entry	ICD 11	Status	REF
Acute otitis media	AB00	Approved	[3]
Bacterial infection	1A00-1C4Z	Approved	[4]
Prostatitis	N.A.	Approved	[3]
Staphylococcus aureus infection	N.A.	Approved	[3]

Cephalexin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bacterial Penicillin binding protein (Bact PBP)	TTJP4SM	NOUNIPROTAC	Binder	[20]

Cephalexin Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug and toxin extrusion protein 1 (SLC47A1)	DTZGT0P	S47A1_HUMAN	Substrate	[21]
Peptide transporter 1 (SLC15A1)	DT9G7XN	S15A1_HUMAN	Substrate	[22]
Peptide transporter 2 (SLC15A2)	DT8QKNP	S15A2_HUMAN	Substrate	[23]

Cephalexin Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[24]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[25]
N-acylhomoserine lactone acylase (lacA)	DEIU0XN	A0A0A1VBK6_9BURK	Metabolism	[26]

Cephalexin Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
HLA class II histocompatibility antigen, DP alpha 1 chain (HLA-DPA1)	OT7OG7Y2	DPA1_HUMAN	Affects Expression	[27]

References

• [1] ClinicalTrials.gov (NCT02911662) Treatment of Asymptomatic Bacteriuria in Pregnancy
• [2] FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 009175.
• [3] Cephalexin FDA Label
• [4] 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: 4832).
• [5] On the nature of the adaptive response induced by mitomycin C in Vibrio cholerae OGAWA 154 cells. Biochem Biophys Res Commun. 1996 Mar 27;220(3):509-14.
• [6] The breast cancer resistance protein (BCRP/ABCG2) affects pharmacokinetics, hepatobiliary excretion, and milk secretion of the antibiotic nitrofurantoin. Mol Pharmacol. 2005 May;67(5):1758-64.
• [7] Role of cytochrome P450 reductase in nitrofurantoin-induced redox cycling and cytotoxicity. Free Radic Biol Med. 2008 Mar 15;44(6):1169-79.
• [8] Isolation of nitrofurantoin-resistant mutants of nitroreductase-producing Clostridium sp. strains from the human intestinal tract. Antimicrob Agents Chemother. 1998 May;42(5):1121-6.
• [9] Reduction of polynitroaromatic compounds: the bacterial nitroreductases. FEMS Microbiol Rev. 2008 May;32(3):474-500.
• [10] Conversion of NfsA, the major Escherichia coli nitroreductase, to a flavin reductase with an activity similar to that of Frp, a flavin reductase in Vibrio harveyi, by a single amino acid substitution. J Bacteriol. 1998 Jan;180(2):422-5.
• [11] 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.
• [12] Biotransformation of 1-nitropyrene in intestinal anaerobic bacteria. Microbiol Immunol. 1982;26(11):993-1005.
• [13] Effects of the flavonoid chrysin on nitrofurantoin pharmacokinetics in rats: potential involvement of ABCG2. Drug Metab Dispos. 2007 Feb;35(2):268-74.
• [14] Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013 Dec;136(2):328-43.
• [15] Effect of common medications on the expression of SARS-CoV-2 entry receptors in liver tissue. Arch Toxicol. 2020 Dec;94(12):4037-4041. doi: 10.1007/s00204-020-02869-1. Epub 2020 Aug 17.
• [16] Evaluating the Role of Multidrug Resistance Protein 3 (MDR3) Inhibition in Predicting Drug-Induced Liver Injury Using 125 Pharmaceuticals. Chem Res Toxicol. 2017 May 15;30(5):1219-1229. doi: 10.1021/acs.chemrestox.7b00048. Epub 2017 May 4.
• [17] Stimulation of de novo glutathione synthesis by nitrofurantoin for enhanced resilience of hepatocytes. Cell Biol Toxicol. 2022 Oct;38(5):847-864. doi: 10.1007/s10565-021-09610-3. Epub 2021 May 22.
• [18] A Gene Expression Biomarker Predicts Heat Shock Factor 1 Activation in a Gene Expression Compendium. Chem Res Toxicol. 2021 Jul 19;34(7):1721-1737. doi: 10.1021/acs.chemrestox.0c00510. Epub 2021 Jun 25.
• [19] Roles of DT diaphorase in the genotoxicity of nitroaromatic compounds in human and fish cell lines. J Toxicol Environ Health. 1997 Oct 10;52(2):137-48. doi: 10.1080/00984109708984057.
• [20] Relationship between penicillin-binding protein patterns and beta-lactamases in clinical isolates of Bacteroides fragilis with different susceptibility to beta-lactam antibiotics. J Med Microbiol. 2004 Mar;53(Pt 3):213-21.
• [21] Reduced renal clearance of a zwitterionic substrate cephalexin in MATE1-deficient mice. J Pharmacol Exp Ther. 2010 Aug;334(2):651-6.
• [22] Direct evidence for efficient transport and minimal metabolism of L-cephalexin by oligopeptide transporter 1 in budded baculovirus fraction. Biol Pharm Bull. 2009 Aug;32(8):1459-61.
• [23] Transport characteristics of a novel peptide transporter 1 substrate, antihypotensive drug midodrine, and its amino acid derivatives. J Pharmacol Exp Ther. 2006 Jul;318(1):455-60.
• [24] Transport and metabolic characterization of Caco-2 cells expressing CYP3A4 and CYP3A4 plus oxidoreductase. Pharm Res. 1999 Sep;16(9):1352-9.
• [25] Population pharmacokinetic analysis of mirtazapine. Eur J Clin Pharmacol. 2004 Sep;60(7):473-80.
• [26] A novel quorum-quenching N-acylhomoserine lactone acylase from Acidovorax sp. strain MR-S7 mediates antibiotic resistance. Appl Environ Microbiol. 2017 Jun 16;83(13). pii: e00080-17.
• [27] 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.