Details of the Drug Combination

General Information of Drug Combination (ID: DCBP8IA)

• Drug Combination Name: Artemisinin + Theophylline
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Artemisinin (DMOY7W3): Small molecular drug
  Theophylline (DMRJFN9): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 29.79
  Bliss Independence Score: 29.79
  Loewe Additivity Score: 38.01
  LHighest Single Agent (HSA) Score: 38.05

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Artemisinin

Disease Entry	ICD 11	Status	REF
Malaria	1F40-1F45	Approved	[2]

Artemisinin Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Plasmodium Dihydroorotate dehydrogenase (Malaria DHOdehase)	TT3PQ2Y	PYRD_PLAF7	Inhibitor	[2]
Sarcoplasmic/endoplasmic reticulum calcium ATPase (ATP2A)	TTZVSJ2	NOUNIPROTAC	Inhibitor	[2]

Artemisinin Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[5]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[6]
Glutathione S-transferase alpha-1 (GSTA1)	DE4ZHS1	GSTA1_HUMAN	Metabolism	[7]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[5]

Artemisinin Interacts with 10 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Glutathione S-transferase A1 (GSTA1)	OTA7K5XA	GSTA1_HUMAN	Decreases Activity	[7]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[8]
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Increases Expression	[8]
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Decreases Activity	[9]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Decreases Activity	[9]
Glutathione S-transferase P (GSTP1)	OTLP0A0Y	GSTP1_HUMAN	Decreases Activity	[7]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[8]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Activity	[10]
Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A)	OT5QQB5L	IDH3A_HUMAN	Decreases Expression	[10]
Nuclear receptor subfamily 1 group I member 3 (NR1I3)	OTS3SGH7	NR1I3_HUMAN	Increases Activity	[11]

Indication(s) of Theophylline

Disease Entry	ICD 11	Status	REF
Bronchitis	CA20	Approved	[3]
Chronic obstructive pulmonary disease	CA22	Approved	[4]
Lung cancer	2C25.0	Approved	[3]
Non-small-cell lung cancer	2C25.Y	Approved	[3]
Pulmonary disease	1B10-1F85	Approved	[3]
Pulmonary emphysema	CA21.Z	Approved	[3]
Severe asthma	CA23	Approved	[3]
Asthma	CA23	Investigative	[3]

Theophylline Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adenosine receptor (ADOR)	TTSLI08	NOUNIPROTAC	Antagonist	[12]

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	[13]

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	[14]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[15]
Cytochrome P450 1A1 (CYP1A1)	DE6OQ3W	CP1A1_HUMAN	Metabolism	[16]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[14]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[17]
Cytochrome P450 1B1 (CYP1B1)	DE9QHP6	CP1B1_HUMAN	Metabolism	[18]

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	[19]
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases ADR	[19]
Alanine aminotransferase 1 (GPT)	OTOXOA0Q	ALAT1_HUMAN	Increases ADR	[19]
Cyclic GMP-AMP phosphodiesterase SMPDL3A (SMPDL3A)	OTQDYH8E	ASM3A_HUMAN	Increases ADR	[19]

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] The fight against drug-resistant malaria: novel plasmodial targets and antimalarial drugs. Curr Med Chem. 2008;15(2):161-71.
• [3] Theophylline FDA Label
• [4] 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).
• [5] Antimalarial artemisinin drugs induce cytochrome P450 and MDR1 expression by activation of xenosensors pregnane X receptor and constitutive androstane receptor. Mol Pharmacol. 2005 Jun;67(6):1954-65.
• [6] Identification of the human cytochrome P450 enzymes involved in the in vitro metabolism of artemisinin. Br J Clin Pharmacol. 1999 Oct;48(4):528-35.
• [7] Inhibition of glutathione S-transferases by antimalarial drugs possible implications for circumventing anticancer drug resistance. Int J Cancer. 2002 Feb 10;97(5):700-5.
• [8] Antimalarial artemisinin drugs induce cytochrome P450 and MDR1 expression by activation of xenosensors pregnane X receptor and constitutive androstane receptor. Mol Pharmacol. 2005 Jun;67(6):1954-65.
• [9] Application of higher throughput screening (HTS) inhibition assays to evaluate the interaction of antiparasitic drugs with cytochrome P450s. Drug Metab Dispos. 2001 Jan;29(1):30-5.
• [10] Identification of Compounds That Inhibit Estrogen-Related Receptor Alpha Signaling Using High-Throughput Screening Assays. Molecules. 2019 Feb 27;24(5):841. doi: 10.3390/molecules24050841.
• [11] In vivo and mechanistic evidence of nuclear receptor CAR induction by artemisinin. Eur J Clin Invest. 2006 Sep;36(9):647-53. doi: 10.1111/j.1365-2362.2006.01700.x.
• [12] Emerging adenosine receptor agonists. Expert Opin Emerg Drugs. 2007 Sep;12(3):479-92.
• [13] 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.
• [14] Characterization of human cytochromes P450 involved in theophylline 8-hydroxylation. Biochem Pharmacol. 1995 Jul 17;50(2):205-11.
• [15] Association between common CYP1A2 polymorphisms and theophylline metabolism in non-smoking healthy volunteers. Basic Clin Pharmacol Toxicol. 2013 Apr;112(4):257-63.
• [16] Specificity of substrate and inhibitor probes for human cytochromes P450 1A1 and 1A2. J Pharmacol Exp Ther. 1993 Apr;265(1):401-7.
• [17] 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.
• [18] Oxidation of xenobiotics by recombinant human cytochrome P450 1B1. Drug Metab Dispos. 1997 May;25(5):617-22.
• [19] 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.