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Imatinib

PubChem CID
5291
Structure
Imatinib_small.png
Imatinib_3D_Structure.png
Molecular Formula
Synonyms
  • Imatinib
  • 152459-95-5
  • STI571
  • Imatinib (STI571)
  • sti-571
Molecular Weight
493.6 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2005-03-25
  • Modify:
    2025-01-04
Description
Imatinib is a benzamide obtained by formal condensation of the carboxy group of 4-[(4-methylpiperazin-1-yl)methyl]benzoic acid with the primary aromatic amino group of 4-methyl-N(3)-[4-(pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine. Used (as its mesylate salt) for treatment of chronic myelogenous leukemia and gastrointestinal stromal tumours. It has a role as an apoptosis inducer, a tyrosine kinase inhibitor and an antineoplastic agent. It is a N-methylpiperazine, a member of pyridines, a member of benzamides, an aromatic amine and a member of pyrimidines. It is functionally related to a benzamide.
Imatinib is a small molecule kinase inhibitor that revolutionized the treatment of cancer, particularly chronic myeloid leukemia, in 2001. It was deemed a "miracle drug" due to its clinical success, as oncologist Dr. Brian noted that "complete hematologic responses were observed in 53 of 54 patients with CML treated with a daily dosage of 300 mg or more and typically occurred in the first four weeks of therapy".. The discovery of imatinib also established a new group of therapy called "targeted therapy", since treatment can be tailored specifically to the unique cancer genetics of each patient. Imatinib was approved on February 1st ,2001 by the FDA and November 7th, 2001 by the EMA; however, its European approval has been withdrawn in October 2023.
Imatinib is a Kinase Inhibitor. The mechanism of action of imatinib is as a Bcr-Abl Tyrosine Kinase Inhibitor, and Cytochrome P450 3A4 Inhibitor, and Cytochrome P450 2D6 Inhibitor.
See also: Imatinib Mesylate (has salt form); IKT-001Pro (is active moiety of).

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Imatinib.png

1.2 3D Conformer

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

4-[(4-methylpiperazin-1-yl)methyl]-N-[4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl]benzamide
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 InChI

InChI=1S/C29H31N7O/c1-21-5-10-25(18-27(21)34-29-31-13-11-26(33-29)24-4-3-12-30-19-24)32-28(37)23-8-6-22(7-9-23)20-36-16-14-35(2)15-17-36/h3-13,18-19H,14-17,20H2,1-2H3,(H,32,37)(H,31,33,34)
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

KTUFNOKKBVMGRW-UHFFFAOYSA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

CC1=C(C=C(C=C1)NC(=O)C2=CC=C(C=C2)CN3CCN(CC3)C)NC4=NC=CC(=N4)C5=CN=CC=C5
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C29H31N7O
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

2.3.2 European Community (EC) Number

2.3.3 UNII

2.3.4 ChEBI ID

2.3.5 ChEMBL ID

2.3.6 DrugBank ID

2.3.7 DSSTox Substance ID

2.3.8 HMDB ID

2.3.9 KEGG ID

2.3.10 Metabolomics Workbench ID

2.3.11 NCI Thesaurus Code

2.3.12 Nikkaji Number

2.3.13 NSC Number

2.3.14 PharmGKB ID

2.3.15 Pharos Ligand ID

2.3.16 RXCUI

2.3.17 Wikidata

2.3.18 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • alpha-(4-methyl-1-piperazinyl)-3'-((4-(3-pyridyl)-2-pyrimidinyl)amino)-p-tolu-p-toluidide
  • CGP 57148
  • CGP-57148
  • CGP57148
  • CGP57148B
  • Gleevec
  • Glivec
  • imatinib
  • imatinib mesylate
  • imatinib methanesulfonate
  • Mesylate, Imatinib
  • Methanesulfonate, Imatinib
  • ST 1571
  • ST1571
  • STI 571
  • STI-571
  • STI571

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
493.6 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3-AA
Property Value
3.5
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
2
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
7
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
7
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
493.25900864 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
493.25900864 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
86.3 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
37
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
706
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Physical Description

Solid

3.2.2 Melting Point

226 °C (mesylate salt)
226 °C (mesylate salt)

