Details of the Drug Combination

General Information of Drug Combination (ID: DCSA8GZ)

• Drug Combination Name: Aripiprazole + Paliperidone
• Indication: Schizophrenia; Status: Phase 4 [1]
• Component Drugs:
  Aripiprazole (DM3NUMH): Small molecular drug
  Paliperidone (DM7NPJS): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Aripiprazole

Disease Entry	ICD 11	Status	REF
Bipolar I disorder	N.A.	Approved	[2]
Erythropoietic porphyrias	5C58.12	Approved	[3]
Schizoaffective disorder	6A21	Approved	[2]
Schizophrenia	6A20	Approved	[4]
Major depressive disorder	6A70.3	Phase 3	[5]
Bipolar disorder	6A60	Application submitted	[6]
Autism	N.A.	Investigative	[2]

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	[9]

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	[10]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[10]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[11]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[11]

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	[12]
Prolactin (PRL)	OTWFQGX7	PRL_HUMAN	Decreases Expression	[13]
Interferon beta (IFNB1)	OTYQGUB5	IFNB_HUMAN	Increases Expression	[12]
Fibronectin (FN1)	OTB5ZN4Q	FINC_HUMAN	Decreases Expression	[12]
G antigen 1 (GAGE1)	OT53E50E	GAGE1_HUMAN	Increases Expression	[12]
Sodium-dependent serotonin transporter (SLC6A4)	OT6FGDLW	SC6A4_HUMAN	Affects Binding	[14]
Cancer/testis antigen 1 (CTAG1B)	OTIQGW6U	CTG1B_HUMAN	Increases Expression	[12]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[15]
Interferon-stimulated gene 20 kDa protein (ISG20)	OTCWRJJW	ISG20_HUMAN	Increases Expression	[12]
Fasciculation and elongation protein zeta-1 (FEZ1)	OTWCXPRE	FEZ1_HUMAN	Increases Expression	[12]
Synaptotagmin-17 (SYT17)	OTTW4MI3	SYT17_HUMAN	Decreases Expression	[12]
Nucleotide-binding oligomerization domain-containing protein 2 (NOD2)	OTPGYWKC	NOD2_HUMAN	Increases Expression	[12]
5-hydroxytryptamine receptor 2A (HTR2A)	OTWXJX0M	5HT2A_HUMAN	Decreases Response To Substance	[16]

Indication(s) of Paliperidone

Disease Entry	ICD 11	Status	REF
Psychotic disorder	6A20-6A25	Approved	[7]
Schizoaffective disorder	6A21	Approved	[7]
Schizophrenia	6A20	Approved	[8]

Paliperidone Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
5-HT receptor (5HTR)	TT85JO3	NOUNIPROTAC	Antagonist	[3]

Paliperidone Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[17]

Paliperidone Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[18]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[19]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[20]

Paliperidone Interacts with 10 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Affects Abundance	[21]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Transport	[22]
Prolactin (PRL)	OTWFQGX7	PRL_HUMAN	Increases Expression	[23]
Interleukin-1 alpha (IL1A)	OTPSGILV	IL1A_HUMAN	Increases Expression	[24]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Expression	[24]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[24]
Phosphatidylcholine translocator ABCB4 (ABCB4)	OTE6PY83	MDR3_HUMAN	Decreases Activity	[25]
5-hydroxytryptamine receptor 2A (HTR2A)	OTWXJX0M	5HT2A_HUMAN	Affects Binding	[26]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[27]
Interleukin-24 (IL24)	OT4VUWH1	IL24_HUMAN	Increases Expression	[24]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Immunoassay	DCWOISJ	N. A.	Phase 1	[28]

References

• [1] ClinicalTrials.gov (NCT06060886) Multidisciplinary Design to Optimize Schizophrenia Treatment Based on Multi-omics Data and Systems Biology Analysis
• [2] Aripiprazole 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: 34).
• [5] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800034267)
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] Paliperidone FDA Label
• [8] 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: 7258).
• [9] Aripiprazole acts as a selective dopamine D2 receptor partial agonist. Expert Opin Investig Drugs. 2007 Jun;16(6):771-5.
• [10] Aripiprazole: a review of its use in schizophrenia and schizoaffective disorder. Drugs. 2004;64(15):1715-36.
• [11] Drug Interactions Flockhart Table
• [12] 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.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Invega (paliperidone) extended release tablets FDA Label
• [18] ABCB1 polymorphisms influence steady-state plasma levels of 9-hydroxyrisperidone and risperidone active moiety. Ther Drug Monit. 2008 Oct;30(5):628-33.
• [19] Interpreting serum risperidone concentrations. Pharmacotherapy. 2005 Feb;25(2):299-302.
• [20] Different enantioselective 9-hydroxylation of risperidone by the two human CYP2D6 and CYP3A4 enzymes. Drug Metab Dispos. 2001 Oct;29(10):1263-8.
• [21] Cytochrome P450 2D6 genotype and steady state plasma levels of risperidone and 9-hydroxyrisperidone. Psychopharmacology (Berl). 1999 Dec;147(3):300-5. doi: 10.1007/s002130051171.
• [22] Blonanserin, a novel atypical antipsychotic agent not actively transported as substrate by P-glycoprotein. Prog Neuropsychopharmacol Biol Psychiatry. 2012 Oct 1;39(1):156-62. doi: 10.1016/j.pnpbp.2012.06.005. Epub 2012 Jun 9.
• [23] Extended-release paliperidone: efficacy, safety and tolerability profile of a new atypical antipsychotic. Drugs Today (Barc). 2007 Apr;43(4):249-58. doi: 10.1358/dot.2007.43.4.1067342.
• [24] An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury. Arch Toxicol. 2021 Jan;95(1):149-168. doi: 10.1007/s00204-020-02882-4. Epub 2020 Aug 20.
• [25] Evaluating the Role of Multidrug Resistance Protein 3 (MDR3) Inhibition in Predicting Drug-Induced Liver Injury Using 125 Pharmaceuticals. Chem Res Toxicol. 2017 May 15;30(5):1219-1229. doi: 10.1021/acs.chemrestox.7b00048. Epub 2017 May 4.
• [26] Risperidone: a novel antipsychotic with balanced serotonin-dopamine antagonism, receptor occupancy profile, and pharmacologic activity. J Clin Psychiatry. 1994 May;55 Suppl:5-12.
• [27] Prolongation of cardiac ventricular repolarization under paliperidone: how and how much?. J Cardiovasc Pharmacol. 2011 Jun;57(6):690-5. doi: 10.1097/FJC.0b013e318217d941.
• [28] ClinicalTrials.gov (NCT02634463) Whole Blood and Plasma Sample Collection for the Development of Antipsychotic Immunoassays From Participants Taking Aripiprazole, Olanzapine, Paliperidone, or Risperidone