Drug Information

Drug (ID: DG00573) and It's Reported Resistant Information

• Name: Ivermectin
• Synonyms: IVERMECTIN; Ivermectin B1a; 70288-86-7; Dihydroavermectin B1a; 22,23-Dihydroavermectin B1a; avermectin H2B1a; 71827-03-7; UNII-91Y2202OUW; 70161-11-4; Ivermectin Component B1a; CHEBI:63941; 91Y2202OUW; (2ae,4e,5's,6s,6'r,7s,8e,11r,13r,15s,17ar,20r,20ar,20bs)-6'-[(2s)-Butan-2-Yl]-20,20b-Dihydroxy-5',6,8,19-Tetramethyl-17-Oxo-3',4',5',6,6',10,11,14,15,17,17a,20,20a,20b-Tetradecahydro-2h,7h-Spiro[11,15-Methanofuro[4,3,2-Pq][2,6]benzodioxacyclooctadecine-13,2'-Pyran]-7-Yl 2,6-Dideoxy-4-O-(2,6-Dideoxy-3-O-Methyl-Alpha-L-Arabino-Hexopyranosyl)-3-O-Methyl-Alpha-L-Arabino-Hexopyranoside; 5-O-demethyl-22,23-dihydroavermectin A1a; MK-933; (1R,4S,5'S,6R,6'R,8R,10E,12S,13S,14E,16E,20R,21R,24S)-6'-[(2S)-butan-2-yl]-21,24-dihydroxy-12-[(2R,4S,5S,6S)-5-[(2S,4S,5S,6S)-5-hydroxy-4-methoxy-6-methyloxan-2-yl]oxy-4-methoxy-6-methyloxan-2-yl]oxy-5',11,13,22-tetramethylspiro[3,7,19-trioxatetracyclo[15.6.1.14,8.020,24]pentacosa-10,14,16,22-tetraene-6,2'-oxane]-2-one; C48H74O14 (B1a form); Ivermectin B1a-d2; C48H74O14; 22,23-Dihydroavermectin B(1)a; NCGC00163233-01; Ivermectin (IVM); IVM; EINECS 276-046-2; dihydro avermectin Bla; BRN 4643153; 22,23-Dihydro-5-O-demethylavermectin A1a; H2B1a; Prestwick3_000156; DSSTox_CID_3181; Ivermectin (MK-0933); DSSTox_RID_76909; DSSTox_GSID_23181; BSPBio_000292; SCHEMBL312795; BPBio1_000322; CHEMBL263291; DTXSID8023181; CHEBI:94551; HMS2089M09; HMS2095O14; HMS3712O14; WCA82703; Tox21_112034; BDBM50409816; MFCD00869511; s1351; AKOS027470116; ZINC238808778; ZINC252286706; AC-6014; CCG-220156; NCGC00186639-01; NCGC00186639-03; AS-14167; BI166167; CAS-71827-03-7; HY-126937; AB00513813; CS-0108408; J10179; 22,23-DIHYDROAVERMECTIN B1A; IVERMECTIN; AB00513813-02; AB00513813-03; AB00513813_04; Avermectin A1a, 22,23-dihydro-5-O-demethyl-; 288I867; Ivermectin, Antibiotic for Culture Media Use Only; Q-201262; BRD-K24652731-001-02-7; BRD-K85554912-001-08-9; Q27132923; Ivermectin, British Pharmacopoeia (BP) Reference Standard; Ivermectin, European Pharmacopoeia (EP) Reference Standard; UNII-8883YP2R6D component AZSNMRSAGSSBNP-XPNPUAGNSA-N; Ivermectin, United States Pharmacopeia (USP) Reference Standard; Ivermectin, Pharmaceutical Secondary Standard; Certified Reference Material; (2aE,4E,5'S,6S,6'R,7S,8E,11R,13R,15S,17aR,20R,20aR,20bS)-6'-[(2S)-butan-2-yl]-20,20b-dihydroxy-5',6,8,19-tetramethyl-17; 22,23-Dihydroavermectin B1; ; ; Heartgard 30; ; ; Ivomec; ; ; Ivosint; ; ; Mectizan; ; ; Stromectol; ; ; Uvemec; ; ; Vermic; ; ; Zimecterin; clooctadecine-13,2'-pyran]-7-yl 2,6-dideoxy-4-O-(2,6-dideoxy-3-O-methyl-alpha-L-arabino-hexopyranosyl)-3-O-methyl-alpha-L-arabino-hexopyranoside
• Indication:
  In total 1 Indication(s)
  Intestinal strongyloidiasis due to nematode parasite [ICD-11: 1F6B]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (3 diseases)
  Onchocerciasis [ICD-11: 1F6A]; [2]
  Pediculosis [ICD-11: 1G00]; [1]
  Scabies [ICD-11: 1G04]; [3]
• Target: Onchocerca Glutamate-gated chloride channel (Onchoc GluCl); Q25634_ONCVO; [3]
• Formula: C48H74O14
• IsoSMILES: CC[C@H](C)[C@@H]1[C@H](CC[C@@]2(O1)C[C@@H]3C[C@H](O2)C/C=C(/[C@H]([C@H](/C=C/C=C/4\\CO[C@H]5[C@@]4([C@@H](C=C([C@H]5O)C)C(=O)O3)O)C)O[C@H]6C[C@@H]([C@H]([C@@H](O6)C)O[C@H]7C[C@@H]([C@H]([C@@H](O7)C)O)OC)OC)\\C)C
• InChI: 1S/C48H74O14/c1-11-25(2)43-28(5)17-18-47(62-43)23-34-20-33(61-47)16-15-27(4)42(26(3)13-12-14-32-24-55-45-40(49)29(6)19-35(46(51)58-34)48(32,45)52)59-39-22-37(54-10)44(31(8)57-39)60-38-21-36(53-9)41(50)30(7)56-38/h12-15,19,25-26,28,30-31,33-45,49-50,52H,11,16-18,20-24H2,1-10H3/b13-12+,27-15+,32-14+/t25-,26-,28-,30-,31-,33+,34-,35-,36-,37-,38-,39-,40+,41-,42-,43+,44-,45+,47+,48+/m0/s1
• InChIKey: AZSNMRSAGSSBNP-XPNPUAGNSA-N
• PubChem CID: 6321424
• ChEBI ID: CHEBI:63941
• TTD Drug ID: D09YHJ
• VARIDT ID: DR00147
• INTEDE ID: DR0899
• DrugBank ID: DB00602