3.2.3 Solubility

Very soluble in water at pH < 5.5 (mesylate salt)
1.46e-02 g/L

3.2.4 LogP

3
3

3.2.5 Collision Cross Section

214.6 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

3.3 Chemical Classes

3.3.1 Drugs

Pharmaceuticals
S10 | SWISSPHARMA | Pharmaceutical List with Consumption Data | DOI:10.5281/zenodo.2623484
Pharmaceuticals -> Listed in ZINC15
S55 | ZINC15PHARMA | Pharmaceuticals from ZINC15 | DOI:10.5281/zenodo.3247749
3.3.1.1 Human Drugs
Breast Feeding; Lactation; Milk, Human; Antineoplastic Agents; Enzyme Inhibitors; Protein Kinase Inhibitors; Signal Transduction Inhibitors; Tyrosine Kinase Inhibitors
Human drug -> Active ingredient (IMATINIB)
Human drugs -> Antineoplastic agents -> Human pharmacotherapeutic group -> EMA Drug Category
Human drugs -> Antineoplastic agents, Protein kinase inhibitors -> Human pharmacotherapeutic group -> EMA Drug Category
Human drugs -> imatinib -> Human pharmacotherapeutic group -> EMA Drug Category
Human drugs -> Protein kinase inhibitors, Antineoplastic agents -> Human pharmacotherapeutic group -> EMA Drug Category
Human drugs -> Protein kinase inhibitors -> Human pharmacotherapeutic group -> EMA Drug Category
Paediatric drug
Targeted therapies

4 Spectral Information

4.1 1D NMR Spectra

4.1.1 13C NMR Spectra

Copyright
Copyright © 2016-2024 W. Robien, Inst. of Org. Chem., Univ. of Vienna. All Rights Reserved.
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4.2 Mass Spectrometry

4.2.1 MS-MS

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Spectra ID
Ionization Mode
Positive
Top 5 Peaks

394.1664 100

222.0913 38.99

379.1429 26.32

99.0916 20.19

264.1131 19.30

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Spectra ID
Ionization Mode
Positive
Top 5 Peaks

378.1351 100

247.0866 83.08

222.0914 80.98

264.1131 33.12

131.0603 31.68

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4.2.2 LC-MS

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Authors
Nikiforos Alygizakis, Katerina Galani, Nikolaos Thomaidis, University of Athens
Instrument
Bruker maXis Impact
Instrument Type
LC-ESI-QTOF
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
ESI
Collision Energy
10 eV
Fragmentation Mode
CID
Column Name
Acclaim RSLC C18 2.2um, 2.1x100mm, Thermo
Retention Time
6.597 min
Precursor m/z
494.2663
Precursor Adduct
[M+H]+
Top 5 Peaks

494.2664 999

495.2694 316

496.2708 51

394.1661 7

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License
CC BY
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Authors
Nikiforos Alygizakis, Katerina Galani, Nikolaos Thomaidis, University of Athens
Instrument
Bruker maXis Impact
Instrument Type
LC-ESI-QTOF
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
ESI
Collision Energy
20 eV
Fragmentation Mode
CID
Column Name
Acclaim RSLC C18 2.2um, 2.1x100mm, Thermo
Retention Time
6.630 min
Precursor m/z
494.2663
Precursor Adduct
[M+H]+
Top 5 Peaks

