Details of the Drug Combination

General Information of Drug Combination (ID: DCZWEU0)

• Drug Combination Name: Olanzapine + Probenecid
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Olanzapine (DMPFN6Y): Small molecular drug
  Probenecid (DMMFWOJ): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 39.15
  Bliss Independence Score: 39.15
  Loewe Additivity Score: 55.87
  LHighest Single Agent (HSA) Score: 55.88

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	[7]

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	[8]

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	[9]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[10]

Olanzapine Interacts with 36 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Activity	[11]
D(2) dopamine receptor (DRD2)	OTBLXKEG	DRD2_HUMAN	Increases Response To Substance	[12]
Lathosterol oxidase (SC5D)	OT41KMW4	SC5D_HUMAN	Increases Expression	[13]
Hydroxymethylglutaryl-CoA synthase, cytoplasmic (HMGCS1)	OTCO26FV	HMCS1_HUMAN	Increases Expression	[13]
Long-chain fatty acid transport protein 2 (SLC27A2)	OT7JEG5F	S27A2_HUMAN	Increases Expression	[14]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[15]
Ceruloplasmin (CP)	OTM8JE4Y	CERU_HUMAN	Affects Phosphorylation	[16]
Prothrombin (F2)	OTNFSM49	THRB_HUMAN	Affects Phosphorylation	[16]
Alpha-1-antichymotrypsin (SERPINA3)	OT9BP2S0	AACT_HUMAN	Increases Phosphorylation	[16]
Alpha-2-macroglobulin (A2M)	OTFTX90K	A2MG_HUMAN	Affects Phosphorylation	[16]
Collagen alpha-1(I) chain (COL1A1)	OTI31178	CO1A1_HUMAN	Decreases Phosphorylation	[16]
Complement component C9 (C9)	OT7I5FDX	CO9_HUMAN	Affects Phosphorylation	[16]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Phosphorylation	[16]
Vitamin D-binding protein (GC)	OTWS63BY	VTDB_HUMAN	Affects Phosphorylation	[16]
Hemopexin (HPX)	OT14T7Q1	HEMO_HUMAN	Affects Phosphorylation	[16]
Histidine-rich glycoprotein (HRG)	OTPLUFOG	HRG_HUMAN	Affects Phosphorylation	[16]
Alpha-1B-glycoprotein (A1BG)	OTFVUGNQ	A1BG_HUMAN	Affects Phosphorylation	[16]
Sex hormone-binding globulin (SHBG)	OTPWU5IW	SHBG_HUMAN	Decreases Expression	[17]
Plasma protease C1 inhibitor (SERPING1)	OT6CVN45	IC1_HUMAN	Affects Phosphorylation	[16]
Complement C4-A (C4A)	OTXMOYXU	CO4A_HUMAN	Decreases Phosphorylation	[16]
Complement component C6 (C6)	OTCKR304	CO6_HUMAN	Affects Phosphorylation	[16]
Solute carrier family 2, facilitated glucose transporter member 4 (SLC2A4)	OTJZG0LD	GLUT4_HUMAN	Increases Expression	[18]
Inter-alpha-trypsin inhibitor heavy chain H2 (ITIH2)	OTG3WBBE	ITIH2_HUMAN	Affects Phosphorylation	[16]
5-hydroxytryptamine receptor 2A (HTR2A)	OTWXJX0M	5HT2A_HUMAN	Affects Binding	[19]
Catenin beta-1 (CTNNB1)	OTZ932A3	CTNB1_HUMAN	Increases Expression	[20]
Pituitary adenylate cyclase-activating polypeptide type I receptor (ADCYAP1R1)	OTNBHULA	PACR_HUMAN	Affects Expression	[6]
Afamin (AFM)	OTPOR8IO	AFAM_HUMAN	Affects Phosphorylation	[16]
5-hydroxytryptamine receptor 6 (HTR6)	OT8GTDDY	5HT6R_HUMAN	Affects Binding	[19]
Bcl-2-interacting killer (BIK)	OTTH1T3D	BIK_HUMAN	Increases Expression	[21]
Inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4)	OT460OO1	ITIH4_HUMAN	Affects Phosphorylation	[16]
Long-chain fatty acid transport protein 5 (SLC27A5)	OT4OK511	S27A5_HUMAN	Increases Expression	[14]
D(3) dopamine receptor (DRD3)	OT0OFFKB	DRD3_HUMAN	Increases ADR	[22]
5-hydroxytryptamine receptor 1A (HTR1A)	OT38K9MK	5HT1A_HUMAN	Increases Response	[23]
5-hydroxytryptamine receptor 2C (HTR2C)	OT6H8DE0	5HT2C_HUMAN	Increases Response To Substance	[24]
Aquaporin-4 (AQP4)	OTA9MYD5	AQP4_HUMAN	Increases Response To Substance	[25]
D(4) dopamine receptor (DRD4)	OTAJTO7N	DRD4_HUMAN	Increases ADR	[22]