Type(s) of Resistant Mechanism of This Drug

  DISM: Drug Inactivation by Structure Modification

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-01: Infectious/parasitic diseases

Pediculosis [ICD-11: 1G00]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Cytochrome P450 family 1 subfamily A member 1 (CYP1A1) [1]

• Resistant Disease: Pediculosis [ICD-11: 1G00.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pediculus humanus; 121225
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Disk diffusion assay
• Mechanism Description: Phylogenetic relatedness of P450 and ABC transporter genes over-transcribed following ivermectin exposure.Knockdown of CYP9AG2 P450 and ABCC4 transporter gene expression by RNA interference and subsequent increase in the sensitivity of lice to ivermectin.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family C4 (ABCC4) [1]

• Resistant Disease: Pediculosis [ICD-11: 1G00.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pediculus humanus; 121225
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Disk diffusion assay
• Mechanism Description: Phylogenetic relatedness of P450 and ABC transporter genes over-transcribed following ivermectin exposure.Knockdown of CYP9AG2 P450 and ABCC4 transporter gene expression by RNA interference and subsequent increase in the sensitivity of lice to ivermectin.

Scabies [ICD-11: 1G04]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Glutathione S-transferase kappa (GST) [3]

• Resistant Disease: Scabies [ICD-11: 1G04.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Sarcoptes scabiei isolates; 52283
• Mechanism Description: The enzyme GST catalyzes the formation of a thioester bond between reduced glutathione and drugs. This bond tags the drug for elimination from the body. Increased activity or expression of GST has been linked to resistance to both permethrin and ivermectin in different mite species.