494.2663 999

495.2695 335

394.1658 129

496.2714 53

217.1322 39

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License
CC BY

6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

Imatinib is indicated for the treatment of adult and pediatric chronic myeloid leukemia with Philadelphia chromosome mutation (Ph+) in blast crisis, accelerated phase, or chronic phase after IFN-alpha therapy failure. Additionally, imatinib is also indicated to treat adult and pediatric Ph+ acute lymphoblastic leukemia, adult myelodysplastic/myeloproliferative diseases, adult aggressive systemic mastocytosis, adult hypereosinophilic syndrome and/or chronic eosinophilic leukemia (CEL), adult dermatofibrosarcoma protuberans, and malignant gastrointestinal stromal tumors (GIST).
Glivec is indicated for the treatment of, , , adult and paediatric patients with newly diagnosed Philadelphia-chromosome (bcr-abl)-positive (Ph+) chronic myeloid leukaemia (CML) for whom bone-marrow transplantation is not considered as the first line of treatment; , adult and paediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy, or in accelerated phase or blast crisis; , adult and paediatric patients with newly diagnosed Philadelphia-chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) integrated with chemotherapy; , adult patients with relapsed or refractory Ph+ ALL as monotherapy; , adult patients with myelodysplastic / myeloproliferative diseases (MDS / MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements; , adult patients with advanced hypereosinophilic syndrome (HES) and / or chronic eosinophilic leukaemia (CEL) with FIP1L1-PDGFRa rearrangement. , , , The effect of Glivec on the outcome of bone-marrow transplantation has not been determined. , , Glivec is indicated for: , , , the treatment of adult patients with Kit (CD 117)-positive unresectable and / or metastatic malignant gastrointestinal stromal tumours (GIST); , the adjuvant treatment of adult patients who are at significant risk of relapse following resection of Kit (CD117)-positive GIST. Patients who have a low or very low risk of recurrence should not receive adjuvant treatment; , the treatment of adult patients with unresectable dermatofibrosarcoma protuberans (DFSP) and adult patients with recurrent and / or metastatic DFSP who are not eligible for surgery. , , , In adult and paediatric patients, the effectiveness of Glivec is based on overall haematological and cytogenetic response rates and progression-free survival in CML, on haematological and cytogenetic response rates in Ph+ ALL, MDS / MPD, on haematological response rates in HES / CEL and on objective response rates in adult patients with unresectable and / or metastatic GIST and DFSP and on recurrence-free survival in adjuvant GIST. The experience with Glivec in patients with MDS / MPD associated with PDGFR gene re-arrangements is very limited (see section 5. 1). Except in newly diagnosed chronic phase CML, there are no controlled trials demonstrating a clinical benefit or increased survival for these diseases. ,

7.2 LiverTox Summary

Imatinib is specific tyrosine kinase receptor inhibitor that is used in the therapy of Philadelphia chromosome-positive chronic myelogenous leukemia and gastrointestinal stromal tumors, both of which are marked by an abnormal, constitutively expressed tyrosine kinase that causes unregulated cell growth. Imatinib therapy is associated with transient elevations in serum aminotransferase levels and rare instances of clinically apparent acute liver injury which can be severe and sometimes fatal.

7.3 Drug Classes

Breast Feeding; Lactation; Milk, Human; Antineoplastic Agents; Enzyme Inhibitors; Protein Kinase Inhibitors; Signal Transduction Inhibitors; Tyrosine Kinase Inhibitors
Antineoplastic Agents

7.4 WHO Essential Medicines

Drug
Drug Classes
Targeted therapies
Formulation
Oral - Solid: 100 mg; 400 mg
Indication
(1) B lymphoblastic leukaemia or lymphoma with t(9:22) (q34;q11.2); BCR-ABL1; (2) Gastrointestinal stromal tumour of unspecified gastrointestinal sites; (3) Chronic myeloid leukaemia, not elsewhere classified

7.5 FDA Approved Drugs

7.6 FDA National Drug Code Directory

7.7 Drug Labels

Drug and label
Active ingredient and drug

7.8 Clinical Trials

7.8.1 ClinicalTrials.gov

7.8.2 EU Clinical Trials Register

7.8.3 NIPH Clinical Trials Search of Japan

7.9 EMA Drug Information

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Medicine
Category
Human drugs
Therapeutic area
Precursor Cell Lymphoblastic Leukemia-Lymphoma; Gastrointestinal Stromal Tumors; Dermatofibrosarcoma; Myelodysplastic-Myeloproliferative Diseases; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Hypereosinophilic Syndrome
Active Substance
imatinib
INN/Common name
imatinib
Pharmacotherapeutic Classes
Antineoplastic agents
Status
This medicine is authorized for use in the European Union
Company
Novartis Europharm Limited
Market Date
2001-11-07
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Category
Human drugs
Therapeutic area
Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Myelodysplastic-Myeloproliferative Diseases; Hypereosinophilic Syndrome; Dermatofibrosarcoma; Gastrointestinal Stromal Tumors
Active Substance
imatinib mesilate
INN/Common name
imatinib
Pharmacotherapeutic Classes
Antineoplastic agents
Status
Withdrawn
Company
Koanaa Healthcare GmbH
Market Date
2021-09-22

8 Pharmacology and Biochemistry

8.1 Pharmacodynamics

Imatinib is a 2-phenylaminopyrimidine derivative neoplastic agent that belongs to the class of tyrosine kinase inhibitors. Although imatinib inhibits a number of tyrosine kinases, it is quite selective toward the BCR-ABL fusion protein that is present in various cancers. BCR-ABL pathway controls many downstream pathways that are heavily implicated in neoplastic growth such as the Ras/MapK pathway (cellular proliferation), Src/Pax/Fak/Rac pathway (cellular motility), and PI/PI3K/AKT/BCL-2 pathway (apoptosis pathway). Therefore, the BCR-ABL pathway is an attractive target for cancer treatment. Although normal cells also depend on these pathways for growth, these cells tend to have redundant tyrosine kinases to continually function in spite of ABL inhibition from imatinib. Cancer cells, on the other hand, can have a dependence on BCR-ABL, thus more heavily impacted by imatinib.

