Details of the Drug Combination

General Information of Drug Combination (ID: DCHK9S7)

• Drug Combination Name: Tacrolimus + Artemisinin
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Tacrolimus (DMZ7XNQ): Small molecular drug
  Artemisinin (DMOY7W3): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 7.79
  Bliss Independence Score: 7.79
  Loewe Additivity Score: 14.53
  LHighest Single Agent (HSA) Score: 14.58

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Tacrolimus

Disease Entry	ICD 11	Status	REF
Graft-versus-host disease	4B24	Approved	[2]
Hepatosplenic T-cell lymphoma	N.A.	Approved	[2]
Kidney transplant rejection	NE84	Approved	[2]
Large granular lymphocytic leukemia	2A90.1	Approved	[2]
Leukemia	N.A.	Approved	[2]
Lupus nephritis	4A40.0Y	Approved	[2]
MALT lymphoma	N.A.	Approved	[2]
Myeloproliferative neoplasm	2A20	Approved	[2]
Nodal marginal zone lymphoma	2A85.0	Approved	[2]
Organ transplant rejection	NE84	Approved	[3]
Primary cutaneous peripheral T-cell lymphoma not otherwise specified	N.A.	Approved	[2]
Recurrent adult burkitt lymphoma	2A85.6	Approved	[2]
Small intestine lymphoma	N.A.	Approved	[2]
Splenic marginal zone lymphoma	N.A.	Approved	[2]
Testicular lymphoma	N.A.	Approved	[2]
Ocular allergy	4A81	Phase 3	[3]
Classic Hodgkin lymphoma	N.A.	Investigative	[2]

Tacrolimus Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Calcineurin (PPP3CA)	TTA4LDE	PP2BA_HUMAN	Inhibitor	[7]

Tacrolimus Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[8]

Tacrolimus Interacts with 5 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[9]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[10]
NADPH-cytochrome P450 reductase (CPR)	DE3N2FM	NCPR_HUMAN	Metabolism	[11]
Ribosomal 23S RNA methyltransferase Erm (erm)	DEW6V07	A0A5N1AHF6_CORAY	Metabolism	[12]
Ribosomal 23S RNA methyltransferase Erm (erm)	DEA65D8	A0A381KDL2_CORJE	Metabolism	[12]

Tacrolimus Interacts with 49 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Methylation	[13]
Cytochrome P450 3A5 (CYP3A5)	OTSXFBXB	CP3A5_HUMAN	Decreases Methylation	[13]
NADPH--cytochrome P450 reductase (POR)	OTVIDOCH	NCPR_HUMAN	Affects Response To Substance	[14]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Response To Substance	[15]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Increases Expression	[16]
Cytochrome b-245 light chain (CYBA)	OT16N9ZO	CY24A_HUMAN	Increases Expression	[16]
Nitric oxide synthase 3 (NOS3)	OTLDT7NR	NOS3_HUMAN	Increases Expression	[16]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[17]
Natural cytotoxicity triggering receptor 3 (NCR3)	OT20M764	NCTR3_HUMAN	Increases Expression	[18]
Hepatocyte growth factor-regulated tyrosine kinase substrate (HGS)	OTCYYCAC	HGS_HUMAN	Increases Expression	[6]
Rho guanine nucleotide exchange factor 11 (ARHGEF11)	OTDOMEH6	ARHGB_HUMAN	Increases Expression	[6]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[19]