ICD-02: Benign/in-situ/malignant neoplasm

Chronic myeloid leukemia [ICD-11: 2A20]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance-associated protein 1 (MRP1) [4]

• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: K562/FLM cells; Blood; Homo sapiens (Human); CVCL_E7CM
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: It was found that ivermectin effectively suppressed the expression of autophagy and transport proteins in K562/FLM cells, reduced the activity of the aforementioned phosphoproteins, and promoted apoptotic cell death. The significant effects of ivermectin might offer a novel therapeutic strategy to overcome flumatinib resistance and optimize the treatment outcomes of CML.

Key Molecule: ATP-binding cassette sub-family C4 (ABCC4) [4]

• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: K562/FLM cells; Blood; Homo sapiens (Human); CVCL_E7CM
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: It was found that ivermectin effectively suppressed the expression of autophagy and transport proteins in K562/FLM cells, reduced the activity of the aforementioned phosphoproteins, and promoted apoptotic cell death. The significant effects of ivermectin might offer a novel therapeutic strategy to overcome flumatinib resistance and optimize the treatment outcomes of CML.

Key Molecule: P-glycoprotein (ABCB1) [4]

• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: K562/FLM cells; Blood; Homo sapiens (Human); CVCL_E7CM
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: It was found that ivermectin effectively suppressed the expression of autophagy and transport proteins in K562/FLM cells, reduced the activity of the aforementioned phosphoproteins, and promoted apoptotic cell death. The significant effects of ivermectin might offer a novel therapeutic strategy to overcome flumatinib resistance and optimize the treatment outcomes of CML.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Signal transducer activator transcription 3 (STAT3) [4]

• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Phosphorylation; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR/STAT3/ERK signalling pathway; Regulation; N.A.
• In Vitro Model: K562/FLM cells; Blood; Homo sapiens (Human); CVCL_E7CM
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: It was found that ivermectin effectively suppressed the expression of autophagy and transport proteins in K562/FLM cells, reduced the activity of the aforementioned phosphoproteins, and promoted apoptotic cell death. The significant effects of ivermectin might offer a novel therapeutic strategy to overcome flumatinib resistance and optimize the treatment outcomes of CML.

Key Molecule: Mitogen-activated protein kinase (MAPK) [4]

• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Phosphorylation; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR/STAT3/ERK signalling pathway; Regulation; N.A.
• In Vitro Model: K562/FLM cells; Blood; Homo sapiens (Human); CVCL_E7CM
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: It was found that ivermectin effectively suppressed the expression of autophagy and transport proteins in K562/FLM cells, reduced the activity of the aforementioned phosphoproteins, and promoted apoptotic cell death. The significant effects of ivermectin might offer a novel therapeutic strategy to overcome flumatinib resistance and optimize the treatment outcomes of CML.

Key Molecule: Oncogenic epidermal growth factor receptor (EGFR) [4]

• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Phosphorylation; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR/STAT3/ERK signalling pathway; Regulation; N.A.
• In Vitro Model: K562/FLM cells; Blood; Homo sapiens (Human); CVCL_E7CM
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: It was found that ivermectin effectively suppressed the expression of autophagy and transport proteins in K562/FLM cells, reduced the activity of the aforementioned phosphoproteins, and promoted apoptotic cell death. The significant effects of ivermectin might offer a novel therapeutic strategy to overcome flumatinib resistance and optimize the treatment outcomes of CML.

References

• Ref 1: Ivermectin: From theory to clinical application .Int J Antimicrob Agents. 2019 Aug;54(2):134-142. doi: 10.1016/j.ijantimicag.2019.05.003. Epub 2019 May 7. 10.1016/j.ijantimicag.2019.05.003
• Ref 2: Anti-Wolbachia drug discovery and development: safe macrofilaricides for onchocerciasis and lymphatic filariasis .Parasitology. 2014 Jan;141(1):119-27. doi: 10.1017/S0031182013001108. Epub 2013 Jul 18. 10.1017/S0031182013001108
• Ref 3: Scabies in the age of increasing drug resistance .PLoS Negl Trop Dis. 2017 Nov 30;11(11):e0005920. doi: 10.1371/journal.pntd.0005920. eCollection 2017 Nov. 10.1371/journal.pntd.0005920
• Ref 4: Overcoming flumatinib resistance in chronic myeloid leukaemia: Insights into cellular mechanisms and ivermectin's therapeutic potential. J Cell Mol Med. 2024 Jul;28(14):e18539.