Indication(s) of Probenecid

Disease Entry	ICD 11	Status	REF
Acute gonococcal cervicitis	N.A.	Approved	[4]
Gout	FA25	Approved	[5]
Hyperuricaemia	5C55.Y	Approved	[5]

Probenecid Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Solute carrier family 22 member 8 (SLC22A8)	TTTQR47	S22A8_HUMAN	Blocker	[27]

Probenecid Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[28]
Organic anion transporting polypeptide 1A2 (SLCO1A2)	DTE2B1D	SO1A2_HUMAN	Substrate	[29]
Monocarboxylate transporter 6 (SLC16A5)	DT3I124	MOT6_HUMAN	Substrate	[30]

Probenecid Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[31]

Probenecid Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Taste receptor type 2 member 38 (TAS2R38)	OTX5MM36	T2R38_HUMAN	Decreases Activity	[32]
Taste receptor type 2 member 43 (TAS2R43)	OT70V8MZ	T2R43_HUMAN	Decreases Activity	[32]
Solute carrier family 22 member 6 (SLC22A6)	OTKRCBVM	S22A6_HUMAN	Decreases Activity	[33]
Organic anion transporter 7 (SLC22A9)	OTO4BJCC	S22A9_HUMAN	Decreases Activity	[33]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[34]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Expression	[34]
Organic anion transporter 3 (SLC22A8)	OT8BY933	S22A8_HUMAN	Decreases Expression	[35]
Solute carrier family 22 member 12 (SLC22A12)	OT72ZAWS	S22AC_HUMAN	Affects Activity	[36]
Solute carrier family 22 member 11 (SLC22A11)	OTAJLNJZ	S22AB_HUMAN	Decreases Activity	[37]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [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] Probenecid 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: 4357).
• [6] 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.
• [7] Olanzapine: an updated review of its use in the management of schizophrenia. Drugs. 2001;61(1):111-61.
• [8] 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.
• [9] Interactions between the cytochrome P450 system and the second-generation antipsychotics. J Psychiatry Neurosci. 2003 Mar;28(2):99-112.
• [10] [Olanzapine: pharmacology, pharmacokinetics and therapeutic drug monitoring]. Fortschr Neurol Psychiatr. 2001 Nov;69(11):510-7.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.
• [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] 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.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] Carboxylic acid drug-induced DNA nicking in HEK293 cells expressing human UDP-glucuronosyltransferases: role of acyl glucuronide metabolites and glycation pathways. Chem Res Toxicol. 2007 Oct;20(10):1520-7. doi: 10.1021/tx700188x. Epub 2007 Sep 20.
• [27] Transport of organic anions across the basolateral membrane of proximal tubule cells. Rev Physiol Biochem Pharmacol. 2003;146:95-158.
• [28] MRP2 (ABCC2) transports taxanes and confers paclitaxel resistance and both processes are stimulated by probenecid. Int J Cancer. 2005 Sep 20;116(5):824-9.
• [29] Characterization of the efflux transport of 17beta-estradiol-D-17beta-glucuronide from the brain across the blood-brain barrier. J Pharmacol Exp Ther. 2001 Jul;298(1):316-22.
• [30] Quercetin, Morin, Luteolin, and Phloretin Are Dietary Flavonoid Inhibitors of Monocarboxylate Transporter 6. Mol Pharm. 2017 Sep 5;14(9):2930-2936.
• [31] Modulation of 3'-azido-3'-deoxythymidine catabolism by probenecid and acetaminophen in freshly isolated rat hepatocytes. Biochem Pharmacol. 1991 Sep 12;42(7):1475-80.
• [32] Probenecid inhibits the human bitter taste receptor TAS2R16 and suppresses bitter perception of salicin. PLoS One. 2011;6(5):e20123.
• [33] Inhibition of organic anion transporter (OAT) activity by cigarette smoke condensate. Toxicol In Vitro. 2017 Oct;44:27-35.
• [34] Evaluation and mechanistic analysis of the cytotoxicity of the acyl glucuronide of nonsteroidal anti-inflammatory drugs. Drug Metab Dispos. 2014 Jan;42(1):1-8. doi: 10.1124/dmd.113.054478. Epub 2013 Oct 8.
• [35] Targeting organic anion transporter 3 with probenecid as a novel anti-influenza a virus strategy. Antimicrob Agents Chemother. 2013 Jan;57(1):475-83. doi: 10.1128/AAC.01532-12. Epub 2012 Nov 5.
• [36] Clinical and molecular analysis of patients with renal hypouricemia in Japan-influence of URAT1 gene on urinary urate excretion. J Am Soc Nephrol. 2004 Jan;15(1):164-73. doi: 10.1097/01.asn.0000105320.04395.d0.
• [37] Neonicotinoid pesticides poorly interact with human drug transporters. J Biochem Mol Toxicol. 2019 Oct;33(10):e22379. doi: 10.1002/jbt.22379. Epub 2019 Jul 31.