General Information of Drug Combination (ID: DC3UJLN)

Drug Combination Name
Ciprofloxacin XR Metronidazole
Indication
Disease Entry Status REF
Crohn's Disease Phase 1 [1]
Component Drugs Ciprofloxacin XR   DM2NLS9 Metronidazole   DMTIVEN
Small molecular drug Small molecular drug
2D MOL 2D MOL
3D MOL 3D MOL

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)
Indication(s) of Ciprofloxacin XR
Disease Entry ICD 11 Status REF
Acute gonococcal cervicitis N.A. Approved [2]
Acute maxillary sinusitis N.A. Approved [2]
Anthrax 1B97 Approved [2]
Bacillary dysentery 1A02 Approved [2]
Bacterial infection 1A00-1C4Z Approved [3]
Chancroid N.A. Approved [2]
Crohn disease DD70 Approved [2]
Cystitis GC00 Approved [2]
Fever MG26 Approved [2]
Gram-positive bacterial infection 1B74-1G40 Approved [4]
Inflammation 1A00-CA43.1 Approved [2]
Malignant otitis externa caused by Pseudomonas aeruginosa N.A. Approved [2]
Prostatitis N.A. Approved [5]
Staphylococcus aureus infection N.A. Approved [2]
Traveler's diarrhea ME05.1 Approved [2]
Cystic fibrosis CA25 Phase 2 [6]
Biliary cancer 2E92.7 Phase 1 [7]
Ciprofloxacin XR Interacts with 4 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Bacterial DNA gyrase (Bact gyrase) TTN6J5F GYRA_STAAU; GYRB_STAAU Modulator [12]
Bacterial Penicillin binding protein (Bact PBP) TTJP4SM NOUNIPROTAC Inhibitor [4]
Staphylococcus Topoisomerase IV (Stap-coc parC) TTIXTO3 PARC_STAAS Modulator [12]
Candida Thymidylate synthase (Candi TMP1) TTU6BFZ TYSY_CANAL Inhibitor [13]
------------------------------------------------------------------------------------
Ciprofloxacin XR Interacts with 4 DTP Molecule(s)
DTP Name DTP ID UniProt ID Mode of Action REF
Breast cancer resistance protein (ABCG2) DTI7UX6 ABCG2_HUMAN Substrate [14]
Multidrug resistance-associated protein 4 (ABCC4) DTCSGPB MRP4_HUMAN Substrate [15]
Organic anion transporter 3 (SLC22A8) DTVP67E S22A8_HUMAN Substrate [16]
Organic anion transporting polypeptide 1A2 (SLCO1A2) DTE2B1D SO1A2_HUMAN Substrate [17]
------------------------------------------------------------------------------------
Ciprofloxacin XR Interacts with 46 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 Expression [18]
Alanine aminotransferase 1 (GPT) OTOXOA0Q ALAT1_HUMAN Increases ADR [19]
Cytochrome P450 1A2 (CYP1A2) OTLLBX48 CP1A2_HUMAN Decreases Activity [20]
Cytochrome P450 3A4 (CYP3A4) OTQGYY83 CP3A4_HUMAN Decreases Activity [20]
Serum paraoxonase/arylesterase 1 (PON1) OTD0Z2XO PON1_HUMAN Decreases Activity [21]
Prominin-1 (PROM1) OTBHV8NX PROM1_HUMAN Increases Expression [18]
Zinc finger protein SNAI2 (SNAI2) OT7Y8EJ2 SNAI2_HUMAN Decreases Expression [18]
Zinc finger protein SNAI1 (SNAI1) OTDPYAMC SNAI1_HUMAN Decreases Expression [18]
Aldehyde dehydrogenase 1A1 (ALDH1A1) OTCUWZKB AL1A1_HUMAN Increases Expression [18]
CD44 antigen (CD44) OT9TTJ41 CD44_HUMAN Increases Expression [18]
Mitogen-activated protein kinase 3 (MAPK3) OTCYKGKO MK03_HUMAN Increases Phosphorylation [18]
Mitogen-activated protein kinase 1 (MAPK1) OTH85PI5 MK01_HUMAN Increases Phosphorylation [18]
RAC-alpha serine/threonine-protein kinase (AKT1) OT8H2YY7 AKT1_HUMAN Increases Phosphorylation [18]
Transcription factor SOX-2 (SOX2) OTFAWCAU SOX2_HUMAN Decreases Expression [18]
POU domain, class 5, transcription factor 1 (POU5F1) OTDHHN7O PO5F1_HUMAN Increases Expression [18]
Caveolin-1 (CAV1) OTEZUR1L CAV1_HUMAN Increases Expression [18]
Homeobox protein NANOG (NANOG) OTUEY1FM NANOG_HUMAN Increases Expression [18]
