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Details

Stereochemistry ABSOLUTE
Molecular Formula 2C20H19N5O6.4Na.5H2O
Molecular Weight 1032.825
Optical Activity UNSPECIFIED
Defined Stereocenters 2 / 2
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of PEMETREXED DISODIUM HEMIPENTAHYDRATE

SMILES

O.O.O.O.O.[Na+].[Na+].[Na+].[Na+].NC1=NC2=C(C(CCC3=CC=C(C=C3)C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)=CN2)C(=O)N1.NC4=NC5=C(C(CCC6=CC=C(C=C6)C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)=CN5)C(=O)N4

InChI

InChIKey=ZCTCZKWJFTYNMZ-WKUCUCPSSA-J
InChI=1S/2C20H21N5O6.4Na.5H2O/c2*21-20-24-16-15(18(29)25-20)12(9-22-16)6-3-10-1-4-11(5-2-10)17(28)23-13(19(30)31)7-8-14(26)27;;;;;;;;;/h2*1-2,4-5,9,13H,3,6-8H2,(H,23,28)(H,26,27)(H,30,31)(H4,21,22,24,25,29);;;;;5*1H2/q;;4*+1;;;;;/p-4/t2*13-;;;;;;;;;/m00........./s1

HIDE SMILES / InChI
Molecular Formula Na
Molecular Weight 22.9898
Charge 1
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE
Molecular Formula H2O
Molecular Weight 18.0153
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE
Molecular Formula C20H21N5O6
Molecular Weight 427.4106
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 1 / 1
E/Z Centers 0
Optical Activity UNSPECIFIED

Description
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/9762351 https://www.ncbi.nlm.nih.gov/pubmed/17308042

Pemetrexed is a new-generation antifolate, approved for the treatment of mesothelioma and non-small cell lung cancer, currently being evaluated for the treatment of a variety of other solid tumors. Pemetrexed, is a folate analog metabolic inhibitor that exerts its action by disrupting folate-dependent metabolic processes essential for cell replication. In vitro studies have shown that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), glycinamide ribonucleotide formyltransferase (GARFT) and and to a lesser extent aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT), which are folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is taken into cells by membrane carriers such as the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT. Polyglutamation is a time- and concentration-dependent process that occurs in tumor cells and, is thought to occur to a lesser extent, in normal tissues. Polyglutamated metabolites are thought to have an increased intracellular half-life resulting in prolonged drug action in malignant cells.

CNS Activity

CNS Penetrant
2554
Curator's Comment: Known to be CNS penetrant in rodents https://www.ncbi.nlm.nih.gov/pubmed/15987831 https://www.ncbi.nlm.nih.gov/pubmed/23297298 Human data not available, but is known that pemetrexed-based treatments controls of brain metastases in the treatment of non-small-cell lung cancer https://www.ncbi.nlm.nih.gov/pubmed/21831719

Originator

Eli Lilly
237
Curator's Comment: # Eli Lilly

Approval Year

2004
210
Targets

Targets

Primary TargetPharmacologyConditionPotency
Inhibitor
8297
 109.0 nM [Ki]
Inhibitor
8297
 7.0 nM [Ki]
Inhibitor
8297
 9300.0 nM [Ki]
Inhibitor
8297
 3580.0 nM [Ki]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Approved
8429
ALIMTA

Approved Use

ALIMTA® is a folate analog metabolic inhibitor indicated for: Locally Advanced or Metastatic Nonsquamous Non-Small Cell Lung Cancer: Initial treatment in combination with cisplatin. (1.1) Maintenance treatment of patients whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. (1.2) After prior chemotherapy as a single-agent. (1.3) Mesothelioma: in combination with cisplatin. (1.4) Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer. (1.5) 1.1 Nonsquamous Non-Small Cell Lung Cancer – Combination with Cisplatin ALIMTA® is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer. 1.2 Nonsquamous Non-Small Cell Lung Cancer – Maintenance ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. 1.3 Nonsquamous Non-Small Cell Lung Cancer – After Prior Chemotherapy ALIMTA is indicated as a single-agent for the treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer after prior chemotherapy. 1.4 Mesothelioma ALIMTA in combination with cisplatin is indicated for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. 1.5 Limitations of Use ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer. [see Clinical Studies (14.1, 14.2, 14.3)

