Details of the Drug Combination

General Information of Drug Combination (ID: DCUCC99)

• Drug Combination Name: Pyrazinamide + Tacrolimus
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Pyrazinamide (DM4IF32): Small molecular drug
  Tacrolimus (DMZ7XNQ): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 21.87
  Bliss Independence Score: 21.87
  Loewe Additivity Score: 32.82
  LHighest Single Agent (HSA) Score: 32.84

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 Tacrolimus

Disease Entry	ICD 11	Status	REF
Graft-versus-host disease	4B24	Approved	[4]
Hepatosplenic T-cell lymphoma	N.A.	Approved	[4]
Kidney transplant rejection	NE84	Approved	[4]
Large granular lymphocytic leukemia	2A90.1	Approved	[4]
Leukemia	N.A.	Approved	[4]
Lupus nephritis	4A40.0Y	Approved	[4]
MALT lymphoma	N.A.	Approved	[4]
Myeloproliferative neoplasm	2A20	Approved	[4]
Nodal marginal zone lymphoma	2A85.0	Approved	[4]
Organ transplant rejection	NE84	Approved	[5]
Primary cutaneous peripheral T-cell lymphoma not otherwise specified	N.A.	Approved	[4]
Recurrent adult burkitt lymphoma	2A85.6	Approved	[4]
Small intestine lymphoma	N.A.	Approved	[4]
Splenic marginal zone lymphoma	N.A.	Approved	[4]
Testicular lymphoma	N.A.	Approved	[4]
Ocular allergy	4A81	Phase 3	[5]
Classic Hodgkin lymphoma	N.A.	Investigative	[4]

Tacrolimus Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Calcineurin (PPP3CA)	TTA4LDE	PP2BA_HUMAN	Inhibitor	[13]

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	[14]

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	[15]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[16]
NADPH-cytochrome P450 reductase (CPR)	DE3N2FM	NCPR_HUMAN	Metabolism	[17]
Ribosomal 23S RNA methyltransferase Erm (erm)	DEW6V07	A0A5N1AHF6_CORAY	Metabolism	[18]
Ribosomal 23S RNA methyltransferase Erm (erm)	DEA65D8	A0A381KDL2_CORJE	Metabolism	[18]

