Details of the Drug Combination

General Information of Drug Combination (ID: DC5KN8C)

• Drug Combination Name: Ranitidine + Omeprazole
• Indication: Eustachian Tube Dysfunction; Status: Phase 4 [1]
• Component Drugs:
  Ranitidine (DM0GUSX): Small molecular drug
  Omeprazole (DM471KJ): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Ranitidine

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

Ranitidine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Histamine H2 receptor (H2R)	TTQHJ1K	HRH2_HUMAN	Antagonist	[6]

Ranitidine Interacts with 5 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[7]
Organic anion transporter 2 (SLC22A7)	DT0OC1Q	S22A7_HUMAN	Substrate	[8]
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[8]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[9]
Organic anion transporter 3 (SLC22A8)	DTVP67E	S22A8_HUMAN	Substrate	[8]

Ranitidine Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[10]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[11]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[11]
Dimethylaniline oxidase 5 (FMO5)	DEBMX7C	FMO5_HUMAN	Metabolism	[12]

Ranitidine Interacts with 12 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Solute carrier family 22 member 1 (SLC22A1)	OT7817I4	S22A1_HUMAN	Affects Transport	[9]
Solute carrier family 22 member 7 (SLC22A7)	OTKTNH1W	S22A7_HUMAN	Increases Uptake	[8]
Solute carrier family 22 member 2 (SLC22A2)	OTGFK1AL	S22A2_HUMAN	Increases Uptake	[8]
Organic anion transporter 3 (SLC22A8)	OT8BY933	S22A8_HUMAN	Increases Uptake	[8]
Renin (REN)	OT52GZR2	RENI_HUMAN	Affects Activity	[13]
Prolactin (PRL)	OTWFQGX7	PRL_HUMAN	Increases Secretion	[14]
Calcitonin (CALCA)	OTZ11LHB	CALC_HUMAN	Increases Expression	[15]
Gastrin (GAST)	OTD0IP9N	GAST_HUMAN	Affects Expression	[16]
Protachykinin-1 (TAC1)	OTM842YW	TKN1_HUMAN	Increases Expression	[15]
Flavin-containing monooxygenase 3 (FMO3)	OT1G2EV3	FMO3_HUMAN	Affects Metabolism	[17]
Solute carrier family 22 member 6 (SLC22A6)	OTKRCBVM	S22A6_HUMAN	Increases Uptake	[8]
Cobalamin binding intrinsic factor (CBLIF)	OTNE20WU	IF_HUMAN	Increases ADR	[18]

Indication(s) of Omeprazole

Disease Entry	ICD 11	Status	REF
Cystic fibrosis	CA25	Approved	[4]
Gastric ulcer	DA60	Approved	[4]
Gastrinoma	2C10.1	Approved	[4]
Gastroesophageal reflux disease	DA22.Z	Approved	[5]
Laryngeal disorder	N.A.	Approved	[4]
Nausea	MD90	Approved	[4]
Peptic esophagitis	N.A.	Approved	[4]
Peptic ulcer	DA61	Approved	[4]
Congenital laryngomalacia	N.A.	Investigative	[4]

Omeprazole 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	[20]

Omeprazole Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[21]

Omeprazole Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[22]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[23]
Cytochrome P450 2C18 (CYP2C18)	DEZMWRE	CP2CI_HUMAN	Metabolism	[24]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[24]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[25]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[22]