Launch Date

2004
Primary
Approved
8429
ALIMTA

Approved Use

ALIMTA® is a folate analog metabolic inhibitor indicated for: Locally Advanced or Metastatic Nonsquamous Non-Small Cell Lung Cancer: Initial treatment in combination with cisplatin. (1.1) Maintenance treatment of patients whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. (1.2) After prior chemotherapy as a single-agent. (1.3) Mesothelioma: in combination with cisplatin. (1.4) Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer. (1.5) 1.1 Nonsquamous Non-Small Cell Lung Cancer – Combination with Cisplatin ALIMTA® is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer. 1.2 Nonsquamous Non-Small Cell Lung Cancer – Maintenance ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. 1.3 Nonsquamous Non-Small Cell Lung Cancer – After Prior Chemotherapy ALIMTA is indicated as a single-agent for the treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer after prior chemotherapy. 1.4 Mesothelioma ALIMTA in combination with cisplatin is indicated for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. 1.5 Limitations of Use ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer. [see Clinical Studies (14.1, 14.2, 14.3)

Launch Date

2004
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
137 μg/mL
EXPERIMENT
https://www.ncbi.nlm.nih.gov/pubmed/16391300
500 mg/m² other, intravenous
dose: 500 mg/m²
route of administration: Intravenous
experiment type: OTHER
co-administered:
PEMETREXED blood
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
164 μg × h/mL
EXPERIMENT
https://www.ncbi.nlm.nih.gov/pubmed/16391300
500 mg/m² other, intravenous
dose: 500 mg/m²
route of administration: Intravenous
experiment type: OTHER
co-administered:
PEMETREXED blood
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
3.71 h
EXPERIMENT
https://www.ncbi.nlm.nih.gov/pubmed/16391300
500 mg/m² other, intravenous
dose: 500 mg/m²
route of administration: Intravenous
experiment type: OTHER
co-administered:
PEMETREXED blood
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
19%
DRUG LABEL
https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021462s021lbl.pdf
PEMETREXED plasma
Homo sapiens
population: UNKNOWN
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
1200 mg/m2 1 times / 2 weeks multiple, intravenous
Highest studied dose
Dose: 1200 mg/m2, 1 times / 2 weeks
Route: intravenous
Route: multiple
Dose: 1200 mg/m2, 1 times / 2 weeks
Sources:
https://pubmed.ncbi.nlm.nih.gov/32520407
unhealthy, 63.7 years (range: 47–77 years)
n = 7
Health Status: unhealthy
Condition: Recurrent or Progressive Central Nervous System Lymphoma
Age Group: 63.7 years (range: 47–77 years)
Sex: M+F
Population Size: 7
Sources:
https://pubmed.ncbi.nlm.nih.gov/32520407
DLT: Lymphopenia...
Other AEs: Neutropenia, Fatigue...
Dose limiting toxicities:
Lymphopenia (grade 4, 2 patients)
Other AEs:
Neutropenia (grade 3-4)
Fatigue (grade 3-4)
Sources:
https://pubmed.ncbi.nlm.nih.gov/32520407
900 mg/m2 1 times / 2 weeks multiple, intravenous
MTD
Dose: 900 mg/m2, 1 times / 2 weeks
Route: intravenous
Route: multiple
Dose: 900 mg/m2, 1 times / 2 weeks
Sources:
https://pubmed.ncbi.nlm.nih.gov/32520407
unhealthy, 63.7 years (range: 47–77 years)
n = 4
Health Status: unhealthy
Condition: Recurrent or Progressive Central Nervous System Lymphoma
Age Group: 63.7 years (range: 47–77 years)
Sex: M+F
Population Size: 4
Sources:
https://pubmed.ncbi.nlm.nih.gov/32520407
Disc. AE: Transaminases increased...
AEs leading to
discontinuation/dose reduction:
Transaminases increased (1 patient)
Sources:
https://pubmed.ncbi.nlm.nih.gov/32520407
600 mg/m2 1 times / 2 weeks multiple, intravenous
Dose: 600 mg/m2, 1 times / 2 weeks
Route: intravenous
Route: multiple
Dose: 600 mg/m2, 1 times / 2 weeks
Sources:
https://pubmed.ncbi.nlm.nih.gov/32520407
unhealthy, 63.7 years (range: 47–77 years)
n = 6
Health Status: unhealthy
Condition: Recurrent or Progressive Central Nervous System Lymphoma
Age Group: 63.7 years (range: 47–77 years)
Sex: M+F
Population Size: 6
Sources:
https://pubmed.ncbi.nlm.nih.gov/32520407
DLT: Neutropenia...
Dose limiting toxicities:
Neutropenia (grade 4, 1 patient)
Sources:
https://pubmed.ncbi.nlm.nih.gov/32520407
AEs

