Details of the Drug Combination

General Information of Drug Combination (ID: DC7RXBH)

• Drug Combination Name: Olanzapine + Spironolactone
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Olanzapine (DMPFN6Y): Small molecular drug
  Spironolactone (DM2AQ5N): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 27.88
  Bliss Independence Score: 27.88
  Loewe Additivity Score: 41.83
  LHighest Single Agent (HSA) Score: 41.83

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Olanzapine

Disease Entry	ICD 11	Status	REF
Bipolar depression	N.A.	Approved	[2]
Major depressive disorder	6A70.3	Approved	[2]
Schizoaffective disorder	6A21	Approved	[2]
Schizophrenia	6A20	Approved	[3]

Olanzapine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Dopamine D2 receptor (D2R)	TTEX248	DRD2_HUMAN	Agonist	[8]

Olanzapine Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[9]

Olanzapine Interacts with 2 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]

Olanzapine Interacts with 63 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Activity	[12]
D(2) dopamine receptor (DRD2)	OTBLXKEG	DRD2_HUMAN	Increases Response To Substance	[13]
Lathosterol oxidase (SC5D)	OT41KMW4	SC5D_HUMAN	Increases Expression	[14]
Low-density lipoprotein receptor (LDLR)	OTH559LU	LDLR_HUMAN	Increases Expression	[14]
3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)	OTRT3F3U	HMDH_HUMAN	Increases Expression	[14]
Hydroxymethylglutaryl-CoA synthase, cytoplasmic (HMGCS1)	OTCO26FV	HMCS1_HUMAN	Increases Expression	[14]
Long-chain fatty acid transport protein 2 (SLC27A2)	OT7JEG5F	S27A2_HUMAN	Increases Expression	[15]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[16]
Ceruloplasmin (CP)	OTM8JE4Y	CERU_HUMAN	Affects Phosphorylation	[17]
Prothrombin (F2)	OTNFSM49	THRB_HUMAN	Affects Phosphorylation	[17]
Complement factor B (CFB)	OTZITNEJ	CFAB_HUMAN	Affects Phosphorylation	[17]
Alpha-1-antichymotrypsin (SERPINA3)	OT9BP2S0	AACT_HUMAN	Increases Phosphorylation	[17]
Alpha-2-macroglobulin (A2M)	OTFTX90K	A2MG_HUMAN	Affects Phosphorylation	[17]
Complement C3 (C3)	OTCH5GS0	CO3_HUMAN	Affects Phosphorylation	[17]
Complement C5 (C5)	OTSL3OIC	CO5_HUMAN	Affects Phosphorylation	[17]
Kininogen-1 (KNG1)	OT4X9LDE	KNG1_HUMAN	Affects Phosphorylation	[17]
Prolactin (PRL)	OTWFQGX7	PRL_HUMAN	Increases Expression	[18]
Insulin (INS)	OTZ85PDU	INS_HUMAN	Increases Expression	[19]
Collagen alpha-1(I) chain (COL1A1)	OTI31178	CO1A1_HUMAN	Decreases Phosphorylation	[17]
Apolipoprotein A-I (APOA1)	OT5THARI	APOA1_HUMAN	Increases Phosphorylation	[17]
Complement component C9 (C9)	OT7I5FDX	CO9_HUMAN	Affects Phosphorylation	[17]
Beta-2-glycoprotein 1 (APOH)	OTFMUX6O	APOH_HUMAN	Affects Phosphorylation	[17]
Fibronectin (FN1)	OTB5ZN4Q	FINC_HUMAN	Affects Phosphorylation	[17]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Phosphorylation	[17]
Vitamin D-binding protein (GC)	OTWS63BY	VTDB_HUMAN	Affects Phosphorylation	[17]
Hemopexin (HPX)	OT14T7Q1	HEMO_HUMAN	Affects Phosphorylation	[17]