Actin-related protein 2/3 complex subunit 5 (ARPC5)	OTFNMMDL	ARPC5_HUMAN	Increases Expression	[6]
G2/mitotic-specific cyclin-B2 (CCNB2)	OTIEXTDK	CCNB2_HUMAN	Decreases Expression	[19]
Zinc finger protein SNAI1 (SNAI1)	OTDPYAMC	SNAI1_HUMAN	Increases Expression	[5]
Insulin (INS)	OTZ85PDU	INS_HUMAN	Decreases Expression	[20]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Secretion	[21]
Interferon gamma (IFNG)	OTXG9JM7	IFNG_HUMAN	Decreases Expression	[22]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Expression	[23]
Collagen alpha-1(I) chain (COL1A1)	OTI31178	CO1A1_HUMAN	Increases Expression	[24]
Fibronectin (FN1)	OTB5ZN4Q	FINC_HUMAN	Increases Expression	[24]
Granulocyte-macrophage colony-stimulating factor (CSF2)	OT1M7D28	CSF2_HUMAN	Decreases Expression	[22]
Interleukin-4 (IL4)	OTOXBWAU	IL4_HUMAN	Decreases Expression	[22]
Interleukin-5 (IL5)	OTAFPSCO	IL5_HUMAN	Decreases Expression	[25]
Interleukin-3 (IL3)	OT0CQ35N	IL3_HUMAN	Decreases Expression	[22]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[26]
Cadherin-1 (CDH1)	OTFJMXPM	CADH1_HUMAN	Decreases Expression	[5]
C-C motif chemokine 5 (CCL5)	OTSCA5CK	CCL5_HUMAN	Decreases Expression	[25]
Ras-related protein Rab-4A (RAB4A)	OT7BL9WW	RAB4A_HUMAN	Increases Expression	[6]
NF-kappa-B inhibitor alpha (NFKBIA)	OTFT924M	IKBA_HUMAN	Decreases Degradation	[21]
T-lymphocyte activation antigen CD80 (CD80)	OTJBLUQE	CD80_HUMAN	Decreases Expression	[27]
T-lymphocyte activation antigen CD86 (CD86)	OTJCSBPC	CD86_HUMAN	Decreases Expression	[27]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[28]
Troponin T, cardiac muscle (TNNT2)	OT80NN7R	TNNT2_HUMAN	Increases Expression	[29]
Tumor necrosis factor ligand superfamily member 6 (FASLG)	OTZARCHH	TNFL6_HUMAN	Decreases Secretion	[30]
Glycogen synthase kinase-3 alpha (GSK3A)	OT0F6DWV	GSK3A_HUMAN	Increases Phosphorylation	[5]
Glycogen synthase kinase-3 beta (GSK3B)	OTL3L14B	GSK3B_HUMAN	Increases Phosphorylation	[5]
Eotaxin (CCL11)	OT3BIFPK	CCL11_HUMAN	Decreases Expression	[25]
C-C chemokine receptor type 3 (CCR3)	OT6GBUFA	CCR3_HUMAN	Decreases Expression	[25]
LIM domain kinase 1 (LIMK1)	OTFZ8MZ0	LIMK1_HUMAN	Increases Expression	[6]
Interleukin-2 (IL2)	OTGI4NSA	IL2_HUMAN	Decreases Expression	[22]
Neutrophil gelatinase-associated lipocalin (LCN2)	OTSB42BR	NGAL_HUMAN	Increases Expression	[24]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[28]
Lethal(2) giant larvae protein homolog 1 (LLGL1)	OTAIQSXZ	L2GL1_HUMAN	Increases Expression	[6]
Calcineurin subunit B type 1 (PPP3R1)	OTGQNFJQ	CANB1_HUMAN	Increases ADR	[31]
Catalase (CAT)	OTHEBX9R	CATA_HUMAN	Decreases Response To Substance	[32]
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Increases Response To Substance	[32]
Peroxisome proliferator-activated receptor alpha (PPARA)	OTK095PP	PPARA_HUMAN	Affects Response To Substance	[14]
Cytochrome P450 3A7 (CYP3A7)	OTTCDHHM	CP3A7_HUMAN	Decreases Methylation	[13]

