Details of the Drug Combination

General Information of Drug Combination (ID: DC2U92O)

• Drug Combination Name: Pyrazinamide + Theophylline
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Pyrazinamide (DM4IF32): Small molecular drug
  Theophylline (DMRJFN9): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 27.93
  Bliss Independence Score: 27.93
  Loewe Additivity Score: 42.58
  LHighest Single Agent (HSA) Score: 42.6

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Pyrazinamide

Disease Entry	ICD 11	Status	REF
Meningeal tuberculosis	N.A.	Approved	[2]
Mycobacterium infection	1B10-1B21	Approved	[3]
Pulmonary tuberculosis	1B10.Z	Approved	[2]

Pyrazinamide Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bacterial Fatty acid synthetase I (Bact inhA)	TTVTX4N	INHA_MYCTU	Inhibitor	[7]

Pyrazinamide Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[8]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[8]
Nicotinamidase (pncA)	DERQS6E	B0VA03_ACIBY	Metabolism	[9]

Pyrazinamide Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Serine/threonine-protein kinase/endoribonuclease IRE1 (ERN1)	OTY9R6FZ	ERN1_HUMAN	Increases Expression	[6]
Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1)	OTM0GDTP	IF2A_HUMAN	Increases Phosphorylation	[6]
Endoplasmic reticulum chaperone BiP (HSPA5)	OTFUIRAO	BIP_HUMAN	Increases Expression	[6]
Cyclic AMP-dependent transcription factor ATF-4 (ATF4)	OTRFV19J	ATF4_HUMAN	Increases Expression	[6]
Cyclic AMP-dependent transcription factor ATF-6 alpha (ATF6)	OTAFHAVI	ATF6A_HUMAN	Increases Expression	[6]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[6]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[6]
Solute carrier family 22 member 12 (SLC22A12)	OT72ZAWS	S22AC_HUMAN	Affects Activity	[10]
Eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3)	OT0DZGY4	E2AK3_HUMAN	Increases Phosphorylation	[6]

Indication(s) of Theophylline

Disease Entry	ICD 11	Status	REF
Bronchitis	CA20	Approved	[4]
Chronic obstructive pulmonary disease	CA22	Approved	[5]
Lung cancer	2C25.0	Approved	[4]
Non-small-cell lung cancer	2C25.Y	Approved	[4]
Pulmonary disease	1B10-1F85	Approved	[4]
Pulmonary emphysema	CA21.Z	Approved	[4]
Severe asthma	CA23	Approved	[4]
Asthma	CA23	Investigative	[4]

Theophylline Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adenosine receptor (ADOR)	TTSLI08	NOUNIPROTAC	Antagonist	[11]

Theophylline Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic anion transporter 2 (SLC22A7)	DT0OC1Q	S22A7_HUMAN	Substrate	[12]

Theophylline Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[13]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[14]
Cytochrome P450 1A1 (CYP1A1)	DE6OQ3W	CP1A1_HUMAN	Metabolism	[15]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[13]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[16]
Cytochrome P450 1B1 (CYP1B1)	DE9QHP6	CP1B1_HUMAN	Metabolism	[17]

Theophylline Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2E1 (CYP2E1)	OTHQ17JG	CP2E1_HUMAN	Increases ADR	[18]
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases ADR	[18]
Alanine aminotransferase 1 (GPT)	OTOXOA0Q	ALAT1_HUMAN	Increases ADR	[18]
Cyclic GMP-AMP phosphodiesterase SMPDL3A (SMPDL3A)	OTQDYH8E	ASM3A_HUMAN	Increases ADR	[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] Pyrazinamide 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: 7287).
• [4] Theophylline 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: 413).
• [6] Pyrazinamide-induced hepatotoxicity is alleviated by 4-PBA via inhibition of the PERK-eIF2-ATF4-CHOP pathway. Toxicology. 2017 Mar 1;378:65-75. doi: 10.1016/j.tox.2017.01.002. Epub 2017 Jan 4.
• [7] Pyrazinamide inhibits the eukaryotic-like fatty acid synthetase I (FASI) of Mycobacterium tuberculosis. Nat Med. 2000 Sep;6(9):1043-7.
• [8] The metabolism of pyrazoloacridine (NSC 366140) by cytochromes p450 and flavin monooxygenase in human liver microsomes. Clin Cancer Res. 2004 Feb 15;10(4):1471-80.
• [9] Specificity and mechanism of Acinetobacter baumanii nicotinamidase: implications for activation of the front-line tuberculosis drug pyrazinamide. Angew Chem Int Ed Engl. 2009;48(48):9176-9.
• [10] 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.
• [11] Emerging adenosine receptor agonists. Expert Opin Emerg Drugs. 2007 Sep;12(3):479-92.
• [12] Possible involvement of organic anion transporter 2 on the interaction of theophylline with erythromycin in the human liver. Drug Metab Dispos. 2005 May;33(5):619-22.
• [13] Characterization of human cytochromes P450 involved in theophylline 8-hydroxylation. Biochem Pharmacol. 1995 Jul 17;50(2):205-11.
• [14] Association between common CYP1A2 polymorphisms and theophylline metabolism in non-smoking healthy volunteers. Basic Clin Pharmacol Toxicol. 2013 Apr;112(4):257-63.
• [15] Specificity of substrate and inhibitor probes for human cytochromes P450 1A1 and 1A2. J Pharmacol Exp Ther. 1993 Apr;265(1):401-7.
• [16] Construction and assessment of models of CYP2E1: predictions of metabolism from docking, molecular dynamics, and density functional theoretical calculations. J Med Chem. 2003 Apr 24;46(9):1645-60.
• [17] Oxidation of xenobiotics by recombinant human cytochrome P450 1B1. Drug Metab Dispos. 1997 May;25(5):617-22.
• [18] 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.