Omeprazole Interacts with 34 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[26]
Cytochrome P450 3A5 (CYP3A5)	OTSXFBXB	CP3A5_HUMAN	Increases Expression	[19]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Increases Expression	[27]
Alcohol dehydrogenase 1C (ADH1C)	OTO1DV7F	ADH1G_HUMAN	Decreases Expression	[28]
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Increases Expression	[28]
Phosphatidylcholine translocator ABCB4 (ABCB4)	OTE6PY83	MDR3_HUMAN	Decreases Expression	[28]
Aldehyde dehydrogenase, dimeric NADP-preferring (ALDH3A1)	OTAYZZE6	AL3A1_HUMAN	Increases Expression	[28]
Retinaldehyde dehydrogenase 3 (ALDH1A3)	OT1C9NKQ	AL1A3_HUMAN	Increases Expression	[28]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Increases Expression	[28]
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Increases Expression	[29]
Cytochrome P450 3A7 (CYP3A7)	OTTCDHHM	CP3A7_HUMAN	Increases Expression	[19]
Solute carrier organic anion transporter family member 1A2 (SLCO1A2)	OTO70C5O	SO1A2_HUMAN	Increases Expression	[19]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Increases Expression	[30]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[31]
Aryl hydrocarbon receptor nuclear translocator (ARNT)	OTMSIEZY	ARNT_HUMAN	Affects Localization	[32]
Aryl hydrocarbon receptor (AHR)	OTFE4EYE	AHR_HUMAN	Decreases Expression	[32]
C-X-C chemokine receptor type 4 (CXCR4)	OTUFSBX2	CXCR4_HUMAN	Decreases Expression	[32]
Transmembrane protease serine 2 (TMPRSS2)	OTN44YQ5	TMPS2_HUMAN	Increases Expression	[33]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[34]
Phospholipid-transporting ATPase ABCA1 (ABCA1)	OT94G6BQ	ABCA1_HUMAN	Increases Expression	[35]
Prolactin (PRL)	OTWFQGX7	PRL_HUMAN	Increases Expression	[36]
HLA class I histocompatibility antigen, B alpha chain (HLA-B)	OTNXFWY2	HLAB_HUMAN	Affects Expression	[37]
Cathepsin B (CTSB)	OTP9G5QB	CATB_HUMAN	Decreases Activity	[38]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[39]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[40]
HLA class I histocompatibility antigen, alpha chain G (HLA-G)	OTMLK1KN	HLAG_HUMAN	Affects Expression	[37]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[41]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[41]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[42]
Cytosolic phospholipase A2 (PLA2G4A)	OTE70SOT	PA24A_HUMAN	Increases Phosphorylation	[43]
Hepcidin (HAMP)	OT607RBL	HEPC_HUMAN	Increases Expression	[44]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Cleavage	[42]
Angiotensin-converting enzyme 2 (ACE2)	OTTRZGU7	ACE2_HUMAN	Decreases Expression	[33]
Potassium-transporting ATPase alpha chain 2 (ATP12A)	OTSQSKEK	AT12A_HUMAN	Increases ADR	[18]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Cough	DCOLNCA	N. A.	Phase 1	[45]