8.2 MeSH Pharmacological Classification

Antineoplastic Agents
Substances that inhibit or prevent the proliferation of NEOPLASMS. (See all compounds classified as Antineoplastic Agents.)
Tyrosine Kinase Inhibitors
Protein kinase inhibitors that inhibit TYROSINE PROTEIN KINASES. (See all compounds classified as Tyrosine Kinase Inhibitors.)

8.3 FDA Pharmacological Classification

1 of 2
FDA UNII
BKJ8M8G5HI
Active Moiety
IMATINIB
Pharmacological Classes
Established Pharmacologic Class [EPC] - Kinase Inhibitor
Pharmacological Classes
Mechanisms of Action [MoA] - Bcr-Abl Tyrosine Kinase Inhibitors
Pharmacological Classes
Mechanisms of Action [MoA] - Cytochrome P450 3A4 Inhibitors
Pharmacological Classes
Mechanisms of Action [MoA] - Cytochrome P450 2D6 Inhibitors
FDA Pharmacology Summary
Imatinib is a Kinase Inhibitor. The mechanism of action of imatinib is as a Bcr-Abl Tyrosine Kinase Inhibitor, and Cytochrome P450 3A4 Inhibitor, and Cytochrome P450 2D6 Inhibitor.
2 of 2
Non-Proprietary Name
IMATINIB
Pharmacological Classes
Kinase Inhibitor [EPC]; Bcr-Abl Tyrosine Kinase Inhibitors [MoA]; Cytochrome P450 3A4 Inhibitors [MoA]; Cytochrome P450 2D6 Inhibitors [MoA]

8.4 ATC Code

L01EA01
L01XE01
S76 | LUXPHARMA | Pharmaceuticals Marketed in Luxembourg | Pharmaceuticals marketed in Luxembourg, as published by d'Gesondheetskeess (CNS, la caisse nationale de sante, www.cns.lu), mapped by name to structures using CompTox by R. Singh et al. (in prep.). List downloaded from https://cns.public.lu/en/legislations/textes-coordonnes/liste-med-comm.html. Dataset DOI:10.5281/zenodo.4587355

L - Antineoplastic and immunomodulating agents

L01 - Antineoplastic agents

L01E - Protein kinase inhibitors

L01EA - Bcr-abl tyrosine kinase inhibitors

L01EA01 - Imatinib

8.5 Absorption, Distribution and Excretion

Absorption
Imatinib is well absorbed after oral administration with Cmax achieved within 2-4 hours post-dose. Mean absolute bioavailability is 98%. Mean imatinib AUC increases proportionally with increasing doses ranging from 25 mg to 1,000 mg. There is no significant change in the pharmacokinetics of imatinib on repeated dosing, and accumulation is 1.5- to 2.5-fold at a steady state when Gleevec is dosed once daily.
Route of Elimination
Imatinib elimination is predominately in the feces, mostly as metabolites. Based on the recovery of compound(s) after an oral 14C-labeled dose of imatinib, approximately 81% of the dose was eliminated within 7 days, in feces (68% of dose) and urine (13% of dose). Unchanged imatinib accounted for 25% of the dose (5% urine, 20% feces), the remainder being metabolites.
Volume of Distribution
Population pharmacokinetics in adult CML patients estimated the steady-state volume of distribution of imatinib to be 295.0 ± 62.5 L.At a dose of 340 mg/m2, the volume of distribution of imatinib in pediatric patients was calculated to be 167 ± 84 L.
Clearance
Typically, clearance of imatinib in a 50-year-old patient weighing 50 kg is expected to be 8 L/h, while for a 50-year-old patient weighing 100 kg the clearance will increase to 14 L/h. The inter-patient variability of 40% in clearance does not warrant initial dose adjustment based on body weight and/or age but indicates the need for close monitoring for treatment-related toxicities.