Apolipoprotein B-100 (APOB)	OTH0UOCZ	APOB_HUMAN	Increases Phosphorylation	[17]
Histidine-rich glycoprotein (HRG)	OTPLUFOG	HRG_HUMAN	Affects Phosphorylation	[17]
Alpha-1B-glycoprotein (A1BG)	OTFVUGNQ	A1BG_HUMAN	Affects Phosphorylation	[17]
Sex hormone-binding globulin (SHBG)	OTPWU5IW	SHBG_HUMAN	Decreases Expression	[20]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[21]
Plasma protease C1 inhibitor (SERPING1)	OT6CVN45	IC1_HUMAN	Affects Phosphorylation	[17]
Apolipoprotein A-IV (APOA4)	OT466POQ	APOA4_HUMAN	Affects Phosphorylation	[17]
Fatty acid-binding protein, liver (FABP1)	OTR34ETM	FABPL_HUMAN	Increases Expression	[15]
Complement factor H (CFH)	OTAGKQTJ	CFAH_HUMAN	Decreases Phosphorylation	[17]
Complement C4-A (C4A)	OTXMOYXU	CO4A_HUMAN	Decreases Phosphorylation	[17]
Clusterin (CLU)	OTQGG0JM	CLUS_HUMAN	Affects Phosphorylation	[17]
Muscarinic acetylcholine receptor M1 (CHRM1)	OTKW3E6B	ACM1_HUMAN	Affects Binding	[22]
Complement component C6 (C6)	OTCKR304	CO6_HUMAN	Affects Phosphorylation	[17]
Solute carrier family 2, facilitated glucose transporter member 4 (SLC2A4)	OTJZG0LD	GLUT4_HUMAN	Increases Expression	[23]
Inter-alpha-trypsin inhibitor heavy chain H2 (ITIH2)	OTG3WBBE	ITIH2_HUMAN	Affects Phosphorylation	[17]
Brain-derived neurotrophic factor (BDNF)	OTLGH7EW	BDNF_HUMAN	Increases Expression	[24]
5-hydroxytryptamine receptor 2A (HTR2A)	OTWXJX0M	5HT2A_HUMAN	Affects Binding	[22]
Catenin beta-1 (CTNNB1)	OTZ932A3	CTNB1_HUMAN	Increases Expression	[25]
Histamine H1 receptor (HRH1)	OT8F9FV6	HRH1_HUMAN	Affects Binding	[22]
Leptin (LEP)	OT5Q7ODW	LEP_HUMAN	Increases Expression	[19]
Pituitary adenylate cyclase-activating polypeptide type I receptor (ADCYAP1R1)	OTNBHULA	PACR_HUMAN	Affects Expression	[7]
Afamin (AFM)	OTPOR8IO	AFAM_HUMAN	Affects Phosphorylation	[17]
Glycogen synthase kinase-3 beta (GSK3B)	OTL3L14B	GSK3B_HUMAN	Decreases Expression	[25]
5-hydroxytryptamine receptor 6 (HTR6)	OT8GTDDY	5HT6R_HUMAN	Affects Binding	[22]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[26]
Bcl-2-interacting killer (BIK)	OTTH1T3D	BIK_HUMAN	Increases Expression	[21]
Inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4)	OT460OO1	ITIH4_HUMAN	Affects Phosphorylation	[17]
Long-chain fatty acid transport protein 5 (SLC27A5)	OT4OK511	S27A5_HUMAN	Increases Expression	[15]
D(3) dopamine receptor (DRD3)	OT0OFFKB	DRD3_HUMAN	Increases ADR	[27]
5-hydroxytryptamine receptor 1A (HTR1A)	OT38K9MK	5HT1A_HUMAN	Increases Response	[28]
5-hydroxytryptamine receptor 2C (HTR2C)	OT6H8DE0	5HT2C_HUMAN	Increases Response To Substance	[29]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Increases Response To Substance	[30]
Aquaporin-4 (AQP4)	OTA9MYD5	AQP4_HUMAN	Increases Response To Substance	[31]
D(4) dopamine receptor (DRD4)	OTAJTO7N	DRD4_HUMAN	Increases ADR	[27]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases ADR	[27]
Methylenetetrahydrofolate reductase (MTHFR)	OTUBJSR7	MTHR_HUMAN	Affects Response To Substance	[32]
Synaptosomal-associated protein 25 (SNAP25)	OTUIQ81Q	SNP25_HUMAN	Affects Response To Substance	[33]

