Drug Information

Drug (ID: DG00249) and It's Reported Resistant Information

• Name: Verapamil
• Synonyms: Arpamyl; Calan; Calcan; Cordilox; Dexverapamil; Dilacoran; Drosteakard; Iproveratril; Isoptimo; Isoptin; Isotopin; Vasolan; Veracim; Verapamilo; Verapamilum; Veraptin; Verexamil; Bosoptin (TN); Calan (TN); D-365; Isoptin (TN); Verapamilo [INN-Spanish]; Verapamilum [INN-Latin]; Verelan (TN); CP-16533-1; Covera-HS (TN); Verapamil (USAN/INN); Verapamil [USAN:BAN:INN]; Verapamil [USAN:INN:BAN]; Alpha-((N-Methyl-N-homoveratryl)-gamma-aminopropyl)-3,4-dimethoxyphenylacetonitrile; Alpha-Isopropyl-alpha-((N-methyl-N-homoveratryl)-gamma-aminopropyl)-3,4-dimethoxyphenylacetonitrile; Alpha-(3-((2-(3,4-Dimethoxyphenyl)ethyl)-methylamino)propyl)-3,4-dimethoxy-alpha-(1-methylethyl)benzeneacetonitrile; (+-)-Verapamil; (+/-)-VERAPAMIL; (1)-3-(3,4-Dimethoxyphenyl)-6-((5,6-dimethoxyphenethyl)methylamino)hexane-3-carbonitrile; 2-(3,4-Dimethoxyphenyl)-5-[2-(3,4-dimethoxyphenyl)ethyl-methyl-amino]-2-(1-methylethyl) pentanenitrile; 2-(3,4-dimethoxyphenyl)-5-[2-(3,4-dimethoxyphenyl)ethyl-methylamino]-2-propan-2-ylpentanenitrile; 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile; 5-((3,4-Dimethoxyphenethyl)methylamino)-2-(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile; 5-[(3,4-Dimethoxyphenethyl)methylamino]-2-(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile; Verapamil (Na-Ca chanel blocker)
• Indication:
  In total 1 Indication(s)
  Hypertension [ICD-11: BA00]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Keloid/hypertrophic scars [ICD-11: EE60]; [2]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Breast cancer [ICD-11: 2C60]; [1]
• Target: Voltage-gated calcium channel alpha Cav3.1 (CACNA1G); CAC1G_HUMAN; [1]
• Formula: C27H38N2O4
• IsoSMILES: CC(C)C(CCCN(C)CCC1=CC(=C(C=C1)OC)OC)(C#N)C2=CC(=C(C=C2)OC)OC
• InChI: 1S/C27H38N2O4/c1-20(2)27(19-28,22-10-12-24(31-5)26(18-22)33-7)14-8-15-29(3)16-13-21-9-11-23(30-4)25(17-21)32-6/h9-12,17-18,20H,8,13-16H2,1-7H3
• InChIKey: SGTNSNPWRIOYBX-UHFFFAOYSA-N
• PubChem CID: 2520
• ChEBI ID: CHEBI:77733
• TTD Drug ID: D0R0FE
• VARIDT ID: DR00264
• DrugBank ID: DB00661

Type(s) of Resistant Mechanism of This Drug

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  IDUE: Irregularity in Drug Uptake and Drug Efflux

Drug Resistance Data Categorized by Their Corresponding Diseases

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

Breast cancer [ICD-11: 2C60]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: H19, imprinted maternally expressed transcript (H19) [1]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MCF-7/AdrVp cells; Breast; Homo sapiens (Human); CVCL_4Y46
• Experiment for Molecule Alteration: RT-PCR; Northern blotting analysis
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: The mRNA of the H19 gene is overexpressed in MCF-7/AdrVp cells relative toparental MCF-7 cells or drug-sensitive MCF-7/AdrVp revertant cells. H19is an imprinted gene with an important role in fetal differentiation, as well as a postulated function as a tumor suppressor gene. Another p95-over-expressing multidrug-resistant cell line, human lung carcinoma NCI-H1688, also displays high levels of 1119 mRNA.

ICD-08: Nervous system diseases

Cerebrovascular disease [ICD-11: 8B22]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [3]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Cerebrovascular disease [ICD-11: 8B22.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7/DX1 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: Sf9 cells; Ovary; Homo sapiens (Human); CVCL_0549
• In Vitro Model: HCMEC/D3 cells; Brain; Homo sapiens (Human); CVCL_U985
• In Vivo Model: Male Sprague-Dawley Rats Brain Capillary Isolation; Mus musculus
• Mechanism Description: In P-gp overexpressing cells and in human brain capillary endothelial hCMEC/D3 cells, the dimer with the shortest tether length (QT2C2) was the most potent inhibitor showing >80-fold better inhibition of P-gp-mediated transport than monomeric QT. QT2C2Me2 increased the accumulation of the P-gp substrate verapamil in rat brain in situ three times more than QT.

ICD-11: Circulatory system diseases

Cardiac arrhythmia [ICD-11: BC9Y]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [3]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Arrhythmia [ICD-11: BC9Y.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7/DX1 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: Sf9 cells; Ovary; Homo sapiens (Human); CVCL_0549
• In Vitro Model: HCMEC/D3 cells; Brain; Homo sapiens (Human); CVCL_U985
• In Vivo Model: Male Sprague-Dawley Rats Brain Capillary Isolation; Mus musculus
• Mechanism Description: In P-gp overexpressing cells and in human brain capillary endothelial hCMEC/D3 cells, the dimer with the shortest tether length (QT2C2) was the most potent inhibitor showing >80-fold better inhibition of P-gp-mediated transport than monomeric QT. QT2C2Me2 increased the accumulation of the P-gp substrate verapamil in rat brain in situ three times more than QT.

ICD-14: Skin diseases

Keloid/hypertrophic scars [ICD-11: EE60]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance-associated protein 1 (MRP1) [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Hypertrophic scar [ICD-11: EE60.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Hypertrophic scar tissue isolates; N.A.
• Experiment for Molecule Alteration: Western blotting assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Fibroblasts derived from hypertrophic scar and normal skin tissues were first compared for their resistance to verapamil and etoposide phosphate. Scar fibroblasts showed stronger resistance to both verapamil and etoposide than normal fibroblasts, also scar fibroblasts expressed more P-glycoprotein and MRP1 than normal fibroblasts.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Hypertrophic scar [ICD-11: EE60.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Hypertrophic scar tissue isolates; N.A.
• Experiment for Molecule Alteration: Western blotting assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Fibroblasts derived from hypertrophic scar and normal skin tissues were first compared for their resistance to verapamil and etoposide phosphate. Scar fibroblasts showed stronger resistance to both verapamil and etoposide than normal fibroblasts, also scar fibroblasts expressed more P-glycoprotein and MRP1 than normal fibroblasts.

References

• Ref 1: H19 gene overexpression in atypical multidrug-resistant cells associated with expression of a 95-kilodalton membrane glycoprotein. Cancer Res. 1996 Jul 1;56(13):2904-7.
• Ref 2: Disruption of the association between drug transporter and actin cytoskeleton abolishes drug resistance in hypertrophic scar .Oncotarget. 2017 Jan 10;8(2):2617-2627. doi: 10.18632/oncotarget.13734. 10.18632/oncotarget.13734
• Ref 3: Reversible dimers of the atypical antipsychotic quetiapine inhibit p-glycoprotein-mediated efflux in vitro with increased binding affinity and in situ at the blood-brain barrier. ACS Chem Neurosci. 2014 Apr 16;5(4):305-17. doi: 10.1021/cn4002329. Epub 2014 Feb 7.