Details of the Drug Combination

General Information of Drug Combination (ID: DCZ2S89)

• Drug Combination Name: Febuxostat + Lansoprazole
• Indication: Gout; Status: Phase 3 [1]
• Component Drugs:
  Febuxostat (DMDEXQ0): Small molecular drug
  Lansoprazole (DMXYLQ3): N.A.

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Febuxostat

Disease Entry	ICD 11	Status	REF
Hyperuricaemia	5C55.Y	Approved	[2]

Febuxostat Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Xanthine dehydrogenase/oxidase (XDH)	TT7RJY8	XDH_HUMAN	Inhibitor	[5]

Febuxostat Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[6]

Febuxostat Interacts with 11 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Ras-related protein M-Ras (MRAS)	OTNCVCQW	RASM_HUMAN	Increases Expression	[4]
Growth arrest and DNA damage-inducible protein GADD45 gamma (GADD45G)	OT8V1J4M	GA45G_HUMAN	Increases Expression	[4]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Increases Expression	[7]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Expression	[7]
Nuclear receptor subfamily 4immunitygroup A member 1 (NR4A1)	OTGP6GA4	NR4A1_HUMAN	Increases Expression	[4]
Mitogen-activated protein kinase 8 (MAPK8)	OTEREYS5	MK08_HUMAN	Increases Phosphorylation	[4]
Dual specificity protein phosphatase 4 (DUSP4)	OT6WAO12	DUS4_HUMAN	Increases Expression	[4]
Dual specificity protein phosphatase 8 (DUSP8)	OTPLMPG9	DUS8_HUMAN	Increases Expression	[4]
Dual specificity protein phosphatase 5 (DUSP5)	OTH96RA7	DUS5_HUMAN	Increases Expression	[4]
Interleukin-1 receptor accessory protein (IL1RAP)	OTEU321R	IL1AP_HUMAN	Increases Expression	[4]
Dual specificity protein phosphatase 10 (DUSP10)	OTNG467B	DUS10_HUMAN	Increases Expression	[4]

Indication(s) of Lansoprazole

Disease Entry	ICD 11	Status	REF
Gastric ulcer	DA60	Approved	[3]
Gastrinoma	2C10.1	Approved	[3]
Peptic ulcer	DA61	Approved	[3]

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	[8]
Cytochrome P450 2C18 (CYP2C18)	DEZMWRE	CP2CI_HUMAN	Metabolism	[9]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[10]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[11]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[12]

Lansoprazole Interacts with 24 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[13]
Cytochrome P450 2C9 (CYP2C9)	OTGLBN29	CP2C9_HUMAN	Increases Hydroxylation	[14]
Cytochrome P450 2C8 (CYP2C8)	OTHCWT42	CP2C8_HUMAN	Increases Hydroxylation	[10]
Cytochrome P450 2C18 (CYP2C18)	OTY687L9	CP2CI_HUMAN	Increases Hydroxylation	[9]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Affects Response To Substance	[15]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Increases Expression	[13]
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Increases Expression	[16]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Increases Expression	[16]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[17]
Phospholipid-transporting ATPase ABCA1 (ABCA1)	OT94G6BQ	ABCA1_HUMAN	Increases Expression	[18]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Increases Expression	[19]
Protransforming growth factor alpha (TGFA)	OTPD1LL9	TGFA_HUMAN	Increases Expression	[19]
Pro-opiomelanocortin (POMC)	OTV41F7T	COLI_HUMAN	Increases Expression	[20]
Gastrin (GAST)	OTD0IP9N	GAST_HUMAN	Increases Expression	[21]
Apolipoprotein E (APOE)	OTFOWL2H	APOE_HUMAN	Increases Expression	[18]
Fibroblast growth factor 2 (FGF2)	OT7YUJ9F	FGF2_HUMAN	Decreases Expression	[19]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[22]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Decreases Expression	[23]
Microtubule-associated protein tau (MAPT)	OTMTP2Z7	TAU_HUMAN	Affects Binding	[24]
Oxysterols receptor LXR-beta (NR1H2)	OT4APA60	NR1H2_HUMAN	Increases Activity	[18]
Hepcidin (HAMP)	OT607RBL	HEPC_HUMAN	Increases Expression	[25]
Oxysterols receptor LXR-alpha (NR1H3)	OT54YZ9I	NR1H3_HUMAN	Increases Activity	[18]
Phosphoethanolamine/phosphocholine phosphatase (PHOSPHO1)	OT43A0JA	PHOP1_HUMAN	Decreases Activity	[26]
Fibroblast growth factor 21 (FGF21)	OT3RXVRD	FGF21_HUMAN	Increases Expression	[27]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Gout	DC5LB46	N. A.	Phase 2	[28]

