Details of the Drug Combination

General Information of Drug Combination (ID: DCL8XQL)

• Drug Combination Name: Sulfinpyrazone + Nizatidine
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Sulfinpyrazone (DMEV954): Small molecular drug
  Nizatidine (DMGFV3Z): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 3.79
  Bliss Independence Score: 3.79
  Loewe Additivity Score: 17.87
  LHighest Single Agent (HSA) Score: 17.89

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Sulfinpyrazone

Disease Entry	ICD 11	Status	REF
Gout	FA25	Approved	[2]

Sulfinpyrazone Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 1 (ABCC1)	TTOI92F	MRP1_HUMAN	Modulator	[5]

Sulfinpyrazone Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[6]

Sulfinpyrazone Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[7]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[8]

Sulfinpyrazone Interacts with 7 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C8 (CYP2C8)	OTHCWT42	CP2C8_HUMAN	Decreases Activity	[9]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[10]
ATP-binding cassette sub-family C member 2 (ABCC2)	OTJSIGV5	MRP2_HUMAN	Decreases Activity	[11]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[7]
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Increases Expression	[12]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[13]
Multidrug resistance-associated protein 1 (ABCC1)	OTGUN89S	MRP1_HUMAN	Decreases Activity	[14]

Indication(s) of Nizatidine

Disease Entry	ICD 11	Status	REF
Acid-reflux disorder	DA22	Approved	[3]
Gastric ulcer	DA60	Approved	[4]
Peptic esophagitis	N.A.	Approved	[4]
Peptic ulcer	DA61	Approved	[4]

Nizatidine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Histamine H2 receptor (H2R)	TTQHJ1K	HRH2_HUMAN	Antagonist	[15]

Nizatidine Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[16]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[17]

Nizatidine Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Calcitonin (CALCA)	OTZ11LHB	CALC_HUMAN	Increases Expression	[18]
Protachykinin-1 (TAC1)	OTM842YW	TKN1_HUMAN	Increases Expression	[18]

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] 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: 5826).
• [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: 7248).
• [4] Nizatidine FDA Label
• [5] Species-dependent transport and modulation properties of human and mouse multidrug resistance protein 2 (MRP2/Mrp2, ABCC2/Abcc2). Drug Metab Dispos. 2008 Apr;36(4):631-40.
• [6] Vinblastine and sulfinpyrazone export by the multidrug resistance protein MRP2 is associated with glutathione export. Br J Cancer. 2000 Aug;83(3):375-83.
• [7] CYP3A4 induction by drugs: correlation between a pregnane X receptor reporter gene assay and CYP3A4 expression in human hepatocytes. Drug Metab Dispos. 2002 Jul;30(7):795-804.
• [8] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [9] Essential requirements for substrate binding affinity and selectivity toward human CYP2 family enzymes. Arch Biochem Biophys. 2003 Jan 1;409(1):32-44.
• [10] A reporter gene assay to assess the molecular mechanisms of xenobiotic-dependent induction of the human CYP3A4 gene in vitro. Xenobiotica. 1999 Mar;29(3):269-79.
• [11] Role of multidrug resistance protein 2 (MRP2, ABCC2) in alkylating agent detoxification: MRP2 potentiates glutathione S-transferase A1-1-mediated resistance to chlorambucil cytotoxicity. J Pharmacol Exp Ther. 2004 Jan;308(1):260-7. doi: 10.1124/jpet.103.057729. Epub 2003 Oct 20.
• [12] Regulation of CYP2B6 in primary human hepatocytes by prototypical inducers. Drug Metab Dispos. 2004 Mar;32(3):348-58.
• [13] Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013 Dec;136(2):328-43.
• [14] Glutathione S-transferase M1 and multidrug resistance protein 1 act in synergy to protect melanoma cells from vincristine effects. Mol Pharmacol. 2004 Apr;65(4):897-905. doi: 10.1124/mol.65.4.897.
• [15] Does the use of nizatidine, as a pro-kinetic agent, improve gastric emptying in patients post-oesophagectomy J Gastrointest Surg. 2009 Mar;13(3):432-7.
• [16] DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. (ID: DB00585)
• [17] Identification of novel substrates and structure-activity relationship of cellular uptake mediated by human organic cation transporters 1 and 2. J Med Chem. 2013 Sep 26;56(18):7232-42.
• [18] Effects of histamine H(2)-receptor antagonists on human plasma levels of calcitonin gene-related peptide, substance P and vasoactive intestinal peptide. J Pharm Pharmacol. 2002 Nov;54(11):1559-63. doi: 10.1211/002235702117.