AEs

AESignificanceDosePopulation
Fatigue grade 3-4
1200 mg/m2 1 times / 2 weeks multiple, intravenous
Highest studied dose
Dose: 1200 mg/m2, 1 times / 2 weeks
Route: intravenous
Route: multiple
Dose: 1200 mg/m2, 1 times / 2 weeks
Sources:
https://pubmed.ncbi.nlm.nih.gov/32520407
unhealthy, 63.7 years (range: 47–77 years)
n = 7
Health Status: unhealthy
Condition: Recurrent or Progressive Central Nervous System Lymphoma
Age Group: 63.7 years (range: 47–77 years)
Sex: M+F
Population Size: 7
Sources:
https://pubmed.ncbi.nlm.nih.gov/32520407
Neutropenia grade 3-4
1200 mg/m2 1 times / 2 weeks multiple, intravenous
Highest studied dose
Dose: 1200 mg/m2, 1 times / 2 weeks
Route: intravenous
Route: multiple
Dose: 1200 mg/m2, 1 times / 2 weeks
Sources:
https://pubmed.ncbi.nlm.nih.gov/32520407
unhealthy, 63.7 years (range: 47–77 years)
n = 7
Health Status: unhealthy
Condition: Recurrent or Progressive Central Nervous System Lymphoma
Age Group: 63.7 years (range: 47–77 years)
Sex: M+F
Population Size: 7
Sources:
https://pubmed.ncbi.nlm.nih.gov/32520407
Lymphopenia grade 4, 2 patients
DLT
1200 mg/m2 1 times / 2 weeks multiple, intravenous
Highest studied dose
Dose: 1200 mg/m2, 1 times / 2 weeks
Route: intravenous
Route: multiple
Dose: 1200 mg/m2, 1 times / 2 weeks
Sources:
https://pubmed.ncbi.nlm.nih.gov/32520407
unhealthy, 63.7 years (range: 47–77 years)
n = 7
Health Status: unhealthy
Condition: Recurrent or Progressive Central Nervous System Lymphoma
Age Group: 63.7 years (range: 47–77 years)
Sex: M+F
Population Size: 7
Sources:
https://pubmed.ncbi.nlm.nih.gov/32520407
Transaminases increased 1 patient
Disc. AE
900 mg/m2 1 times / 2 weeks multiple, intravenous
MTD
Dose: 900 mg/m2, 1 times / 2 weeks
Route: intravenous
Route: multiple
Dose: 900 mg/m2, 1 times / 2 weeks
Sources:
https://pubmed.ncbi.nlm.nih.gov/32520407
unhealthy, 63.7 years (range: 47–77 years)
n = 4
Health Status: unhealthy
Condition: Recurrent or Progressive Central Nervous System Lymphoma
Age Group: 63.7 years (range: 47–77 years)
Sex: M+F
Population Size: 4
Sources:
https://pubmed.ncbi.nlm.nih.gov/32520407
Neutropenia grade 4, 1 patient
DLT, Disc. AE
600 mg/m2 1 times / 2 weeks multiple, intravenous
Dose: 600 mg/m2, 1 times / 2 weeks
Route: intravenous
Route: multiple
Dose: 600 mg/m2, 1 times / 2 weeks
Sources:
https://pubmed.ncbi.nlm.nih.gov/32520407
unhealthy, 63.7 years (range: 47–77 years)
n = 6
Health Status: unhealthy
Condition: Recurrent or Progressive Central Nervous System Lymphoma
Age Group: 63.7 years (range: 47–77 years)
Sex: M+F
Population Size: 6
Sources:
https://pubmed.ncbi.nlm.nih.gov/32520407
Overview

