Details of the Drug Combination

General Information of Drug Combination (ID: DCL6B98)

• Drug Combination Name: Spironolactone + Aciclovir
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Spironolactone (DM2AQ5N): Small molecular drug
  Aciclovir (DMYLOVR): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 8.8
  Bliss Independence Score: 8.8
  Loewe Additivity Score: 19.56
  LHighest Single Agent (HSA) Score: 19.56

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Spironolactone

Disease Entry	ICD 11	Status	REF
Chronic heart failure	BD1Z	Approved	[2]
Congestive heart failure	BD10	Approved	[3]
Edema	MG29	Approved	[2]
Hyperaldosteronism	5A72	Approved	[2]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[4]

Spironolactone Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Mineralocorticoid receptor (MR)	TT26PHO	MCR_HUMAN	Modulator	[12]

Spironolactone Interacts with 21 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[13]
Cytochrome P450 2C8 (CYP2C8)	OTHCWT42	CP2C8_HUMAN	Decreases Activity	[14]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[15]
Serine/threonine-protein kinase Sgk1 (SGK1)	OT301T1U	SGK1_HUMAN	Increases Expression	[16]
Tissue-type plasminogen activator (PLAT)	OTQPDNAB	TPA_HUMAN	Increases Expression	[17]
Angiotensinogen (AGT)	OTBZLYR3	ANGT_HUMAN	Increases Expression	[18]
Natriuretic peptides A (NPPA)	OTMQNTNX	ANF_HUMAN	Decreases Expression	[19]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Expression	[20]
Collagen alpha-1(III) chain (COL3A1)	OTT1EMLM	CO3A1_HUMAN	Decreases Expression	[19]
Trefoil factor 1 (TFF1)	OTCYQH4F	TFF1_HUMAN	Increases Expression	[21]
Plasminogen activator inhibitor 1 (SERPINE1)	OTT0MPQ3	PAI1_HUMAN	Decreases Expression	[17]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[22]
Mineralocorticoid receptor (NR3C2)	OT0F2V2Z	MCR_HUMAN	Increases Activity	[23]
Myb-related protein A (MYBL1)	OTBJMC2P	MYBA_HUMAN	Increases Expression	[16]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Affects Binding	[24]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Decreases Expression	[19]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[25]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[25]
Protein GREB1 (GREB1)	OTU6ZA26	GREB1_HUMAN	Increases Expression	[16]
Renin (REN)	OT52GZR2	RENI_HUMAN	Decreases Response To Substance	[26]
Serum paraoxonase/lactonase 3 (PON3)	OT80W9TA	PON3_HUMAN	Increases Hydrolysis	[27]

Indication(s) of Aciclovir

Disease Entry	ICD 11	Status	REF
Genital herpes	1A94	Approved	[5]
Herpes simplex encephalitis	N.A.	Approved	[6]
Herpes simplex infection	1F00	Approved	[7]
Herpes simplex labialis	1F00.01	Approved	[8]
Varicella	1E90	Approved	[9]
Virus infection	1A24-1D9Z	Approved	[10]
Herpes simplex virus infection	1F00	Phase 3	[11]

Aciclovir Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Herpes simplex virus DNA polymerase UL30 (HSV UL30)	TTIU7X1	DPOL_HHV11	Modulator	[12]
Varicella-zoster virus DNA polymerase (VZV ORF28)	TTHPJTK	DPOL_VZVD	Modulator	[28]

Aciclovir Interacts with 9 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[29]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[30]
Organic anion transporter 2 (SLC22A7)	DT0OC1Q	S22A7_HUMAN	Substrate	[31]
Multidrug and toxin extrusion protein 1 (SLC47A1)	DTZGT0P	S47A1_HUMAN	Substrate	[32]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[33]
Organic anion transporter 1 (SLC22A6)	DTQ23VB	S22A6_HUMAN	Substrate	[33]
Organic anion transporter 3 (SLC22A8)	DTVP67E	S22A8_HUMAN	Substrate	[34]
Multidrug and toxin extrusion protein 2 (SLC47A2)	DT3TX4H	S47A2_HUMAN	Substrate	[32]
Alanine/serine/cysteine/threonine transporter 2 (SLC1A5)	DTW7AE3	AAAT_HUMAN	Substrate	[35]

Aciclovir Interacts with 12 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Affects Transport	[36]
Indoleamine 2,3-dioxygenase 1 (IDO1)	OT91DBN7	I23O1_HUMAN	Decreases Activity	[37]
3-hydroxyanthranilate 3,4-dioxygenase (HAAO)	OTK9Y6SG	3HAO_HUMAN	Decreases Activity	[37]
Interleukin-1 alpha (IL1A)	OTPSGILV	IL1A_HUMAN	Increases Expression	[38]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Expression	[38]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Increases Expression	[38]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[38]
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Increases Expression	[38]
Interleukin-24 (IL24)	OT4VUWH1	IL24_HUMAN	Increases Expression	[38]
Major histocompatibility complex class I-related gene protein (MR1)	OTZU3XX7	HMR1_HUMAN	Affects Expression	[39]
Cystine/glutamate transporter (SLC7A11)	OTKJ6PXW	XCT_HUMAN	Increases Expression	[38]
Myelin basic protein (MBP)	OTFZCEDB	MBP_HUMAN	Increases ADR	[40]

