Details of the Drug Combination

General Information of Drug Combination (ID: DC8MTNA)

• Drug Combination Name: Clarithromycin + Pantoprazole
• Indication: Drug Interaction; Status: Phase 1 [1]
• Component Drugs:
  Clarithromycin (DM4M1SG): Small molecular drug
  Pantoprazole (DMSVOCZ): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Clarithromycin

Disease Entry	ICD 11	Status	REF
Acute maxillary sinusitis	N.A.	Approved	[2]
Acute otitis media	AB00	Approved	[2]
Bacterial infection	1A00-1C4Z	Approved	[3]
Mycoplasma pneumoniae pneumonia	N.A.	Approved	[2]
Staphylococcus aureus infection	N.A.	Approved	[2]
Streptococcal pneumonia	N.A.	Approved	[2]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[4]
Pneumonia caused by chlamydia	N.A.	Investigative	[2]

Clarithromycin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bacterial 50S ribosomal RNA (Bact 50S rRNA)	TTUWYEA	NOUNIPROTAC	Binder	[7]

Clarithromycin Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[8]

Clarithromycin Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[9]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[10]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[11]

Clarithromycin Interacts with 15 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Expression	[12]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[13]
Phytanoyl-CoA dioxygenase, peroxisomal (PHYH)	OTUG4BWA	PAHX_HUMAN	Decreases Expression	[14]
Lanosterol synthase (LSS)	OT9W2SFH	LSS_HUMAN	Decreases Expression	[14]
Inhibin beta E chain (INHBE)	OTOI2NYG	INHBE_HUMAN	Increases Expression	[14]
Acid ceramidase (ASAH1)	OT1DNGXL	ASAH1_HUMAN	Increases Expression	[14]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[15]
Cytochrome c oxidase subunit 2 (COX2)	OTTMVBJJ	COX2_HUMAN	Decreases Expression	[16]
Protein c-Fos (FOS)	OTJBUVWS	FOS_HUMAN	Increases Expression	[17]
Interleukin-4 (IL4)	OTOXBWAU	IL4_HUMAN	Decreases Expression	[18]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[19]
Integrin beta-4 (ITGB4)	OT28UK84	ITB4_HUMAN	Decreases Expression	[20]
Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1)	OT8SPJNX	KCNQ1_HUMAN	Increases ADR	[21]
Translation initiation factor IF-2, mitochondrial (MTIF2)	OTAIOZ0J	IF2M_HUMAN	Decreases Response To Substance	[16]
Misshapen-like kinase 1 (MINK1)	OTKB0RA8	MINK1_HUMAN	Increases ADR	[21]

Indication(s) of Pantoprazole

Disease Entry	ICD 11	Status	REF
Gastrinoma	2C10.1	Approved	[5]
Gastroesophageal reflux disease	DA22.Z	Approved	[6]
Peptic ulcer	DA61	Approved	[5]

Pantoprazole Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Gastric H(+)/K(+) ATPase (Proton pump)	TTLOKXP	ATP4A_HUMAN; ATP4B_HUMAN	Modulator	[22]

Pantoprazole Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[23]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[24]

Pantoprazole Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[25]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[26]
Sulfotransferase 1A1 (SULT1A1)	DEYWLRK	ST1A1_HUMAN	Metabolism	[25]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[27]

Pantoprazole Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Phospholipid-transporting ATPase ABCA1 (ABCA1)	OT94G6BQ	ABCA1_HUMAN	Increases Expression	[28]
Hepcidin (HAMP)	OT607RBL	HEPC_HUMAN	Increases Expression	[29]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Helicobacter Pylori Infection	DCOMMIN	N. A.	Phase 1	[30]
Dyspepsia	DCQ9MIX	N. A.	Phase 1	[31]

References

• [1] ClinicalTrials.gov (NCT03011996) To Investigate PK and PD of CJ-12420, Clarithromycin, Amoxicillin After Multiple Dose Administration
• [2] Clarithromycin FDA Label
• [3] Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
• [4] Anti-inflammatory Clarithromycin for Improving COVID-19 Infection Early (ACHIEVE)
• [5] Pantoprazole FDA Label
• [6] 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: 7260).
• [7] Structural basis for the interaction of antibiotics with the peptidyl transferase centre in eubacteria. Nature. 2001 Oct 25;413(6858):814-21.
• [8] 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.
• [9] Pharmacokinetic variability of clarithromycin and differences in CYP3A4 activity in patients with cystic fibrosis. J Cyst Fibros. 2014 Mar;13(2):179-85.
• [10] Drug Interactions Flockhart Table
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• [12] Use of immortalized human hepatocytes to predict the magnitude of clinical drug-drug interactions caused by CYP3A4 induction. Drug Metab Dispos. 2006 Oct;34(10):1742-8.
• [13] Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model. Toxicol Sci. 2013 Dec;136(2):581-94. doi: 10.1093/toxsci/kft205. Epub 2013 Sep 19.
• [14] A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system. Toxicol Sci. 2005 Feb;83(2):282-92.
• [15] Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013 Dec;136(2):328-43.
• [16] A genome-wide analysis of targets of macrolide antibiotics in mammalian cells. J Biol Chem. 2020 Feb 14;295(7):2057-2067. doi: 10.1074/jbc.RA119.010770. Epub 2020 Jan 8.
• [17] Liver toxicity of macrolide antibiotics in zebrafish. Toxicology. 2020 Aug;441:152501. doi: 10.1016/j.tox.2020.152501. Epub 2020 May 23.
• [18] 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.
• [19] T-cell involvement in drug-induced acute generalized exanthematous pustulosis. J Clin Invest. 2001 Jun;107(11):1433-41. doi: 10.1172/JCI12118.
• [20] Effects of eight antibacterial agents on cell survival and expression of epithelial-cell- or cell-adhesion-related genes in human gingival epithelial cells. J Periodontal Res. 2004 Feb;39(1):50-8. doi: 10.1111/j.1600-0765.2004.00704.x.
• [21] 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.
• [22] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [23] A novel screening strategy to identify ABCB1 substrates and inhibitors. Naunyn Schmiedebergs Arch Pharmacol. 2009 Jan;379(1):11-26.
• [24] Mechanism of the pharmacokinetic interaction between methotrexate and benzimidazoles: potential role for breast cancer resistance protein in clinical drug-drug interactions. Cancer Res. 2004 Aug 15;64(16):5804-11.
• [25] Interaction of proton pump inhibitors with cytochromes P450: consequences for drug interactions. Yale J Biol Med. 1996 May-Jun;69(3):203-9.
• [26] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [27] Proton pump inhibitors: from CYP2C19 pharmacogenetics to precision medicine. Expert Opin Drug Metab Toxicol. 2018 Apr;14(4):447-460.
• [28] 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.
• [29] Proton pump inhibitors block iron absorption through direct regulation of hepcidin via the aryl hydrocarbon receptor-mediated pathway. Toxicol Lett. 2020 Jan;318:86-91. doi: 10.1016/j.toxlet.2019.10.016. Epub 2019 Oct 24.
• [30] ClinicalTrials.gov (NCT04621487) Quadruple vs Tailored Therapy in the Treatment of Helicobacter Pylori Infection
• [31] ClinicalTrials.gov (NCT04697641) Helicobacter Pylori Eradication in Functional Dyspepsia