Indication(s) of Spironolactone

Disease Entry	ICD 11	Status	REF
Chronic heart failure	BD1Z	Approved	[4]
Congestive heart failure	BD10	Approved	[5]
Edema	MG29	Approved	[4]
Hyperaldosteronism	5A72	Approved	[4]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[6]

Spironolactone Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Mineralocorticoid receptor (MR)	TT26PHO	MCR_HUMAN	Modulator	[34]

Spironolactone Interacts with 21 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[35]
Cytochrome P450 2C8 (CYP2C8)	OTHCWT42	CP2C8_HUMAN	Decreases Activity	[36]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[37]
Serine/threonine-protein kinase Sgk1 (SGK1)	OT301T1U	SGK1_HUMAN	Increases Expression	[38]
Tissue-type plasminogen activator (PLAT)	OTQPDNAB	TPA_HUMAN	Increases Expression	[39]
Angiotensinogen (AGT)	OTBZLYR3	ANGT_HUMAN	Increases Expression	[40]
Natriuretic peptides A (NPPA)	OTMQNTNX	ANF_HUMAN	Decreases Expression	[41]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Expression	[42]
Collagen alpha-1(III) chain (COL3A1)	OTT1EMLM	CO3A1_HUMAN	Decreases Expression	[41]
Trefoil factor 1 (TFF1)	OTCYQH4F	TFF1_HUMAN	Increases Expression	[43]
Plasminogen activator inhibitor 1 (SERPINE1)	OTT0MPQ3	PAI1_HUMAN	Decreases Expression	[39]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[44]
Mineralocorticoid receptor (NR3C2)	OT0F2V2Z	MCR_HUMAN	Increases Activity	[45]
Myb-related protein A (MYBL1)	OTBJMC2P	MYBA_HUMAN	Increases Expression	[38]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Affects Binding	[46]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Decreases Expression	[41]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[47]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[47]
Protein GREB1 (GREB1)	OTU6ZA26	GREB1_HUMAN	Increases Expression	[38]
Renin (REN)	OT52GZR2	RENI_HUMAN	Decreases Response To Substance	[48]
Serum paraoxonase/lactonase 3 (PON3)	OT80W9TA	PON3_HUMAN	Increases Hydrolysis	[49]

