Details of the Drug Combination

General Information of Drug Combination (ID: DCGS5EY)

• Drug Combination Name: Cyproheptadine + Ondansetron
• Indication: Nausea; Status: Phase 1 [1]
• Component Drugs:
  Cyproheptadine (DM92AH3): Small molecular drug
  Ondansetron (DMOTQ1I): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Cyproheptadine

Disease Entry	ICD 11	Status	REF
Allergic rhinitis	CA08.0	Approved	[2]
Leukemia	N.A.	Approved	[2]
Malnutrition	5B50-5B71	Approved	[2]
Rhinitis	FA20	Approved	[3]
Urticaria	EB00-EB05	Approved	[2]
Weight gain	MG43.6	Approved	[2]
Pruritus	EC90	Investigative	[2]

Cyproheptadine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Histamine H1 receptor (H1R)	TTTIBOJ	HRH1_HUMAN	Antagonist	[6]

Cyproheptadine Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[7]
UDP-glucuronosyltransferase 1A3 (UGT1A3)	DEF2WXN	UD13_HUMAN	Metabolism	[8]

Cyproheptadine Interacts with 6 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Pro-opiomelanocortin (POMC)	OTV41F7T	COLI_HUMAN	Decreases Secretion	[9]
Prolactin (PRL)	OTWFQGX7	PRL_HUMAN	Decreases Secretion	[9]
Somatotropin (GH1)	OT92RTRD	SOMA_HUMAN	Increases Expression	[9]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[10]
5-hydroxytryptamine receptor 7 (HTR7)	OT44DEWB	5HT7R_HUMAN	Affects Binding	[11]
Heat shock factor protein 1 (HSF1)	OTYNJ4KP	HSF1_HUMAN	Increases Activity	[12]

Indication(s) of Ondansetron

Disease Entry	ICD 11	Status	REF
Chemotherapy-induced nausea	MD90	Approved	[4]
Malignant glioma	2A00.0	Approved	[5]
Nausea	MD90	Approved	[5]
Vomiting	MD90	Approved	[5]
Alcohol dependence	6C40.2	Phase 2	[4]
Gastroenteritis	N.A.	Investigative	[5]

Ondansetron Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
5-HT 3 receptor (5HT3R)	TTNXLKE	NOUNIPROTAC	Agonist	[13]

Ondansetron Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[14]

Ondansetron Interacts with 7 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[15]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[16]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[17]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[18]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[19]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[18]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[20]

Ondansetron Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Expression	[21]

References

• [1] ClinicalTrials.gov (NCT03593811) Noninvasive Markers of Functional Nausea in Children
• [2] Cyproheptadine FDA Label
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [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: 2290).
• [5] Ondansetron FDA Label
• [6] Cyproheptadine displays preclinical activity in myeloma and leukemia. Blood. 2008 Aug 1;112(3):760-9.
• [7] Effect of common exon variant (p.P364L) on drug glucuronidation by the human UDP-glucuronosyltransferase 1 family. Basic Clin Pharmacol Toxicol. 2011 Dec;109(6):486-93.
• [8] Glucuronidation of amines and other xenobiotics catalyzed by expressed human UDP-glucuronosyltransferase 1A3. Drug Metab Dispos. 1998 Jun;26(6):507-12.
• [9] [Toxicity of cyproheptadine. Side effects and accidental overdosage (author's transl)]. Monatsschr Kinderheilkd (1902). 1978 Mar;126(3):123-6.
• [10] Association of CYP1A1 and CYP1B1 inhibition in in vitro assays with drug-induced liver injury. J Toxicol Sci. 2021;46(4):167-176. doi: 10.2131/jts.46.167.
• [11] Clozapine and other competitive antagonists reactivate risperidone-inactivated h5-HT7 receptors: radioligand binding and functional evidence for GPCR homodimer protomer interactions. Psychopharmacology (Berl). 2010 Dec;212(4):687-97. doi: 10.1007/s00213-010-2001-x. Epub 2010 Sep 9.
• [12] 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.
• [13] Treatment of pruritus in chronic liver disease with the 5-hydroxytryptamine receptor type 3 antagonist ondansetron: a randomized, placebo-controlled, double-blind cross-over trial. Eur J Gastroenterol Hepatol. 1998 Oct;10(10):865-70.
• [14] Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther. 2004 Jan;75(1):13-33.
• [15] The effect of rifampin on the pharmacokinetics of oral and intravenous ondansetron. Clin Pharmacol Ther. 1999 Apr;65(4):377-81.
• [16] Effects of serotonin-3 receptor antagonists on cytochrome P450 activities in human liver microsomes. Biol Pharm Bull. 2006 Sep;29(9):1931-5.
• [17] Cytochrome P450 2D6 metabolism and 5-hydroxytryptamine type 3 receptor antagonists for postoperative nausea and vomiting. Med Sci Monit. 2005 Oct;11(10):RA322-8.
• [18] Multiple forms of cytochrome P450 are involved in the metabolism of ondansetron in humans. Drug Metab Dispos. 1995 Nov;23(11):1225-30.
• [19] Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of dolasetron. Comparison with other indole-containing 5-HT3 antagonists. Drug Metab Dispos. 1996 May;24(5):602-9.
• [20] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [21] Serotonin type-3 receptor antagonists selectively kill melanoma cells through classical apoptosis, microtubule depolymerisation, ERK activation, and NF-B downregulation. Cell Biol Toxicol. 2023 Jun;39(3):1119-1135. doi: 10.1007/s10565-021-09667-0. Epub 2021 Oct 15.