8.6 Metabolism / Metabolites

CYP3A4 is the major enzyme responsible for the metabolism of imatinib. Other cytochrome P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play a minor role in its metabolism. The main circulating active metabolite in humans is the N-demethylated piperazine derivative, formed predominantly by CYP3A4. It shows in vitro potency similar to the parent imatinib.
Imatinib has known human metabolites that include N-desmethylimatinib.
S73 | METXBIODB | Metabolite Reaction Database from BioTransformer | DOI:10.5281/zenodo.4056560

8.7 Biological Half-Life

Following oral administration in healthy volunteers, the elimination half-lives of imatinib and its major active metabolite, the N-desmethyl derivative (CGP74588), are approximately 18 and 40 hours, respectively.

8.8 Mechanism of Action

Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the BCR-ABL tyrosine kinase, the constitutively active tyrosine kinase created by the Philadelphia chromosome abnormality in CML.Although the function of normal BCR is still unclear, ABL activation is overexpressed in various tumors and is heavily implicated in cancer cells growth and survival. Imatinib inhibits the BCR-ABL protein by binding to the ATP pocket in the active site, thus preventing downstream phosphorylation of target protein. Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular events. In vitro, imatinib inhibits proliferation and induces apoptosis in GIST cells, which express an activating c-Kit mutation.

8.9 Human Metabolite Information

8.9.1 Cellular Locations

  • Cytoplasm
  • Membrane

8.9.2 Metabolite Pathways

8.10 Transformations

9 Use and Manufacturing

9.1 Uses

Use (kg; approx.) in Germany (2009): >1000

Use (kg; exact) in Germany (2009): 1300

Consumption (g per capita; approx.) in Germany (2009): 0.0122

Consumption (g per capita; exact) in Germany (2009): 0.0159

Excretion rate: 0.25

Calculated removal (%): 5.8

9.1.1 Use Classification

Human drugs -> Antineoplastic agents -> Human pharmacotherapeutic group -> EMA Drug Category
Human drugs -> Antineoplastic agents, Protein kinase inhibitors -> Human pharmacotherapeutic group -> EMA Drug Category
Human drugs -> imatinib -> Human pharmacotherapeutic group -> EMA Drug Category
Human drugs -> Protein kinase inhibitors, Antineoplastic agents -> Human pharmacotherapeutic group -> EMA Drug Category
Human drugs -> Protein kinase inhibitors -> Human pharmacotherapeutic group -> EMA Drug Category
Human Drugs -> EU pediatric investigation plans

10 Safety and Hazards

10.1 Hazards Identification

10.1.1 GHS Classification

Pictogram(s)
Irritant
Health Hazard
Signal
Danger
GHS Hazard Statements

H302 (10%): Harmful if swallowed [Warning Acute toxicity, oral]

H315 (20%): Causes skin irritation [Warning Skin corrosion/irritation]

H319 (20%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]

H335 (10%): May cause respiratory irritation [Warning Specific target organ toxicity, single exposure; Respiratory tract irritation]

H341 (70%): Suspected of causing genetic defects [Warning Germ cell mutagenicity]

H351 (70%): Suspected of causing cancer [Warning Carcinogenicity]

H360 (70%): May damage fertility or the unborn child [Danger Reproductive toxicity]

H361 (10%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]

H362 (70%): May cause harm to breast-fed children [Reproductive toxicity, effects on or via lactation]

Precautionary Statement Codes

P203, P260, P261, P263, P264, P264+P265, P270, P271, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P318, P319, P321, P330, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501

(The corresponding statement to each P-code can be found at the GHS Classification page.)

ECHA C&L Notifications Summary

Aggregated GHS information provided per 10 reports by companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

10.1.2 Hazard Classes and Categories

Skin Irrit. 2 (20%)

Eye Irrit. 2A (20%)

STOT SE 3 (10%)

Muta. 2 (70%)

Carc. 2 (70%)

Repr. 1B (70%)

Repr. 2 (10%)

10.2 Regulatory Information

REACH Registered Substance

11 Toxicity

11.1 Toxicological Information

11.1.1 Hepatotoxicity

Imatinib therapy is associated with three forms of acute liver injury: transient and usually asymptomatic elevations in serum enzymes during treatment, clinically apparent acute hepatitis, and reactivation of an underlying chronic hepatitis B.

Elevations in serum aminotransferase levels are common during imatinib therapy, but ALT levels above 5 times the upper limit of the normal range occur in only 2% to 4% of patients treated for 6 months or more. In addition, mild elevations in serum bilirubin can occur. These abnormalities are usually mild, asymptomatic, and resolve despite continuing therapy. Nevertheless, dose adjustment or temporary discontinuation and restarting at a lower dose may be needed and is recommended if levels are markedly elevated (ALT or AST persistently >5 times ULN or bilirubin >3 times ULN).