Indication(s) of Artemisinin

Disease Entry	ICD 11	Status	REF
Malaria	1F40-1F45	Approved	[4]

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	[4]
Sarcoplasmic/endoplasmic reticulum calcium ATPase (ATP2A)	TTZVSJ2	NOUNIPROTAC	Inhibitor	[4]

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	[33]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[34]
Glutathione S-transferase alpha-1 (GSTA1)	DE4ZHS1	GSTA1_HUMAN	Metabolism	[35]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[33]

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	[35]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[36]
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Increases Expression	[36]
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Decreases Activity	[37]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Decreases Activity	[37]
Glutathione S-transferase P (GSTP1)	OTLP0A0Y	GSTP1_HUMAN	Decreases Activity	[35]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[36]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Activity	[38]
Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A)	OT5QQB5L	IDH3A_HUMAN	Decreases Expression	[38]
Nuclear receptor subfamily 1 group I member 3 (NR1I3)	OTS3SGH7	NR1I3_HUMAN	Increases Activity	[39]

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] Tacrolimus 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: 6784).
• [4] The fight against drug-resistant malaria: novel plasmodial targets and antimalarial drugs. Curr Med Chem. 2008;15(2):161-71.
• [5] GSK3, snail, and adhesion molecule regulation by cyclosporine A in renal tubular cells. Toxicol Sci. 2012 Jun;127(2):425-37. doi: 10.1093/toxsci/kfs108. Epub 2012 Mar 12.
• [6] Calcineurin is an important factor involved in glucose uptake in human adipocytes. Mol Cell Biochem. 2018 Aug;445(1-2):157-168. doi: 10.1007/s11010-017-3261-0. Epub 2018 Jan 27.
• [7] Emerging drugs for ocular allergy. Expert Opin Emerg Drugs. 2005 Aug;10(3):505-20.
• [8] Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016 Jan 1;370(1):153-64.
• [9] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [10] Tacrolimus pharmacokinetics and pharmacogenetics: influence of adenosine triphosphate-binding cassette B1 (ABCB1) and cytochrome (CYP) 3A polymorphisms. Fundam Clin Pharmacol. 2007 Aug;21(4):427-35.
• [11] Polymorphisms in cytochrome P450 oxidoreductase and its effect on drug metabolism and efficacy. Pharmacogenet Genomics. 2017 Sep;27(9):337-346.
• [12] High frequency of macrolide resistance mechanisms in clinical isolates of Corynebacterium species. Microb Drug Resist. 2010 Dec;16(4):273-7.
• [13] Contribution of CYP3A5 to the in vitro hepatic clearance of tacrolimus. Clin Chem. 2005 Aug;51(8):1374-81.
• [14] Single-nucleotide polymorphisms in P450 oxidoreductase and peroxisome proliferator-activated receptor- are associated with the development of new-onset diabetes after transplantation in kidney transplant recipients treated with tacrolimus. Pharmacogenet Genomics. 2013 Dec;23(12):649-57. doi: 10.1097/FPC.0000000000000001.
• [15] Neurotoxicity induced by tacrolimus after liver transplantation: relation to genetic polymorphisms of the ABCB1 (MDR1) gene. Transplantation. 2002 Aug 27;74(4):571-2. doi: 10.1097/00007890-200208270-00024.
• [16] Oxidative stress in kidney transplant patients with calcineurin inhibitor-induced hypertension: effect of ramipril. J Cardiovasc Pharmacol. 2002 Oct;40(4):625-31.
• [17] A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development. Toxicol Sci. 2013 Nov;136(1):216-41.
• [18] Mycophenolic acid inhibits natural killer cell proliferation and cytotoxic function: a possible disadvantage of including mycophenolate mofetil in the graft-versus-host disease prophylaxis regimen. Biol Blood Marrow Transplant. 2011 Feb;17(2):205-13. doi: 10.1016/j.bbmt.2010.08.014. Epub 2010 Aug 22.
• [19] CyclinB2 and BIRC5 genes as surrogate biomarkers for neurite outgrowth in SH-SY5Y subclonal cells. Neuropharmacology. 2006 Jun;50(8):1041-7. doi: 10.1016/j.neuropharm.2006.02.004. Epub 2006 Mar 30.
• [20] Effects of immunosuppressive drugs on in vitro neogenesis of human islets: mycophenolate mofetil inhibits the proliferation of ductal cells. Am J Transplant. 2007 Apr;7(4):1021-6. doi: 10.1111/j.1600-6143.2006.01728.x.
• [21] FK506 inhibits tumour necrosis factor-alpha secretion in human keratinocytes via regulation of nuclear factor-kappaB. Br J Dermatol. 2005 Oct;153(4):725-32. doi: 10.1111/j.1365-2133.2005.06779.x.
• [22] Tacrolimus suppressed the production of cytokines involved in atopic dermatitis by direct stimulation of human PBMC system. (Comparison with steroids). Int Immunopharmacol. 2001 Jun;1(6):1219-26. doi: 10.1016/s1567-5769(01)00059-5.
• [23] Profiling the immunotoxicity of chemicals based on in vitro evaluation by a combination of the Multi-ImmunoTox assay and the IL-8 Luc assay. Arch Toxicol. 2018 Jun;92(6):2043-2054. doi: 10.1007/s00204-018-2199-7. Epub 2018 Mar 29.
• [24] Tacrolimus-induced nephrotoxicity in mice is associated with microRNA deregulation. Arch Toxicol. 2018 Apr;92(4):1539-1550. doi: 10.1007/s00204-018-2158-3. Epub 2018 Jan 23.
• [25] Tacrolimus decreases the expression of eotaxin, CCR3, RANTES and interleukin-5 in atopic dermatitis. Br J Dermatol. 2005 Jun;152(6):1173-81. doi: 10.1111/j.1365-2133.2005.06474.x.
• [26] A Quantitative Approach to Screen for Nephrotoxic Compounds In Vitro. J Am Soc Nephrol. 2016 Apr;27(4):1015-28. doi: 10.1681/ASN.2015010060. Epub 2015 Aug 10.
• [27] Tacrolimus ointment causes inflammatory dendritic epidermal cell depletion but no Langerhans cell apoptosis in patients with atopic dermatitis. J Allergy Clin Immunol. 2004 Jul;114(1):137-43. doi: 10.1016/j.jaci.2004.03.021.
• [28] Immunosuppressive calcineurin inhibitor cyclosporine A?induces proapoptotic endoplasmic reticulum stress in renal tubular cells. J Biol Chem. 2022 Mar;298(3):101589. doi: 10.1016/j.jbc.2022.101589. Epub 2022 Jan 14.
• [29] Multicenter prospective investigation on cardiovascular adverse effects of tacrolimus in kidney transplantations. Cardiovasc Drugs Ther. 2003 Mar;17(2):141-9. doi: 10.1023/a:1025339819051.
• [30] Targeting keratinocyte apoptosis in the treatment of atopic dermatitis and allergic contact dermatitis. J Allergy Clin Immunol. 2001 Nov;108(5):839-46. doi: 10.1067/mai.2001.118796.
• [31] 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.
• [32] Hydrogen peroxide mediates FK506-induced cytotoxicity in renal cells. Kidney Int. 2004 Jan;65(1):139-47. doi: 10.1111/j.1523-1755.2004.00380.x.
• [33] 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.
• [34] 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.
• [35] 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.
• [36] 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.
• [37] 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.
• [38] 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.
• [39] 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.