Transmembrane protease serine 2 (TMPRSS2) OTN44YQ5 TMPS2_HUMAN Decreases Expression [22]
Microphthalmia-associated transcription factor (MITF) OT6XJCZH MITF_HUMAN Decreases Expression [23]
Transforming growth factor beta-1 proprotein (TGFB1) OTV5XHVH TGFB1_HUMAN Increases Expression [24]
Interferon gamma (IFNG) OTXG9JM7 IFNG_HUMAN Decreases Expression [25]
HLA class II histocompatibility antigen, DRB1 beta chain (HLA-DRB1) OTRGGIFP DRB1_HUMAN Affects Expression [26]
Interstitial collagenase (MMP1) OTI4I2V1 MMP1_HUMAN Increases Expression [27]
Interleukin-4 (IL4) OTOXBWAU IL4_HUMAN Decreases Expression [25]
Stromelysin-1 (MMP3) OTGBI74Z MMP3_HUMAN Increases Expression [27]
Poly polymerase 1 (PARP1) OT310QSG PARP1_HUMAN Increases Cleavage [28]
Interleukin-8 (CXCL8) OTS7T5VH IL8_HUMAN Decreases Secretion [29]
Solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1) OTA675TJ GTR1_HUMAN Decreases Expression [30]
DNA topoisomerase 2-alpha (TOP2A) OT6LPS08 TOP2A_HUMAN Affects Binding [31]
HLA class I histocompatibility antigen, alpha chain E (HLA-E) OTX1CTFB HLAE_HUMAN Affects Expression [26]
G2/mitotic-specific cyclin-B1 (CCNB1) OT19S7E5 CCNB1_HUMAN Decreases Expression [28]
HLA class I histocompatibility antigen, alpha chain G (HLA-G) OTMLK1KN HLAG_HUMAN Affects Expression [26]
G1/S-specific cyclin-E1 (CCNE1) OTLD7UID CCNE1_HUMAN Decreases Expression [28]
Cyclin-dependent kinase 2 (CDK2) OTB5DYYZ CDK2_HUMAN Decreases Phosphorylation [28]
Cyclin-dependent kinase inhibitor 1 (CDKN1A) OTQWHCZE CDN1A_HUMAN Decreases Expression [28]
Caspase-3 (CASP3) OTIJRBE7 CASP3_HUMAN Increases Activity [32]
Collagenase 3 (MMP13) OTY8BZIE MMP13_HUMAN Decreases Expression [33]
Caspase-9 (CASP9) OTD4RFFG CASP9_HUMAN Increases Activity [34]
Apoptosis regulator BAX (BAX) OTAW0V4V BAX_HUMAN Increases Expression [28]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) OT2YYI1A MCL1_HUMAN Increases Expression [23]
Potassium voltage-gated channel subfamily H member 2 (KCNH2) OTZX881H KCNH2_HUMAN Affects Binding [35]
Caspase-8 (CASP8) OTA8TVI8 CASP8_HUMAN Increases Activity [34]
Glucose-6-phosphate 1-dehydrogenase (G6PD) OT300SMK G6PD_HUMAN Increases Response To Substance [36]
Aspartate aminotransferase, mitochondrial (GOT2) OT6XBWN0 AATM_HUMAN Increases ADR [19]
DNA gyrase subunit A (gyrA) OTFI7I9Z GYRA_AERSA Increases ADR [19]
Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) OTPGYWKC NOD2_HUMAN Decreases Response To Substance [37]
------------------------------------------------------------------------------------
⏷ Show the Full List of 46 DOT(s)
Indication(s) of Metronidazole
Disease Entry ICD 11 Status REF
Abscess N.A. Approved [8]
Amoebiasis 1A36 Approved [9]
Anaerobic bacteria infectious disease N.A. Approved [8]
Bacteremia 1A73 Approved [8]
Bacterial vaginosis MF3A Approved [8]
Bladder squamous cell carcinoma N.A. Approved [8]
Endometritis N.A. Approved [8]
Liver abscess (disease) N.A. Approved [8]
Peritonitis N.A. Approved [8]
Trichomoniasis N.A. Approved [8]
Crohn disease DD70 Phase 3 [10]
Perianal crohn disease DD70.4 Phase 3 [11]
Giardiasis N.A. Investigative [8]
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 [38]
------------------------------------------------------------------------------------
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 [39]
UDP-glucuronosyltransferase 1A1 (UGT1A1) DEYGVN4 UD11_HUMAN Metabolism [40]
Cytochrome P450 2A6 (CYP2A6) DEJVYAZ CP2A6_HUMAN Metabolism [41]
Cytochrome P450 3A5 (CYP3A5) DEIBDNY CP3A5_HUMAN Metabolism [41]