In addition, imatinib has been linked to rare instances of clinically apparent acute liver injury with jaundice. The time to onset has varied from 6 days to as long as several years after starting treatment, the usual latency being 2 to 6 months (Cases 1 and 2). The pattern of serum enzyme elevations is typically hepatocellular, although cholestatic and mixed forms of hepatitis have also been reported. The injury can be severe and instances of acute liver failure and death have been reported as well as severe hepatitis resulting in a posthepatitic cirrhosis. Immunoallergic features (rash, fever and eosinophilia) are not common, but some patients develop low levels of autoantibodies and instances of chronic hepatitis on long term imatinib have been reported. More importantly, many instances of an apparent clinical response to prednisone therapy have been described. Recurrence of injury is common with reexposure, but concurrent prednisone therapy may blunt or prevent the recurrence of liver injury and, in some instances, has allowed for continued, long term therapy despite a previous bout of clinically apparent liver injury on imatinib.

Finally, there have been several instances of reactivation of chronic hepatitis B during imatinib therapy in patients with inactive hepatitis B or the HBsAg carrier state (Case 3). The clinical presentation is generally with an acute hepatitis like syndrome with marked elevations in serum ALT and minimal changes in alkaline phosphatase levels. Typically, hepatitis B virus (HBV) DNA is present in serum in increasing levels early in the course of reactivation which rapidly falls to pretreatment levels with recovery. Patients may also test positive for IgM antibody to hepatitis B core antigen (IgM anti-HBc). Reactivation of hepatitis B due to imatinib can be severe and fatal instances have been reported.

Likelihood score: B (likely cause of clinically apparent liver injury as well as reactivation of hepatitis B).

11.1.2 Drug Induced Liver Injury

Compound
imatinib
DILI Annotation
Most-DILI-Concern
Severity Grade
8
Label Section
Warnings and precautions
References

M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007

M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

11.1.3 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

Limited information indicates that maternal doses of imatinib up to 400 mg daily produce low levels of the drug and its active metabolite in milk. Although a few breastfed infants apparently experienced no adverse effects during maternal use of imatinib, no long-term data are available. Until more data are available, imatinib should be used only with careful monitoring during breastfeeding. National Comprehensive Cancer Network guidelines, the manufacturer and some authors recommend that breastfeeding be discontinued during imatinib therapy and for 1 month after therapy.

◉ Effects in Breastfed Infants

A woman receiving oral imatinib 400 mg daily for chronic myeloid leukemia breastfed her infant. No adverse effects were noted in the infant during the first 2 months of nursing.

One woman with chronic myelogenous leukemia received imatinib 400 mg daily throughout pregnancy and during breastfeeding (extent not stated) for nearly 6 months postpartum. Her infant reportedly grew and developed normally.

A woman with chronic myeloid leukemia received imatinib 400 mg daily starting at week 8 of pregnancy and continuing throughout 8 months of breastfeeding (extent not stated). The infant was healthy, but an atrial septal defect was repaired at 30 months of age. It was thought to be unrelated to imatinib therapy.

A pregnant woman with Philadelphia chromosome-positive chronic myelogenous leukemia was started on imatinib 400 mg daily during pregnancy. After delivery, her preterm infant was fed colostrum until the middle of the fifth day postpartum when exclusive formula feeding was instituted. The infant was treated for apnea of prematurity and discharged on day 25 of life. No adverse effects on growth or development were noted during the first year of life.

◉ Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

11.1.4 Protein Binding

At clinically relevant concentrations of imatinib, binding to plasma proteins in in vitro experiments is approximately 95%, mostly to albumin and α1-acid glycoprotein.

12 Associated Disorders and Diseases

13 Literature

13.1 Consolidated References

13.2 NLM Curated PubMed Citations

13.3 Springer Nature References

13.4 Thieme References

13.5 Wiley References

13.6 Nature Journal References

13.7 Chemical Co-Occurrences in Literature

13.8 Chemical-Gene Co-Occurrences in Literature

13.9 Chemical-Disease Co-Occurrences in Literature

14 Patents

14.1 Depositor-Supplied Patent Identifiers

14.2 WIPO PATENTSCOPE

14.3 Chemical Co-Occurrences in Patents

14.4 Chemical-Disease Co-Occurrences in Patents

14.5 Chemical-Gene Co-Occurrences in Patents

15 Interactions and Pathways

15.1 Protein Bound 3D Structures

15.1.1 Ligands from Protein Bound 3D Structures

PDBe Ligand Code
PDBe Structure Code
PDBe Conformer

15.2 Chemical-Target Interactions

15.3 Drug-Drug Interactions

15.4 Drug-Food Interactions

  • Avoid grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which can increase serum levels of imatinib.
  • Exercise caution with St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce the serum concentration of imatinib.
  • Take with a full glass of water. Taking imatinib with water may reduce gastric irritation.
  • Take with food. Food reduces gastric irritation.

