Details of the Drug Combination

General Information of Drug Combination (ID: DC5LU8O)

• Drug Combination Name: Diazoxide + Probenecid
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Diazoxide (DML1538): Small molecular drug
  Probenecid (DMMFWOJ): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 3.15
  Bliss Independence Score: 3.15
  Loewe Additivity Score: 3.6
  LHighest Single Agent (HSA) Score: 3.64

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Diazoxide

Disease Entry	ICD 11	Status	REF
Congenital hyperinsulinism	5A4Y	Approved	[2]
Hyperinsulinemia	5A4Y	Approved	[2]
Hypertension	BA00-BA04	Approved	[3]
Hypertensive emergency	BA03	Approved	[2]
Insulinoma	2C10.1	Approved	[2]
Malignant essential hypertension	BA00	Approved	[2]

Diazoxide Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Potassium channel unspecific (KC)	TT1VOHK	NOUNIPROTAC	Modulator	[6]

Diazoxide Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Secretion	[7]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Secretion	[7]
Nuclear factor NF-kappa-B p105 subunit (NFKB1)	OTNRRD8I	NFKB1_HUMAN	Increases Activity	[8]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Decreases Secretion	[7]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[9]
Catenin beta-1 (CTNNB1)	OTZ932A3	CTNB1_HUMAN	Decreases Expression	[9]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Increases Expression	[8]
ATP-sensitive inward rectifier potassium channel 11 (KCNJ11)	OTPUUELV	KCJ11_HUMAN	Decreases Expression	[10]

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	[12]

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	[13]
Organic anion transporting polypeptide 1A2 (SLCO1A2)	DTE2B1D	SO1A2_HUMAN	Substrate	[14]
Monocarboxylate transporter 6 (SLC16A5)	DT3I124	MOT6_HUMAN	Substrate	[15]

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	[16]

Probenecid Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-binding cassette sub-family C member 2 (ABCC2)	OTJSIGV5	MRP2_HUMAN	Increases Activity	[17]
Multidrug resistance-associated protein 1 (ABCC1)	OTGUN89S	MRP1_HUMAN	Decreases Activity	[18]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Expression	[19]
Taste receptor type 2 member 38 (TAS2R38)	OTX5MM36	T2R38_HUMAN	Decreases Activity	[20]
Taste receptor type 2 member 43 (TAS2R43)	OT70V8MZ	T2R43_HUMAN	Decreases Activity	[20]
Solute carrier family 22 member 6 (SLC22A6)	OTKRCBVM	S22A6_HUMAN	Decreases Activity	[21]
Organic anion transporter 7 (SLC22A9)	OTO4BJCC	S22A9_HUMAN	Decreases Activity	[21]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[22]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Expression	[22]
Sodium-coupled monocarboxylate transporter 1 (SLC5A8)	OTA0WELF	SC5A8_HUMAN	Decreases Activity	[23]
Organic anion transporter 3 (SLC22A8)	OT8BY933	S22A8_HUMAN	Decreases Expression	[24]
Solute carrier family 22 member 12 (SLC22A12)	OT72ZAWS	S22AC_HUMAN	Affects Activity	[25]
Solute carrier family 22 member 11 (SLC22A11)	OTAJLNJZ	S22AB_HUMAN	Decreases Activity	[26]

References

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• [2] Diazoxide FDA Label
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• [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] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [7] Antihypertensive drugs clonidine, diazoxide, hydralazine and furosemide regulate the production of cytokines by placentas and peripheral blood mononuclear cells in normal pregnancy. J Hypertens. 2006 May;24(5):915-22. doi: 10.1097/01.hjh.0000222762.84605.03.
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• [20] Probenecid inhibits the human bitter taste receptor TAS2R16 and suppresses bitter perception of salicin. PLoS One. 2011;6(5):e20123.
• [21] Inhibition of organic anion transporter (OAT) activity by cigarette smoke condensate. Toxicol In Vitro. 2017 Oct;44:27-35.
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• [23] The human tumour suppressor gene SLC5A8 expresses a Na+-monocarboxylate cotransporter. J Physiol. 2004 Jun 15;557(Pt 3):719-31. doi: 10.1113/jphysiol.2004.063859. Epub 2004 Apr 16.
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• [26] 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.