Overview

CYP3A4CYP2C9CYP2D6hERG
inhibitor
1587
inhibitor
1767
inhibitor
1852
inhibitor
1612

OverviewOther

Other InhibitorOther SubstrateOther Inducer
CYP1A2
1524

MRP5
22
OAT3
339

OAT4
78

MRP5
40
Drug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
CYP1A2
1692
 not significant
CYP2C9
1819
 not significant
CYP2D6
1891
 not significant
CYP3A4
1925
 not significant
MRP5
48
 yes [Ki 300 uM]
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
MRP5
40
 yes
OAT4
78
 yes
OAT3
339
 yes
weak (co-administration study)
Comment: coadministration with ibuprofen decreased the clearance of pemetrexed and increased its expsoure (AUC) by ~ 20%
Page: 17.0
Tox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
hERG
1647
Sourcing

Sourcing

Vendor/AggregatorIDURL
ChEBI
CHEBI:63616
https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:63616
ChemicalBook
CB4170583
https://www.chemicalbook.com/ChemicalProductProperty_EN_CB4170583
MolPort
MolPort-016-638-470
https://www.molport.com/shop/molecule-link/MolPort-016-638-470
MolPort
MolPort-020-179-988
https://www.molport.com/shop/molecule-link/MolPort-020-179-988
ZINC
ZINC000001540998
http://zinc15.docking.org/substances/ZINC000001540998
eMolecules
30513153
https://www.emolecules.com/cgi-bin/more?vid=30513153
eMolecules
37036813
https://www.emolecules.com/cgi-bin/more?vid=37036813
PubMed

PubMed

TitleDatePubMed
Pemetrexed disodium: a novel antifolate clinically active against multiple solid tumors.
2001
A new route to 7-substituted derivatives of n-[4-(2-[2-amino-3,4-dihydro-4-oxo-7H-pyrrolo(2,3-d)pyrimidin-5-yl]ethyl)benzoyl]-L-glutamic acid [ALIMTA (LY231514, MTA)].
2001 Jun 1
Pemetrexed (Alimta): a novel multitargeted antifolate agent.
2003 Apr
Biochemical pharmacology of pemetrexed.
2004 Nov
Pemetrexed: a multitargeted antifolate.
2005 Sep
Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications.
2007 Feb
Pemetrexed: a review of its use in the management of advanced non-squamous non-small cell lung cancer.
2009 Nov 12
Patents