References

• [1] ClinicalTrials.gov (NCT02139046) Efficacy and Safety of Extended Release and Immediate Release Febuxostat in Participants With Gout
• [2] 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: 6817).
• [3] Lansoprazole FDA Label
• [4] Febuxostat Increases Ventricular Arrhythmogenesis Through Calcium Handling Dysregulation in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Toxicol Sci. 2022 Sep 24;189(2):216-224. doi: 10.1093/toxsci/kfac073.
• [5] Clinical pipeline report, company report or official report of Takeda (2009).
• [6] In vitro drug-drug interaction studies with febuxostat, a novel non-purine selective inhibitor of xanthine oxidase: plasma protein binding, identification of metabolic enzymes and cytochrome P450 inhibition. Xenobiotica. 2008 May;38(5):496-510.
• [7] Allopurinol induces innate immune responses through mitogen-activated protein kinase signaling pathways in HL-60 cells. J Appl Toxicol. 2016 Sep;36(9):1120-8. doi: 10.1002/jat.3272. Epub 2015 Dec 7.
• [8] 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.
• [9] Oxidative metabolism of lansoprazole by human liver cytochromes P450. Mol Pharmacol. 1995 Feb;47(2):410-8.
• [10] Identification of the human P450 enzymes involved in lansoprazole metabolism. J Pharmacol Exp Ther. 1996 May;277(2):805-16.
• [11] 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.
• [12] Effects of clarithromycin on lansoprazole pharmacokinetics between CYP2C19 genotypes. Br J Clin Pharmacol. 2005 Mar;59(3):302-9.
• [13] Measurement of cytochrome P450 gene induction in human hepatocytes using quantitative real-time reverse transcriptase-polymerase chain reaction. Drug Metab Dispos. 2000 Jul;28(7):781-8.
• [14] Stereoselective metabolism of lansoprazole by human liver cytochrome P450 enzymes. Drug Metab Dispos. 2003 Oct;31(10):1227-34.
• [15] 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.
• [16] Time-dependent transcriptional induction of CYP1A1, CYP1A2 and CYP1B1 mRNAs by H+/K+ -ATPase inhibitors and other xenobiotics. Xenobiotica. 2003 Feb;33(2):107-18.
• [17] 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.
• [18] 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.
• [19] Effect of chronic duodenal ulceration and its treatment with lanzoprazole or sucralfate on gastroduodenal mucosal protein turnover and TGF-alpha, bFGF, and EGF receptor expression in humans. Dig Dis Sci. 1998 Dec;43(12):2764-70. doi: 10.1023/a:1026680017329.
• [20] 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.
• [21] Influence of lansoprazole on intragastric 24-hour pH, meal-stimulated gastric acid secretion, and concentrations of gastrointestinal hormones and enzymes in serum and gastric juice in healthy volunteers. Digestion. 1995;56(2):137-44. doi: 10.1159/000201233.
• [22] Beyond gastric acid reduction: proton pump inhibitors induce heme oxygenase-1 in gastric and endothelial cells. Biochem Biophys Res Commun. 2006 Jul 7;345(3):1014-21. doi: 10.1016/j.bbrc.2006.04.170. Epub 2006 May 6.
• [23] 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.
• [24] Selective interaction of lansoprazole and astemizole with tau polymers: potential new clinical use in diagnosis of Alzheimer's disease. J Alzheimers Dis. 2010;19(2):573-89. doi: 10.3233/JAD-2010-1262.
• [25] 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.
• [26] 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.
• [27] Increased immunoreactivity and concentration of basic fibroblast growth factor in lansoprazole-treated gastric mucosa. J Clin Gastroenterol. 1995;21 Suppl 1:S24-9.
• [28] ClinicalTrials.gov (NCT02128490) Efficacy and Safety of Extended Release and Immediate Release Febuxostat in Participants With Gout and Moderate Renal Impairment