Cytochrome P450 3A7 (CYP3A7) DERD86B CP3A7_HUMAN Metabolism [41]
Cytochrome P450 2C9 (CYP2C9) DE5IED8 CP2C9_HUMAN Metabolism [42]
Nitroreductase (NTR) DE8R7QY A0A482G3K9_GIAIN Metabolism [43]
Nitroreductase (NTR) DE2VSMT A2DZ34_TRIVA Metabolism [43]
Nitroreductase (NTR) DEQGIMN A4K8Z3_ENTHI Metabolism [43]
Nitroreductase (NTR) DEP7ECA B1R7B9_CLOPF Metabolism [44]
Nitroreductase (NTR) DEAN5EW NFSB_ENTCL Metabolism [45]
Nitroreductase (NTR) DE3U2Y6 A0A377KR04_ENTCA Metabolism [46]
Nitroreductase (NTR) DEUW4J0 A0A376H6M5_ENTGA Metabolism [46]
Nitroreductase (NTR) DELAPDY A0A1C0X0J8_BACFG Metabolism [47]
------------------------------------------------------------------------------------
⏷ Show the Full List of 14 DME(s)
Metronidazole Interacts with 4 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Proepiregulin (EREG) OTRM4NQY EREG_HUMAN Increases Expression [48]
HLA class II histocompatibility antigen, DRB1 beta chain (HLA-DRB1) OTRGGIFP DRB1_HUMAN Affects Expression [26]
HLA class II histocompatibility antigen, DQ beta 1 chain (HLA-DQB1) OTVVI3UI DQB1_HUMAN Affects Expression [26]
Interleukin-24 (IL24) OT4VUWH1 IL24_HUMAN Increases Expression [48]
------------------------------------------------------------------------------------

References

1 ClinicalTrials.gov (NCT00257699) Study of Antibiotics in the Treatment of Colonic Crohn's Disease
2 A standard database for drug repositioning. Sci Data. 2017 Mar 14;4:170029.
3 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
4 Emerging drugs for bacterial urinary tract infections. Expert Opin Emerg Drugs. 2005 May;10(2):275-98.
5 Comparison of a 3-day with a 1-day regimen of an extended-release formulation of ciprofloxacin as antimicrobial prophylaxis for patients undergoing transrectal needle biopsy of the prostate. BJU Int. 2007 Jul;100(1):51-7.
6 Inhaled Ciprofloxacin for the Management of Infections in Non-Cystic Fibrosis Bronchiectasis (BE) Patients
7 Low folate conditions may enhance the interaction of trifluorothymidine with antifolates in colon cancer cells. Cancer Chemother Pharmacol. 2006 Jan;57(2):171-9.
8 Metronidazole FDA Label
9 FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 018517.
10 ClinicalTrials.gov (NCT00509639) Evaluation of Topical 10% Metronidazole Ointment for the Treatment of Active Perianal Crohn's Disease. U.S. National Institutes of Health.
11 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
12 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
13 Loss of folylpoly-gamma-glutamate synthetase activity is a dominant mechanism of resistance to polyglutamylation-dependent novel antifolates in multiple human leukemia sublines. Int J Cancer. 2003 Feb 20;103(5):587-99.
14 Fluoroquinolone efflux mediated by ABC transporters. J Pharm Sci. 2008 Sep;97(9):3483-93.
15 Identification of the efflux transporter of the fluoroquinolone antibiotic ciprofloxacin in murine macrophages: studies with ciprofloxacin-resistant cells. Antimicrob Agents Chemother. 2009 Jun;53(6):2410-6.
16 Organic anion transporter 3 (oat3/slc22a8) interacts with carboxyfluoroquinolones, and deletion increases systemic exposure to ciprofloxacin. Mol Pharmacol. 2008 Jul;74(1):122-31.
17 Fruit juice inhibition of uptake transport: a new type of food-drug interaction. Br J Clin Pharmacol. 2010 Nov;70(5):645-55.
18 Ciprofloxacin mediates cancer stem cell phenotypes in lung cancer cells through caveolin-1-dependent mechanism. Chem Biol Interact. 2016 Apr 25;250:1-11.
19 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.