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] Spironolactone 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: 2875).
• [4] Spironolactone in Covid-19 Induced ARDS
• [5] Genital herpes. BMJ Clin Evid. 2011 Apr 15;2011:1603.
• [6] Management of suspected viral encephalitis in adults--Association of British Neurologists and British Infection Association National Guidelines. J Infect. 2012 Apr;64(4):347-73.
• [7] Prevention and management of genital herpes simplex infection during pregnancy and delivery: Guidelines from the French College of Gynaecologists and Obstetricians (CNGOF). Eur J Obstet Gynecol Reprod Biol. 2018 May;224:93-101.
• [8] Interventions for prevention of herpes simplex labialis (cold sores on the lips). Cochrane Database Syst Rev. 2015 Aug 7;2015(8):CD010095.
• [9] Neonatal varicella. Arch Dis Child. 2023 Oct 31:archdischild-2022-324820.
• [10] 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: 4829).
• [11] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [12] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [13] Receptor-dependent regulation of the CYP3A4 gene. Toxicology. 2002 Dec 27;181-182:199-202.
• [14] Examination of 209 drugs for inhibition of cytochrome P450 2C8. J Clin Pharmacol. 2005 Jan;45(1):68-78.
• [15] Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013 Dec;136(2):328-43.
• [16] A Gene Expression Biomarker Identifies Chemical Modulators of Estrogen Receptor in an MCF-7 Microarray Compendium. Chem Res Toxicol. 2021 Feb 15;34(2):313-329. doi: 10.1021/acs.chemrestox.0c00243. Epub 2021 Jan 6.
• [17] Effect of spironolactone on impaired fibrinolysis of hypertensive patients. Kidney Blood Press Res. 2002;25(4):260-4. doi: 10.1159/000066348.
• [18] Amiloride, spironolactone, and potassium chloride in thiazide-treated hypertensive patients. Clin Pharmacol Ther. 1980 Apr;27(4):533-43. doi: 10.1038/clpt.1980.75.
• [19] Effect of spironolactone on plasma brain natriuretic peptide and left ventricular remodeling in patients with congestive heart failure. J Am Coll Cardiol. 2001 Apr;37(5):1228-33. doi: 10.1016/s0735-1097(01)01116-0.
• [20] Spironolactone induces apoptosis in human mononuclear cells. Association between apoptosis and cytokine suppression. Apoptosis. 2006 Apr;11(4):573-9. doi: 10.1007/s10495-006-4919-3.
• [21] Evaluation of an imaging-based in vitro screening platform for estrogenic activity with OECD reference chemicals. Toxicol In Vitro. 2022 Jun;81:105348. doi: 10.1016/j.tiv.2022.105348. Epub 2022 Mar 18.
• [22] Pregnane X receptor mediates the induction of P-glycoprotein by spironolactone in HepG2 cells. Toxicology. 2011 Jul 11;285(1-2):18-24. doi: 10.1016/j.tox.2011.03.015. Epub 2011 Apr 1.
• [23] The human mineralocorticoid receptor only partially differentiates between different ligands after expression in fission yeast. FEMS Yeast Res. 2005 Apr;5(6-7):627-33. doi: 10.1016/j.femsyr.2004.12.007.
• [24] Comparison of the Hershberger assay and androgen receptor binding assay of twelve chemicals. Toxicology. 2004 Feb 15;195(2-3):177-86. doi: 10.1016/j.tox.2003.09.012.
• [25] Palmitate increases the susceptibility of cells to drug-induced toxicity: an in vitro method to identify drugs with potential contraindications in patients with metabolic disease. Toxicol Sci. 2012 Oct;129(2):346-62. doi: 10.1093/toxsci/kfs208. Epub 2012 Jun 14.
• [26] Clinical and biochemical effects of spironolactone administered once daily in primary hypertension. Multicenter Sweden study. Hypertension. 1980 Sep-Oct;2(5):672-9. doi: 10.1161/01.hyp.2.5.672.
• [27] Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities. J Lipid Res. 2005 Jun;46(6):1239-47. doi: 10.1194/jlr.M400511-JLR200. Epub 2005 Mar 16.
• [28] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [29] Gene expression in the human intestine and correlation with oral valacyclovir pharmacokinetic parameters. J Pharmacol Exp Ther. 2003 Aug;306(2):778-86.
• [30] Acyclovir is a substrate for the human breast cancer resistance protein (BCRP/ABCG2): implications for renal tubular transport and acyclovir-induced nephrotoxicity. Can J Physiol Pharmacol. 2011 Sep;89(9):675-80.
• [31] Organic anion transporter 2 (SLC22A7) is a facilitative transporter of cGMP. Mol Pharmacol. 2008 Apr;73(4):1151-8.
• [32] Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H(+)-organic cation antiporters. Biochem Pharmacol. 2007 Jul 15;74(2):359-71.
• [33] Human organic anion transporters and human organic cation transporters mediate renal antiviral transport. J Pharmacol Exp Ther. 2002 Mar;300(3):918-24.
• [34] Expression of organic anion transporter 2 in the human kidney and its potential role in the tubular secretion of guanine-containing antiviral drugs. Drug Metab Dispos. 2012 Mar;40(3):617-24.
• [35] Amino Acid Transporter ATB0,+ as a delivery system for drugs and prodrugs. Curr Drug Targets Immune Endocr Metabol Disord. 2005 Dec;5(4):357-64.
• [36] Acyclovir is a substrate for the human breast cancer resistance protein (BCRP/ABCG2): implications for renal tubular transport and acyclovir-induced nephrotoxicity. Can J Physiol Pharmacol. 2011 Sep;89(9):675-80. doi: 10.1139/y11-045. Epub 2011 Aug 22.
• [37] Mechanisms by which acyclovir reduces the oxidative neurotoxicity and biosynthesis of quinolinic acid. Life Sci. 2007 Feb 13;80(10):918-25.
• [38] An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury. Arch Toxicol. 2021 Jan;95(1):149-168. doi: 10.1007/s00204-020-02882-4. Epub 2020 Aug 20.
• [39] 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.
• [40] 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.