References

• [1] ClinicalTrials.gov (NCT02123498) The Study of Eustachian Tube Dysfunction and Laryngopharyngeal Reflux
• [2] Ranitidine FDA Label
• [3] 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: 1234).
• [4] Omeprazole FDA Label
• [5] 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: 4279).
• [6] Knockouts model the 100 best-selling drugs--will they model the next 100 Nat Rev Drug Discov. 2003 Jan;2(1):38-51.
• [7] 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.
• [8] A species difference in the transport activities of H2 receptor antagonists by rat and human renal organic anion and cation transporters. J Pharmacol Exp Ther. 2005 Oct;315(1):337-45.
• [9] Differential substrate and inhibitory activities of ranitidine and famotidine toward human organic cation transporter 1 (hOCT1; SLC22A1), hOCT2 (SLC22A2), and hOCT3 (SLC22A3). J Pharmacol Exp Ther. 2005 Dec;315(3):1288-97.
• [10] Comparative in vitro and in vivo inhibition of cytochrome P450 CYP1A2, CYP2D6, and CYP3A by H2-receptor antagonists. Clin Pharmacol Ther. 1999 Apr;65(4):369-76.
• [11] Oxidation of ranitidine by isozymes of flavin-containing monooxygenase and cytochrome P450. Jpn J Pharmacol. 2000 Oct;84(2):213-20.
• [12] Drug metabolism by flavin-containing monooxygenases of human and mouse. Expert Opin Drug Metab Toxicol. 2017 Feb;13(2):167-181.
• [13] Effects of histamine H2-receptor blockade on the cardiovascular reflex response to lower-body negative pressure in man. Acta Physiol Scand. 1990 May;139(1):161-72. doi: 10.1111/j.1748-1716.1990.tb08909.x.
• [14] [Impotence and gynecomastia secondary to hyperprolactinemia induced by ranitidine]. Therapie. 1994 Jul-Aug;49(4):361-2.
• [15] Effects of histamine H(2)-receptor antagonists on human plasma levels of calcitonin gene-related peptide, substance P and vasoactive intestinal peptide. J Pharm Pharmacol. 2002 Nov;54(11):1559-63. doi: 10.1211/002235702117.
• [16] Effects of three H2-receptor antagonists (cimetidine, famotidine, ranitidine) on serum gastrin level. Int J Clin Pharmacol Res. 2002;22(2):29-35.
• [17] Evaluation of fresh and cryopreserved hepatocytes as in vitro drug metabolism tools for the prediction of metabolic clearance. Drug Metab Dispos. 2004 Nov;32(11):1247-53. doi: 10.1124/dmd.104.000026. Epub 2004 Jul 30.
• [18] 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.
• [19] Use of mRNA expression to detect the induction of drug metabolising enzymes in rat and human hepatocytes. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):86-96.
• [20] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [21] A novel screening strategy to identify ABCB1 substrates and inhibitors. Naunyn Schmiedebergs Arch Pharmacol. 2009 Jan;379(1):11-26.
• [22] 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.
• [23] Impact of intestinal CYP2C19 genotypes on the interaction between tacrolimus and omeprazole, but not lansoprazole, in adult living-donor liver transplant patients. Drug Metab Dispos. 2009 Apr;37(4):821-6.
• [24] Human CYP2C19 is a major omeprazole 5-hydroxylase, as demonstrated with recombinant cytochrome P450 enzymes. Drug Metab Dispos. 1996 Oct;24(10):1081-7.
• [25] Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug Metab Dispos. 2004 Aug;32(8):821-7.
• [26] A cell-based reporter gene assay for determining induction of CYP3A4 in a high-volume system. J Pharmacol Exp Ther. 2002 Oct;303(1):412-23.
• [27] 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.
• [28] Evaluation of gene induction of drug-metabolizing enzymes and transporters in primary culture of human hepatocytes using high-sensitivity real-time reverse transcription PCR. Yakugaku Zasshi. 2002 May;122(5):339-61.
• [29] HepaRG cells as an in vitro model for evaluation of cytochrome P450 induction in humans. Drug Metab Dispos. 2008 Jan;36(1):137-45.
• [30] A novel xenobiotic responsive element regulated by aryl hydrocarbon receptor is involved in the induction of BCRP/ABCG2 in LS174T cells. Biochem Pharmacol. 2010 Dec 1;80(11):1754-61.
• [31] Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. Toxicol Sci. 2010 Dec; 118(2):485-500.
• [32] Omeprazole inhibits pancreatic cancer cell invasion through a nongenomic aryl hydrocarbon receptor pathway. Chem Res Toxicol. 2015 May 18;28(5):907-18.
• [33] 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.
• [34] Environmental contaminants activate human and polar bear (Ursus maritimus) pregnane X receptors (PXR, NR1I2) differently. Toxicol Appl Pharmacol. 2015 Apr 1;284(1):54-64. doi: 10.1016/j.taap.2015.02.001. Epub 2015 Feb 10.
• [35] 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.
• [36] Hyperprolactinaemia induced by proton pump inhibitor. J Pak Med Assoc. 2010 Aug;60(8):689-90.
• [37] 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.
• [38] Proton pump inhibitors interfere with the anti-tumor potency of RC48ADC. Toxicol In Vitro. 2022 Mar;79:105292. doi: 10.1016/j.tiv.2021.105292. Epub 2021 Dec 3.
• [39] 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.
• [40] Omeprazole induces apoptosis in jurkat cells. Int J Immunopathol Pharmacol. 2004 Sep-Dec;17(3):331-42. doi: 10.1177/039463200401700313.
• [41] High-content imaging-based BAC-GFP toxicity pathway reporters to assess chemical adversity liabilities. Arch Toxicol. 2017 Mar;91(3):1367-1383. doi: 10.1007/s00204-016-1781-0. Epub 2016 Jun 29.
• [42] Omeprazole induces apoptosis in normal human polymorphonuclear leucocytes. Int J Immunopathol Pharmacol. 2008 Jan-Mar;21(1):73-85. doi: 10.1177/039463200802100109.
• [43] TCDD and omeprazole prime platelets through the aryl hydrocarbon receptor (AhR) non-genomic pathway. Toxicol Lett. 2015 May 19;235(1):28-36. doi: 10.1016/j.toxlet.2015.03.005. Epub 2015 Mar 19.
• [44] 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.
• [45] ClinicalTrials.gov (NCT00668317) Bronchial Hyper-responsiveness in Reflux Cough