References

• [1] Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
• [2] Olanzapine 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: 47).
• [4] Spironolactone 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: 2875).
• [6] Spironolactone in Covid-19 Induced ARDS
• [7] Neuroleptic Drugs and PACAP Differentially Affect the mRNA Expression of Genes Encoding PAC1/VPAC Type Receptors. Neurochem Res. 2017 Apr;42(4):943-952. doi: 10.1007/s11064-016-2127-2. Epub 2016 Nov 30.
• [8] Olanzapine: an updated review of its use in the management of schizophrenia. Drugs. 2001;61(1):111-61.
• [9] 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.
• [10] Interactions between the cytochrome P450 system and the second-generation antipsychotics. J Psychiatry Neurosci. 2003 Mar;28(2):99-112.
• [11] [Olanzapine: pharmacology, pharmacokinetics and therapeutic drug monitoring]. Fortschr Neurol Psychiatr. 2001 Nov;69(11):510-7.
• [12] Evaluation of antipsychotic drugs as inhibitors of multidrug resistance transporter P-glycoprotein. Psychopharmacology (Berl). 2006 Sep;187(4):415-23. doi: 10.1007/s00213-006-0437-9. Epub 2006 Jun 30.
• [13] Dopamine receptor D2 gene is associated with weight gain in schizophrenic patients under long-term atypical antipsychotic treatment. Pharmacogenet Genomics. 2010 Jun;20(6):359-66. doi: 10.1097/FPC.0b013e3283397d06.
• [14] Drug-induced activation of SREBP-controlled lipogenic gene expression in CNS-related cell lines: marked differences between various antipsychotic drugs. BMC Neurosci. 2006 Oct 20;7:69.
• [15] Up-regulation of hepatic fatty acid transporters and inhibition/down-regulation of hepatic OCTN2 contribute to olanzapine-induced liver steatosis. Toxicol Lett. 2019 Nov;316:183-193. doi: 10.1016/j.toxlet.2019.08.013. Epub 2019 Aug 19.
• [16] In vitro approach to assess the potential for risk of idiosyncratic adverse reactions caused by candidate drugs. Chem Res Toxicol. 2012 Aug 20;25(8):1616-32. doi: 10.1021/tx300091x. Epub 2012 May 31.
• [17] Effects of olanzapine on serum protein phosphorylation patterns in patients with schizophrenia. Proteomics Clin Appl. 2015 Oct;9(9-10):907-16. doi: 10.1002/prca.201400148. Epub 2015 May 15.
• [18] The effects of olanzapine, risperidone, and haloperidol on plasma prolactin levels in patients with schizophrenia. Clin Ther. 2000 Sep;22(9):1085-96. doi: 10.1016/S0149-2918(00)80086-7.
• [19] Recovery from new-onset diabetes in a schizophrenic man after withdrawal of olanzapine. Psychosomatics. 2002 Jan-Feb;43(1):67-70. doi: 10.1176/appi.psy.43.1.67.
• [20] Hormonal markers of metabolic dysregulation in patients with severe mental disorders after olanzapine treatment under real-life conditions. J Clin Psychopharmacol. 2009 Apr;29(2):109-16. doi: 10.1097/JCP.0b013e31819b95fc.
• [21] Clozapine induces oxidative stress and proapoptotic gene expression in neutrophils of schizophrenic patients. J Clin Psychopharmacol. 2005 Oct;25(5):419-26. doi: 10.1097/01.jcp.0000177668.42640.fe.
• [22] No evidence for binding of clozapine, olanzapine and/or haloperidol to selected receptors involved in body weight regulation. Pharmacogenomics J. 2007 Aug;7(4):275-81. doi: 10.1038/sj.tpj.6500418. Epub 2006 Sep 19.
• [23] Effects of different antipsychotics and the antidepressant mirtazapine on glucose transporter mRNA levels in human blood cells. J Psychiatr Res. 2006 Jun;40(4):374-9. doi: 10.1016/j.jpsychires.2005.04.016. Epub 2005 Jul 5.
• [24] The differential effects of neuroleptic drugs and PACAP on the expression of BDNF mRNA and protein in a human glioblastoma cell line. Acta Neurobiol Exp (Wars). 2017;77(3):205-213.
• [25] Famotidine has a neuroprotective effect on MK-801 induced toxicity via the Akt/GSK-3/-catenin signaling pathway in the SH-SY5Y cell line. Chem Biol Interact. 2019 Dec 1;314:108823. doi: 10.1016/j.cbi.2019.108823. Epub 2019 Sep 26.
• [26] Effects of cyamemazine on hERG, INa, ICa, Ito, Isus and IK1 channel currents, and on the QTc interval in guinea pigs. Eur J Pharmacol. 2006 Feb 27;532(3):270-8. doi: 10.1016/j.ejphar.2005.12.079. Epub 2006 Feb 21.
