Details of the Drug Combination

General Information of Drug Combination (ID: DCR2A8B)

• Drug Combination Name: Quetiapine + Aripiprazole
• Indication: Schizophrenia; Status: Phase 2 [1]
• Component Drugs:
  Quetiapine (DM1N62C): Small molecular drug
  Aripiprazole (DM3NUMH): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Quetiapine

Disease Entry	ICD 11	Status	REF
Anorexia nervosa cachexia	6B80	Approved	[2]
Bipolar depression	N.A.	Approved	[2]
Bipolar disorder	6A60	Approved	[2]
Bipolar I disorder	N.A.	Approved	[2]
Delirium	N.A.	Approved	[2]
Major depressive disorder	6A70.3	Approved	[2]
Methamphetamine dependence	6C46.2	Approved	[2]
Schizoaffective disorder	6A21	Approved	[2]
Schizophrenia	6A20	Approved	[3]
Alcohol dependence	6C40.2	Phase 3	[4]

Quetiapine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Dopamine D2 receptor (D2R)	TTEX248	DRD2_HUMAN	Agonist	[10]

Quetiapine Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[11]
Solute carrier family 22 member 23 (SLC22A23)	DTMJK12	S22AN_HUMAN	Substrate	[12]

Quetiapine Interacts with 5 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[13]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[14]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[15]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[14]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[14]

Indication(s) of Aripiprazole

Disease Entry	ICD 11	Status	REF
Bipolar I disorder	N.A.	Approved	[5]
Erythropoietic porphyrias	5C58.12	Approved	[6]
Schizoaffective disorder	6A21	Approved	[5]
Schizophrenia	6A20	Approved	[7]
Major depressive disorder	6A70.3	Phase 3	[8]
Bipolar disorder	6A60	Application submitted	[9]
Autism	N.A.	Investigative	[5]

Aripiprazole Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Dopamine D2 receptor (D2R)	TTEX248	DRD2_HUMAN	Agonist	[16]

Aripiprazole Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[17]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[17]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[18]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[18]

Aripiprazole Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Toll-like receptor 5 (TLR5)	OT8ZYKJ6	TLR5_HUMAN	Increases Expression	[19]
Prolactin (PRL)	OTWFQGX7	PRL_HUMAN	Decreases Expression	[20]
Interferon beta (IFNB1)	OTYQGUB5	IFNB_HUMAN	Increases Expression	[19]
Fibronectin (FN1)	OTB5ZN4Q	FINC_HUMAN	Decreases Expression	[19]
G antigen 1 (GAGE1)	OT53E50E	GAGE1_HUMAN	Increases Expression	[19]
Sodium-dependent serotonin transporter (SLC6A4)	OT6FGDLW	SC6A4_HUMAN	Affects Binding	[21]
Cancer/testis antigen 1 (CTAG1B)	OTIQGW6U	CTG1B_HUMAN	Increases Expression	[19]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[22]
Interferon-stimulated gene 20 kDa protein (ISG20)	OTCWRJJW	ISG20_HUMAN	Increases Expression	[19]
Fasciculation and elongation protein zeta-1 (FEZ1)	OTWCXPRE	FEZ1_HUMAN	Increases Expression	[19]
Synaptotagmin-17 (SYT17)	OTTW4MI3	SYT17_HUMAN	Decreases Expression	[19]
Nucleotide-binding oligomerization domain-containing protein 2 (NOD2)	OTPGYWKC	NOD2_HUMAN	Increases Expression	[19]
5-hydroxytryptamine receptor 2A (HTR2A)	OTWXJX0M	5HT2A_HUMAN	Decreases Response To Substance	[23]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Schizophrenia	DCXCB60	N. A.	Phase 1	[24]

References

• [1] ClinicalTrials.gov (NCT01129674) A Long-Term, Open-Label, Study on Schizophrenia
• [2] Quetiapine FDA Label
• [3] The pipeline and future of drug development in schizophrenia. Mol Psychiatry. 2007 Oct;12(10):904-22.
• [4] ClinicalTrials.gov (NCT02362412) Study to Evaluate the Effects of Switching Different Strength Forms of FK949E in Bipolar Disorder Patients With Major Depressive Episodes. U.S. National Institutes ofHealth.
• [5] Aripiprazole FDA Label
• [6] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [7] 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: 34).
• [8] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800034267)
• [9] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [10] Receptor reserve-dependent properties of antipsychotics at human dopamine D2 receptors. Eur J Pharmacol. 2009 Apr 1;607(1-3):35-40.
• [11] Identification of P-glycoprotein substrates and inhibitors among psychoactive compounds--implications for pharmacokinetics of selected substrates. J Pharm Pharmacol. 2004 Aug;56(8):967-75.
• [12] Genome-wide association study of antipsychotic-induced QTc interval prolongation. Pharmacogenomics J. 2012 Apr;12(2):165-72.
• [13] Metabolism of the active metabolite of quetiapine, N-desalkylquetiapine in vitro. Drug Metab Dispos. 2012 Sep;40(9):1778-84.
• [14] A liquid chromatographic-electrospray-tandem mass spectrometric method for quantitation of quetiapine in human plasma and liver microsomes: application to study in vitro metabolism. J Anal Toxicol. 2004 Sep;28(6):443-8.
• [15] Influence of ABCB1 and CYP3A5 genetic polymorphisms on the pharmacokinetics of quetiapine in healthy volunteers. Pharmacogenet Genomics. 2014 Jan;24(1):35-42.
• [16] Aripiprazole acts as a selective dopamine D2 receptor partial agonist. Expert Opin Investig Drugs. 2007 Jun;16(6):771-5.
• [17] Aripiprazole: a review of its use in schizophrenia and schizoaffective disorder. Drugs. 2004;64(15):1715-36.
• [18] Drug Interactions Flockhart Table
• [19] Small Molecule Antipsychotic Aripiprazole Potentiates Ozone-Induced Inflammation in Airway Epithelium. Chem Res Toxicol. 2019 Oct 21;32(10):1997-2005. doi: 10.1021/acs.chemrestox.9b00149. Epub 2019 Sep 11.
• [20] The efficacy, safety, and tolerability of aripiprazole for the treatment of schizoaffective disorder: results from a pooled analysis of a sub-population of subjects from two randomized, double-blind, placebo-controlled, pivotal trials. J Affect Disord. 2009 May;115(1-2):18-26. doi: 10.1016/j.jad.2008.12.017. Epub 2009 Feb 23.
• [21] Design and synthesis of novel arylpiperazine derivatives containing the imidazole core targeting 5-HT(2A) receptor and 5-HT transporter. J Med Chem. 2011 Sep 22;54(18):6305-18. doi: 10.1021/jm200682b. Epub 2011 Aug 23.
• [22] Why are most phospholipidosis inducers also hERG blockers?. Arch Toxicol. 2017 Dec;91(12):3885-3895. doi: 10.1007/s00204-017-1995-9. Epub 2017 May 27.
• [23] Pharmacologic analysis of non-synonymous coding h5-HT2A SNPs reveals alterations in atypical antipsychotic and agonist efficacies. Pharmacogenomics J. 2006 Jan-Feb;6(1):42-51. doi: 10.1038/sj.tpj.6500342.
• [24] ClinicalTrials.gov (NCT01164059) Clinical Effectiveness of Newer Antipsychotics in Comparison With Conventional Antipsychotics in Schizophrenia