20 Methadone, ciprofloxacin, and adverse drug reactions. Lancet. 2000 Dec 16;356(9247):2069-70.
21 Effects of some antibiotics on paraoxonase from human serum in vitro and from mouse serum and liver in vivo. Biol Pharm Bull. 2006 Aug;29(8):1559-63.
22 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.
23 The role of MITF and Mcl-1 proteins in the antiproliferative and proapoptotic effect of ciprofloxacin in amelanotic melanoma cells: In silico and in vitro study. Toxicol In Vitro. 2020 Aug;66:104884. doi: 10.1016/j.tiv.2020.104884. Epub 2020 May 8.
24 Ciprofloxacin decreases survival in HT-29 cells via the induction of TGF-beta1 secretion and enhances the anti-proliferative effect of 5-fluorouracil. Br J Pharmacol. 2009 Jun;157(3):362-70. doi: 10.1111/j.1476-5381.2009.00161.x. Epub 2009 Apr 9.
25 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.
26 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.
27 Ciprofloxacin enhances the stimulation of matrix metalloproteinase 3 expression by interleukin-1beta in human tendon-derived cells. A potential mechanism of fluoroquinolone-induced tendinopathy. Arthritis Rheum. 2002 Nov;46(11):3034-40. doi: 10.1002/art.10617.
28 Ciprofloxacin mediated cell growth inhibition, S/G2-M cell cycle arrest, and apoptosis in a human transitional cell carcinoma of the bladder cell line. Clin Cancer Res. 2000 Mar;6(3):891-900.
29 Quinolones as enhancers of camptothecin-induced cytotoxic and anti-topoisomerase I effects. Biochem Pharmacol. 2008 Mar 15;75(6):1272-81. doi: 10.1016/j.bcp.2007.11.014. Epub 2007 Dec 3.
30 Disturbance of cellular glucose transport by two prevalently used fluoroquinolone antibiotics ciprofloxacin and levofloxacin involves glucose transporter type 1. Toxicol Lett. 2009 Jan 30;184(2):81-4. doi: 10.1016/j.toxlet.2008.10.017. Epub 2008 Oct 28.
31 Interactions between the etoposide derivative F14512 and human type II topoisomerases: implications for the C4 spermine moiety in promoting enzyme-mediated DNA cleavage. Biochemistry. 2011 Apr 19;50(15):3240-9. doi: 10.1021/bi200094z. Epub 2011 Mar 28.
32 Role of mitochondria in ciprofloxacin induced apoptosis in bladder cancer cells. J Urol. 2002 Mar;167(3):1288-94.
33 Contrasting effects of fluoroquinolone antibiotics on the expression of the collagenases, matrix metalloproteinases (MMP)-1 and -13, in human tendon-derived cells. Rheumatology (Oxford). 2005 Dec;44(12):1514-7. doi: 10.1093/rheumatology/kei087. Epub 2005 Sep 7.
34 Ciprofloxacin induces apoptosis and inhibits proliferation of human colorectal carcinoma cells. Br J Cancer. 2002 Feb 1;86(3):443-8. doi: 10.1038/sj.bjc.6600079.
35 Computational and experimental studies on the inhibitory mechanism of hydroxychloroquine on hERG. Toxicology. 2021 Jun 30;458:152822. doi: 10.1016/j.tox.2021.152822. Epub 2021 May 28.
36 Ciprofloxacin-induced acute haemolytic anaemia in a patient with glucose-6-phosphate dehydrogenase Mediterranean deficiency: a case report. Ann Hematol. 2010 Sep;89(9):935-7. doi: 10.1007/s00277-010-0903-7. Epub 2010 Feb 2.
37 NOD2/CARD15 gene variants are linked to failure of antibiotic treatment in perianal fistulating Crohn's disease. Am J Gastroenterol. 2008 May;103(5):1197-202. doi: 10.1111/j.1572-0241.2007.01741.x. Epub 2008 Mar 26.
38 DNA breakage due to metronidazole treatment. Mutat Res. 2001 Jul 1;478(1-2):153-8.
39 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.
40 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.
41 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.
42 Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
43 Giardia, Entamoeba, and Trichomonas enzymes activate metronidazole (nitroreductases) and inactivate metronidazole (nitroimidazole reductases). Antimicrob Agents Chemother. 2009 Feb;53(2):458-64.
44 Acetamide--a metabolite of metronidazole formed by the intestinal flora. Biochem Pharmacol. 1979 Dec 15;28(24):3611-5.
45 Overexpression, isotopic labeling, and spectral characterization of Enterobacter cloacae nitroreductase. Protein Expr Purif. 1998 Jun;13(1):53-60.
46 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.
47 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
48 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.