15.5 Pathways

16 Biological Test Results

16.1 BioAssay Results

17 Classification

17.1 MeSH Tree

17.2 NCI Thesaurus Tree

17.3 ChEBI Ontology

17.4 KEGG: ATC

17.5 KEGG: Target-based Classification of Drugs

17.6 KEGG: Drug Groups

17.7 WHO ATC Classification System

17.8 FDA Pharm Classes

17.9 ChemIDplus

17.10 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

17.11 ChEMBL Target Tree

17.12 UN GHS Classification

17.13 NORMAN Suspect List Exchange Classification

17.14 CCSBase Classification

17.15 EPA DSSTox Classification

17.16 MolGenie Organic Chemistry Ontology

18 Information Sources

  1. BindingDB
    LICENSE
    All data curated by BindingDB staff are provided under the Creative Commons Attribution 3.0 License (https://creativecommons.org/licenses/by/3.0/us/).
    https://www.bindingdb.org/rwd/bind/info.jsp
    4-[(4-methylpiperazin-1-yl)methyl]-N-[4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl]benzamide
    https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=13530
  2. Chemical Probes Portal
  3. Comparative Toxicogenomics Database (CTD)
    LICENSE
    It is to be used only for research and educational purposes. Any reproduction or use for commercial purpose is prohibited without the prior express written permission of NC State University.
    http://ctdbase.org/about/legal.jsp
  4. Drug Gene Interaction database (DGIdb)
    LICENSE
    The data used in DGIdb is all open access and where possible made available as raw data dumps in the downloads section.
    http://www.dgidb.org/downloads
  5. DrugBank
    LICENSE
    Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)
    https://www.drugbank.ca/legal/terms_of_use
  6. IUPHAR/BPS Guide to PHARMACOLOGY
    LICENSE
    The Guide to PHARMACOLOGY database is licensed under the Open Data Commons Open Database License (ODbL) https://opendatacommons.org/licenses/odbl/. Its contents are licensed under a Creative Commons Attribution-ShareAlike 4.0 International License (http://creativecommons.org/licenses/by-sa/4.0/)
    https://www.guidetopharmacology.org/about.jsp#license
    Guide to Pharmacology Target Classification
    https://www.guidetopharmacology.org/targets.jsp
  7. Therapeutic Target Database (TTD)
  8. CAS Common Chemistry
    LICENSE
    The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc/4.0/
  9. ChemIDplus
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  10. DTP/NCI
    LICENSE
    Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source.
    https://www.cancer.gov/policies/copyright-reuse
  11. EPA DSSTox
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  12. European Chemicals Agency (ECHA)
    LICENSE
    Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page.
    https://echa.europa.eu/web/guest/legal-notice
    Benzamide, 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-
    https://chem.echa.europa.eu/100.122.739
    Benzamide, 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]- (EC: 604-855-6)
    https://echa.europa.eu/information-on-chemicals/cl-inventory-database/-/discli/details/82124
  13. FDA Global Substance Registration System (GSRS)
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  14. Human Metabolome Database (HMDB)
    LICENSE
    HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications.
    http://www.hmdb.ca/citing
  15. CCSbase
    CCSbase Classification
    https://ccsbase.net/
  16. ChEBI
  17. FDA Pharm Classes
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  18. LiverTox
  19. NCI Thesaurus (NCIt)
    LICENSE
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    https://www.cancer.gov/policies/copyright-reuse
  20. Open Targets
    LICENSE
    Datasets generated by the Open Targets Platform are freely available for download.
    https://platform-docs.opentargets.org/licence
  21. ChEMBL
    LICENSE
    Access to the web interface of ChEMBL is made under the EBI's Terms of Use (http://www.ebi.ac.uk/Information/termsofuse.html). The ChEMBL data is made available on a Creative Commons Attribution-Share Alike 3.0 Unported License (http://creativecommons.org/licenses/by-sa/3.0/).
    http://www.ebi.ac.uk/Information/termsofuse.html
  22. NORMAN Suspect List Exchange
    LICENSE
    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    https://creativecommons.org/licenses/by/4.0/
    IMATINIB
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  23. ClinicalTrials.gov
    LICENSE
