Details of the Drug Combination

General Information of Drug Combination (ID: DCGG3NA)

• Drug Combination Name: Acetazolamide + Epinephrine
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Acetazolamide (DM1AF5U): Small molecular drug
  Epinephrine (DM3KJBC): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 7.16
  Bliss Independence Score: 7.16
  Loewe Additivity Score: 8.67
  LHighest Single Agent (HSA) Score: 8.69

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Acetazolamide

Disease Entry	ICD 11	Status	REF
Absence epilepsy	N.A.	Approved	[2]
Altitude sickness	N.A.	Approved	[2]
Edema	MG29	Approved	[2]
Glaucoma/ocular hypertension	9C61	Approved	[3]

Acetazolamide Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Carbonic anhydrase I (CA-I)	TTHQPL7	CAH1_HUMAN	Modulator	[7]

Acetazolamide Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Carbonic anhydrase 12 (CA12)	OT6WNFU8	CAH12_HUMAN	Decreases Activity	[8]
Carbonic anhydrase 9 (CA9)	OTNA51XT	CAH9_HUMAN	Decreases Activity	[8]
Rho GTPase-activating protein 45 (ARHGAP45)	OTL86FEQ	HMHA1_HUMAN	Affects Expression	[9]
Parathyroid hormone/parathyroid hormone-related peptide receptor (PTH1R)	OTQF5ZAK	PTH1R_HUMAN	Increases ADR	[10]

Indication(s) of Epinephrine

Disease Entry	ICD 11	Status	REF
Acute asthma	CA23	Approved	[4]
Allergy	4A80-4A85	Approved	[5]
Anaphylaxis	N.A.	Approved	[4]
Bronchiectasis	CA24	Approved	[4]
Bronchitis	CA20	Approved	[4]
Periodontitis	DA0C	Approved	[4]
Pulmonary emphysema	CA21.Z	Approved	[4]
Severe asthma	CA23	Approved	[4]
Asthma	CA23	Investigative	[4]

Epinephrine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adrenergic receptor beta-1 (ADRB1)	TTR6W5O	ADRB1_HUMAN	Agonist	[11]

Epinephrine Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic cation transporter 3 (SLC22A3)	DT6201N	S22A3_HUMAN	Substrate	[12]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[13]

Epinephrine Interacts with 5 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[14]
Sulfotransferase 1A1 (SULT1A1)	DEYWLRK	ST1A1_HUMAN	Metabolism	[15]
Thiopurine methyltransferase (TPMT)	DEFQ8VO	TPMT_HUMAN	Metabolism	[16]
Catechol O-methyltransferase (COMT)	DEV3T4A	COMT_HUMAN	Metabolism	[17]
Monoamine oxidase type A (MAO-A)	DERE4TU	AOFA_HUMAN	Metabolism	[18]

Epinephrine Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Solute carrier family 22 member 3 (SLC22A3)	OTQYGVXX	S22A3_HUMAN	Increases Uptake	[19]
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Increases Expression	[20]
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Activity	[21]
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Increases Activity	[22]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Decreases Cleavage	[23]
Alpha-1D adrenergic receptor (ADRA1D)	OTW2CD1O	ADA1D_HUMAN	Increases Activity	[24]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Increases Expression	[25]
Alpha-1A adrenergic receptor (ADRA1A)	OTUIWCL5	ADA1A_HUMAN	Increases Activity	[24]
Alpha-1B adrenergic receptor (ADRA1B)	OTSAYAFD	ADA1B_HUMAN	Increases Activity	[24]
Tumor necrosis factor ligand superfamily member 6 (FASLG)	OTZARCHH	TNFL6_HUMAN	Increases Expression	[25]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases ADR	[10]
Equilibrative nucleoside transporter 4 (SLC29A4)	OTWTZXMX	S29A4_HUMAN	Increases Uptake	[19]
Alpha-2A adrenergic receptor (ADRA2A)	OTZFGOTP	ADA2A_HUMAN	Increases ADR	[10]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [2] Acetazolamide 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: 6792).
• [4] Epinephrine 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: 509).
• [6] Tamm-Horsfall protein accumulation in glomeruli during acetazolamide-induced acute renal failure. Am J Nephrol. 1989;9(1):56-7. doi: 10.1159/000167936.
• [7] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [8] Targeting hypoxic tumor cell viability with carbohydrate-based carbonic anhydrase IX and XII inhibitors. J Med Chem. 2011 Oct 13;54(19):6905-18.
• [9] Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
• [10] 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.
• [11] Adrenergic activation of electrogenic K+ secretion in guinea pig distal colonic epithelium: involvement of beta1- and beta2-adrenergic receptors. Am J Physiol Gastrointest Liver Physiol. 2009 Aug;297(2):G269-77.
• [12] Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain. Neuropharmacology. 2006 Jun;50(8):941-52.
• [13] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [14] Steroid glucuronides: human circulatory levels and formation by LNCaP cells. J Steroid Biochem Mol Biol. 1991;40(4-6):593-8.
• [15] Crystal structure of human sulfotransferase SULT1A3 in complex with dopamine and 3'-phosphoadenosine 5'-phosphate. Biochem Biophys Res Commun. 2005 Sep 23;335(2):417-23.
• [16] Adrenal catecholamines and their metabolism in the vitamin A deficient rat. Ann Nutr Metab. 1983;27(3):220-7.
• [17] Different metabolism of norepinephrine and epinephrine by catechol-O-methyltransferase and monoamine oxidase in rats. J Pharmacol Exp Ther. 1994 Mar;268(3):1242-51.
• [18] Role of monoamine-oxidase-A-gene variation in the development of glioblastoma in males: a case control study. J Neurooncol. 2019 Nov;145(2):287-294.
• [19] Selective transport of monoamine neurotransmitters by human plasma membrane monoamine transporter and organic cation transporter 3. J Pharmacol Exp Ther. 2010 Dec;335(3):743-53. doi: 10.1124/jpet.110.170142. Epub 2010 Sep 21.
• [20] Epinephrine upregulates superoxide dismutase in human coronary artery endothelial cells. Free Radic Biol Med. 2001 Jan 15;30(2):148-53.
• [21] Hypokalemia from beta2-receptor stimulation by circulating epinephrine. N Engl J Med. 1983 Dec 8;309(23):1414-9. doi: 10.1056/NEJM198312083092303.
• [22] Myocardial ischaemia and ventricular arrhthymias precipitated by physiological concentrations of adrenaline in patients with coronary artery disease. Br Heart J. 1992 May;67(5):419-20. doi: 10.1136/hrt.67.5.419-b.
• [23] Epinephrine facilitates the growth of T cell lymphoma by altering cell proliferation, apoptosis, and glucose metabolism. Chem Biol Interact. 2023 Jan 5;369:110278. doi: 10.1016/j.cbi.2022.110278. Epub 2022 Nov 22.
• [24] Carvedilol selectively inhibits oscillatory intracellular calcium changes evoked by human alpha1D- and alpha1B-adrenergic receptors. Cardiovasc Res. 2004 Sep 1;63(4):662-72. doi: 10.1016/j.cardiores.2004.05.014.
• [25] Carvedilol prevents epinephrine-induced apoptosis in human coronary artery endothelial cells: modulation of Fas/Fas ligand and caspase-3 pathway. Cardiovasc Res. 2000 Feb;45(3):788-94. doi: 10.1016/s0008-6363(99)00369-7.