Patents

JP2011510954A
143
JP2011512332A
13
WO/2010/030598A2
9
WO/2016/059238A1
9

Sample Use Guides

In Vivo Use Guide
Combination ALIMTA (pemetrexed disodium) use in Non-Small Cell Lung Cancer and Mesothelioma: Recommended dose of ALIMTA is 500 mg/m2 i.v. on Day 1 of each 21-day cycle in combination with cisplatin 75 mg/m2 i.v. beginning 30 minutes after ALIMTA administration. Single-Agent use in Non-Small Cell Lung Cancer: Recommended dose of ALIMTA is 500 mg/m2 i.v. on Day 1 of each 21-day cycle. Dose Reductions: Dose reductions or discontinuation may be needed based on toxicities from the preceding cycle of therapy.
Route of Administration: Intravenous
In Vitro Use Guide
pemetrexed has a potent cytotoxic effect against human peripheral blood lymphocytes at concentrations 25, 50, 75 and 100 μg/mL (concentrations roughly 2,25–9 times less than the maximum plasma level (225 μg/mL) achieved in patients receiving this drug) based on the top concentration (100 μg/mL)
Substance Class Chemical
Created
by admin
on Sat Dec 16 10:55:31 GMT 2023
Edited
by admin
on Sat Dec 16 10:55:31 GMT 2023
Record UNII
F4GSH45R4C
Record Status Validated (UNII)
Record Version
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Name Type Language
PEMETREXED DISODIUM HEMIPENTAHYDRATE
WHO-DD  
Common Name English
PEMETREXED SODIUM HYDRATE (2:4:5)
Common Name English
PEMETREXED DISODIUM 2.5 HYDRATE
Common Name English
PEMETREXED DISODIUM 2.5-HYDRATE [EP MONOGRAPH]
Common Name English
Pemetrexed disodium hemipentahydrate [WHO-DD]
Common Name English
PEMETREXED SODIUM HEMIPENTAHYDRATE [JAN]
Common Name English
L-GLUTAMIC ACID, N-(4-(2-(2-AMINO-4,7-DIHYDRO-4-OXO-3H-PYRROLO(2,3-D)PYRIMIDIN-5-YL)ETHYL)BENZOYL)-, SODIUM SALT, HYDRATE (2:4:5)
Systematic Name English
PEMETREXED SODIUM HEMIPENTAHYDRATE
JAN  
Common Name English
Classification Tree Code System Code
EMA ASSESSMENT REPORTS PEMTREXED ACCORD(AUTHORIZED: CARCINOMA, NON-SMALL-CELL LUNG, MESOTHELIOMA)
Created by admin on Sat Dec 16 10:55:31 GMT 2023 , Edited by admin on Sat Dec 16 10:55:31 GMT 2023
EMA ASSESSMENT REPORTS CIAMBRA (AUTHORIZED: CARCINOMA, NON-SMALL-CELL LUNG, MESOTHELIOMA)
Created by admin on Sat Dec 16 10:55:31 GMT 2023 , Edited by admin on Sat Dec 16 10:55:31 GMT 2023
EMA ASSESSMENT REPORTS PEMETREXED SANDOZ (AUTHORIZED: CARCINOMA, NON-SMALL-CELL LUNG, MESOTHELIOMA)
Created by admin on Sat Dec 16 10:55:31 GMT 2023 , Edited by admin on Sat Dec 16 10:55:31 GMT 2023
Code System Code Type Description
EVMPD
SUB170786
Created by admin on Sat Dec 16 10:55:31 GMT 2023 , Edited by admin on Sat Dec 16 10:55:31 GMT 2023
PRIMARY
EPA CompTox
DTXSID10189239
Created by admin on Sat Dec 16 10:55:31 GMT 2023 , Edited by admin on Sat Dec 16 10:55:31 GMT 2023
PRIMARY
RXCUI
2056898
Created by admin on Sat Dec 16 10:55:31 GMT 2023 , Edited by admin on Sat Dec 16 10:55:31 GMT 2023
PRIMARY
DRUG BANK
DBSALT001782
Created by admin on Sat Dec 16 10:55:31 GMT 2023 , Edited by admin on Sat Dec 16 10:55:31 GMT 2023
PRIMARY
SMS_ID
100000159976
Created by admin on Sat Dec 16 10:55:31 GMT 2023 , Edited by admin on Sat Dec 16 10:55:31 GMT 2023
PRIMARY
FDA UNII
F4GSH45R4C
Created by admin on Sat Dec 16 10:55:31 GMT 2023 , Edited by admin on Sat Dec 16 10:55:31 GMT 2023
PRIMARY
PUBCHEM
135564527
Created by admin on Sat Dec 16 10:55:31 GMT 2023 , Edited by admin on Sat Dec 16 10:55:31 GMT 2023
PRIMARY
CAS
357166-30-4
Created by admin on Sat Dec 16 10:55:31 GMT 2023 , Edited by admin on Sat Dec 16 10:55:31 GMT 2023
PRIMARY
DAILYMED
F4GSH45R4C
Created by admin on Sat Dec 16 10:55:31 GMT 2023 , Edited by admin on Sat Dec 16 10:55:31 GMT 2023
PRIMARY
Related Record Type Details
Structure of PEMETREXED DISODIUM
ANHYDROUS->SOLVATE
Structure of PEMETREXED
PARENT -> SALT/SOLVATE
Related Record Type Details
Structure of PEMETREXED
ACTIVE MOIETY
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