    The ClinicalTrials.gov data carry an international copyright outside the United States and its Territories or Possessions. Some ClinicalTrials.gov data may be subject to the copyright of third parties; you should consult these entities for any additional terms of use.
    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  24. DailyMed
  25. Drug Induced Liver Injury Rank (DILIrank) Dataset
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  26. European Medicines Agency (EMA)
    LICENSE
    Information on the European Medicines Agency's (EMA) website is subject to a disclaimer and copyright and limited reproduction notices.
    https://www.ema.europa.eu/en/about-us/legal-notice
  27. Drugs and Lactation Database (LactMed)
  28. Drugs@FDA
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  29. WHO Model Lists of Essential Medicines
    LICENSE
    Permission from WHO is not required for the use of WHO materials issued under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Intergovernmental Organization (CC BY-NC-SA 3.0 IGO) license.
    https://www.who.int/about/policies/publishing/copyright
  30. EU Clinical Trials Register
  31. WHO Anatomical Therapeutic Chemical (ATC) Classification
    LICENSE
    Use of all or parts of the material requires reference to the WHO Collaborating Centre for Drug Statistics Methodology. Copying and distribution for commercial purposes is not allowed. Changing or manipulating the material is not allowed.
    https://www.whocc.no/copyright_disclaimer/
  32. National Drug Code (NDC) Directory
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  33. NIST Mass Spectrometry Data Center
    LICENSE
    Data covered by the Standard Reference Data Act of 1968 as amended.
    https://www.nist.gov/srd/public-law
  34. Japan Chemical Substance Dictionary (Nikkaji)
  35. KEGG
    LICENSE
    Academic users may freely use the KEGG website. Non-academic use of KEGG generally requires a commercial license
    https://www.kegg.jp/kegg/legal.html
    Anatomical Therapeutic Chemical (ATC) classification
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
    Target-based classification of drugs
    http://www.genome.jp/kegg-bin/get_htext?br08310.keg
  36. MassBank Europe
  37. MassBank of North America (MoNA)
    LICENSE
    The content of the MoNA database is licensed under CC BY 4.0.
    https://mona.fiehnlab.ucdavis.edu/documentation/license
  38. Metabolomics Workbench
  39. Nature Chemical Biology
  40. NIPH Clinical Trials Search of Japan
  41. NLM RxNorm Terminology
    LICENSE
    The RxNorm Terminology is created by the National Library of Medicine (NLM) and is in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from NLM. Credit to the U.S. National Library of Medicine as the source is appreciated but not required. The full RxNorm dataset requires a free license.
    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  42. PharmGKB
    LICENSE
    PharmGKB data are subject to the Creative Commons Attribution-ShareALike 4.0 license (https://creativecommons.org/licenses/by-sa/4.0/).
    https://www.pharmgkb.org/page/policies
  43. Pharos
    LICENSE
    Data accessed from Pharos and TCRD is publicly available from the primary sources listed above. Please respect their individual licenses regarding proper use and redistribution.
    https://pharos.nih.gov/about
  44. Protein Data Bank in Europe (PDBe)
  45. RCSB Protein Data Bank (RCSB PDB)
    LICENSE
    Data files contained in the PDB archive (ftp://ftp.wwpdb.org) are free of all copyright restrictions and made fully and freely available for both non-commercial and commercial use. Users of the data should attribute the original authors of that structural data.
    https://www.rcsb.org/pages/policies
  46. SpectraBase
  47. Springer Nature
  48. Thieme Chemistry
    LICENSE
    The Thieme Chemistry contribution within PubChem is provided under a CC-BY-NC-ND 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc-nd/4.0/
  49. Wikidata
  50. Wikipedia
  51. Wiley
  52. Medical Subject Headings (MeSH)
    LICENSE
    Works produced by the U.S. government are not subject to copyright protection in the United States. Any such works found on National Library of Medicine (NLM) Web sites may be freely used or reproduced without permission in the U.S.
    https://www.nlm.nih.gov/copyright.html
  53. PubChem
  54. GHS Classification (UNECE)
  55. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  56. PATENTSCOPE (WIPO)
  57. NCBI
CONTENTS