• [27] 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.
• [28] Serotonin-1A receptor gene polymorphism and the ability of antipsychotic drugs to improve attention in schizophrenia. Adv Ther. 2010 May;27(5):307-13. doi: 10.1007/s12325-010-0035-4. Epub 2010 Jun 8.
• [29] Olanzapine-induced weight gain is associated with the -759C/T and -697G/C polymorphisms of the HTR2C gene. Pharmacogenomics J. 2009 Aug;9(4):234-41. doi: 10.1038/tpj.2009.18. Epub 2009 May 12.
• [30] DRD2/AKT1 interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia. Proc Natl Acad Sci U S A. 2011 Jan 18;108(3):1158-63. doi: 10.1073/pnas.1013535108. Epub 2010 Dec 27.
• [31] Different impacts of aquaporin 4 and MAOA allele variation among olanzapine, risperidone, and paliperidone in schizophrenia. J Clin Psychopharmacol. 2012 Jun;32(3):394-7. doi: 10.1097/JCP.0b013e31825370f4.
• [32] MTHFR and risk of metabolic syndrome in patients with schizophrenia. Schizophr Res. 2010 Aug;121(1-3):193-8. doi: 10.1016/j.schres.2010.05.030. Epub 2010 Jun 12.
• [33] The SNAP-25 gene may be associated with clinical response and weight gain in antipsychotic treatment of schizophrenia. Neurosci Lett. 2005 May 6;379(2):81-9. doi: 10.1016/j.neulet.2004.12.037. Epub 2005 Jan 26.
• [34] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [35] Receptor-dependent regulation of the CYP3A4 gene. Toxicology. 2002 Dec 27;181-182:199-202.
• [36] Examination of 209 drugs for inhibition of cytochrome P450 2C8. J Clin Pharmacol. 2005 Jan;45(1):68-78.
• [37] Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013 Dec;136(2):328-43.
• [38] A Gene Expression Biomarker Identifies Chemical Modulators of Estrogen Receptor in an MCF-7 Microarray Compendium. Chem Res Toxicol. 2021 Feb 15;34(2):313-329. doi: 10.1021/acs.chemrestox.0c00243. Epub 2021 Jan 6.
• [39] Effect of spironolactone on impaired fibrinolysis of hypertensive patients. Kidney Blood Press Res. 2002;25(4):260-4. doi: 10.1159/000066348.
• [40] Amiloride, spironolactone, and potassium chloride in thiazide-treated hypertensive patients. Clin Pharmacol Ther. 1980 Apr;27(4):533-43. doi: 10.1038/clpt.1980.75.
• [41] Effect of spironolactone on plasma brain natriuretic peptide and left ventricular remodeling in patients with congestive heart failure. J Am Coll Cardiol. 2001 Apr;37(5):1228-33. doi: 10.1016/s0735-1097(01)01116-0.
• [42] Spironolactone induces apoptosis in human mononuclear cells. Association between apoptosis and cytokine suppression. Apoptosis. 2006 Apr;11(4):573-9. doi: 10.1007/s10495-006-4919-3.
• [43] Evaluation of an imaging-based in vitro screening platform for estrogenic activity with OECD reference chemicals. Toxicol In Vitro. 2022 Jun;81:105348. doi: 10.1016/j.tiv.2022.105348. Epub 2022 Mar 18.
• [44] Pregnane X receptor mediates the induction of P-glycoprotein by spironolactone in HepG2 cells. Toxicology. 2011 Jul 11;285(1-2):18-24. doi: 10.1016/j.tox.2011.03.015. Epub 2011 Apr 1.
• [45] The human mineralocorticoid receptor only partially differentiates between different ligands after expression in fission yeast. FEMS Yeast Res. 2005 Apr;5(6-7):627-33. doi: 10.1016/j.femsyr.2004.12.007.
• [46] Comparison of the Hershberger assay and androgen receptor binding assay of twelve chemicals. Toxicology. 2004 Feb 15;195(2-3):177-86. doi: 10.1016/j.tox.2003.09.012.
• [47] Palmitate increases the susceptibility of cells to drug-induced toxicity: an in vitro method to identify drugs with potential contraindications in patients with metabolic disease. Toxicol Sci. 2012 Oct;129(2):346-62. doi: 10.1093/toxsci/kfs208. Epub 2012 Jun 14.
• [48] Clinical and biochemical effects of spironolactone administered once daily in primary hypertension. Multicenter Sweden study. Hypertension. 1980 Sep-Oct;2(5):672-9. doi: 10.1161/01.hyp.2.5.672.
• [49] Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities. J Lipid Res. 2005 Jun;46(6):1239-47. doi: 10.1194/jlr.M400511-JLR200. Epub 2005 Mar 16.