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	[19]
Cytochrome P450 3A5 (CYP3A5)	OTSXFBXB	CP3A5_HUMAN	Decreases Methylation	[19]
NADPH--cytochrome P450 reductase (POR)	OTVIDOCH	NCPR_HUMAN	Affects Response To Substance	[20]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Response To Substance	[21]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Increases Expression	[22]
Cytochrome b-245 light chain (CYBA)	OT16N9ZO	CY24A_HUMAN	Increases Expression	[22]
Nitric oxide synthase 3 (NOS3)	OTLDT7NR	NOS3_HUMAN	Increases Expression	[22]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[23]
Natural cytotoxicity triggering receptor 3 (NCR3)	OT20M764	NCTR3_HUMAN	Increases Expression	[24]
Hepatocyte growth factor-regulated tyrosine kinase substrate (HGS)	OTCYYCAC	HGS_HUMAN	Increases Expression	[12]
Rho guanine nucleotide exchange factor 11 (ARHGEF11)	OTDOMEH6	ARHGB_HUMAN	Increases Expression	[12]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[25]
Actin-related protein 2/3 complex subunit 5 (ARPC5)	OTFNMMDL	ARPC5_HUMAN	Increases Expression	[12]
G2/mitotic-specific cyclin-B2 (CCNB2)	OTIEXTDK	CCNB2_HUMAN	Decreases Expression	[25]
Zinc finger protein SNAI1 (SNAI1)	OTDPYAMC	SNAI1_HUMAN	Increases Expression	[11]
Insulin (INS)	OTZ85PDU	INS_HUMAN	Decreases Expression	[26]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Secretion	[27]
Interferon gamma (IFNG)	OTXG9JM7	IFNG_HUMAN	Decreases Expression	[28]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Expression	[29]
Collagen alpha-1(I) chain (COL1A1)	OTI31178	CO1A1_HUMAN	Increases Expression	[30]
Fibronectin (FN1)	OTB5ZN4Q	FINC_HUMAN	Increases Expression	[30]
Granulocyte-macrophage colony-stimulating factor (CSF2)	OT1M7D28	CSF2_HUMAN	Decreases Expression	[28]
Interleukin-4 (IL4)	OTOXBWAU	IL4_HUMAN	Decreases Expression	[28]
Interleukin-5 (IL5)	OTAFPSCO	IL5_HUMAN	Decreases Expression	[31]
Interleukin-3 (IL3)	OT0CQ35N	IL3_HUMAN	Decreases Expression	[28]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[32]
Cadherin-1 (CDH1)	OTFJMXPM	CADH1_HUMAN	Decreases Expression	[11]
C-C motif chemokine 5 (CCL5)	OTSCA5CK	CCL5_HUMAN	Decreases Expression	[31]
Ras-related protein Rab-4A (RAB4A)	OT7BL9WW	RAB4A_HUMAN	Increases Expression	[12]
NF-kappa-B inhibitor alpha (NFKBIA)	OTFT924M	IKBA_HUMAN	Decreases Degradation	[27]
T-lymphocyte activation antigen CD80 (CD80)	OTJBLUQE	CD80_HUMAN	Decreases Expression	[33]
T-lymphocyte activation antigen CD86 (CD86)	OTJCSBPC	CD86_HUMAN	Decreases Expression	[33]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[34]
Troponin T, cardiac muscle (TNNT2)	OT80NN7R	TNNT2_HUMAN	Increases Expression	[35]
Tumor necrosis factor ligand superfamily member 6 (FASLG)	OTZARCHH	TNFL6_HUMAN	Decreases Secretion	[36]
Glycogen synthase kinase-3 alpha (GSK3A)	OT0F6DWV	GSK3A_HUMAN	Increases Phosphorylation	[11]
Glycogen synthase kinase-3 beta (GSK3B)	OTL3L14B	GSK3B_HUMAN	Increases Phosphorylation	[11]
Eotaxin (CCL11)	OT3BIFPK	CCL11_HUMAN	Decreases Expression	[31]
C-C chemokine receptor type 3 (CCR3)	OT6GBUFA	CCR3_HUMAN	Decreases Expression	[31]
LIM domain kinase 1 (LIMK1)	OTFZ8MZ0	LIMK1_HUMAN	Increases Expression	[12]
Interleukin-2 (IL2)	OTGI4NSA	IL2_HUMAN	Decreases Expression	[28]
Neutrophil gelatinase-associated lipocalin (LCN2)	OTSB42BR	NGAL_HUMAN	Increases Expression	[30]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[34]
Lethal(2) giant larvae protein homolog 1 (LLGL1)	OTAIQSXZ	L2GL1_HUMAN	Increases Expression	[12]
Calcineurin subunit B type 1 (PPP3R1)	OTGQNFJQ	CANB1_HUMAN	Increases ADR	[37]
Catalase (CAT)	OTHEBX9R	CATA_HUMAN	Decreases Response To Substance	[38]
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Increases Response To Substance	[38]
Peroxisome proliferator-activated receptor alpha (PPARA)	OTK095PP	PPARA_HUMAN	Affects Response To Substance	[20]
Cytochrome P450 3A7 (CYP3A7)	OTTCDHHM	CP3A7_HUMAN	Decreases Methylation	[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] 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] Tacrolimus 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: 6784).
• [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] 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.
• [12] 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.
• [13] Emerging drugs for ocular allergy. Expert Opin Emerg Drugs. 2005 Aug;10(3):505-20.
• [14] 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.
• [15] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [16] 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.
• [17] Polymorphisms in cytochrome P450 oxidoreductase and its effect on drug metabolism and efficacy. Pharmacogenet Genomics. 2017 Sep;27(9):337-346.
• [18] High frequency of macrolide resistance mechanisms in clinical isolates of Corynebacterium species. Microb Drug Resist. 2010 Dec;16(4):273-7.
• [19] Contribution of CYP3A5 to the in vitro hepatic clearance of tacrolimus. Clin Chem. 2005 Aug;51(8):1374-81.
• [20] 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.
• [21] 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.
• [22] Oxidative stress in kidney transplant patients with calcineurin inhibitor-induced hypertension: effect of ramipril. J Cardiovasc Pharmacol. 2002 Oct;40(4):625-31.
• [23] A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development. Toxicol Sci. 2013 Nov;136(1):216-41.
• [24] 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.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] 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.
• [31] 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.
• [32] 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.
• [33] 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.
• [34] 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.
• [35] 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.
• [36] 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.
• [37] 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.
• [38] 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.