U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ACHIRAL
Molecular Formula C19H23N5O3
Molecular Weight 369.4176
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of TRIMETREXATE

SMILES

COC1=CC(NCC2=C(C)C3=C(N)N=C(N)N=C3C=C2)=CC(OC)=C1OC

InChI

InChIKey=NOYPYLRCIDNJJB-UHFFFAOYSA-N
InChI=1S/C19H23N5O3/c1-10-11(5-6-13-16(10)18(20)24-19(21)23-13)9-22-12-7-14(25-2)17(27-4)15(8-12)26-3/h5-8,22H,9H2,1-4H3,(H4,20,21,23,24)

HIDE SMILES / InChI
Molecular Formula C19H23N5O3
Molecular Weight 369.4176
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Description

Trimetrexate, a second-generation folate antagonist which was used under brand name NEUTREXIN with concurrent leucovorin administration (leucovorin protection) was indicated as an alternative therapy for the treatment of moderate-to-severe Pneumocystis carinii pneumonia (PCP) in immunocompromised patients, including patients with the acquired immunodeficiency syndrome (AIDS). Nevertheless, this product was discontinued. In present time, trimetrexate with a different combinations is in the phase II of clinical trial for the treatment the following cancer diseases: pancreatic cancer and colorectal cancer (in combination with fluorouracil and leucovorin) and to treat a refractory acute leukemia in combination with leucovorin. Trimetrexate is a competitive inhibitor of dihydrofolate reductase (DHFR) from bacterial, protozoan, and mammalian sources. DHFR catalyzes the reduction of intracellular dihydrofolate to the active coenzyme tetrahydrofolate. Inhibition of DHFR results in the depletion of this coenzyme, leading directly to interference with thymidylate biosynthesis, as well as inhibition of folate-dependent formyltransferases, and indirectly to inhibition of purine biosynthesis. The result is disruption of DNA, RNA, and protein synthesis, with consequent cell death.

Originator

Pfizer
420
Curator's Comment: # Pfizer

Approval Year

1993
138
Targets

Targets

Primary TargetPharmacologyConditionPotency
Inhibitor
8504
Dihydrofolate reductase
61
Target ID: P00374
Gene ID: 1719.0
Gene Symbol: DHFR
Target Organism: Homo sapiens (Human)
Inhibitor
8504
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Curative
Approved
8583
NEUTREXIN

Approved Use

Neutrexin (trimetrexate glucuronate for injection) with concurrent leucovorin administration (leucovorin protection) is indicated as an alternative therapy for the treatment of moderate-to-severe Pneumocystis carinii pneumonia (PCP) in immunocompromised patients, including patients with the acquired immunodeficiency syndrome (AIDS), who are intolerant of, or are refractory to, trimethoprim-sulfamethoxazole therapy or for whom trimethoprim-sulfamethoxazole is contraindicated. This indication is based on the results of a randomized, controlled double-blind trial comparing Neutrexin with concurrent leucovorin protection (TMTX/LV) to trimethoprim sulfamethoxazole (TMP/SMX) in patients with moderate-to-severe Pneumocystis carinii pneumonia, as well as results of a Treatment IND.

Launch Date

1993
Primary
Phase II
1147
Unknown

Approved Use

Unknown
Primary
Phase II
1147
Unknown

Approved Use

Unknown
Primary
Phase II
1147
Unknown

Approved Use

Unknown
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
3.1 mg/L
REVIEW
https://www.ncbi.nlm.nih.gov/pubmed/7789290
30 mg/m² 1 times / day steady-state, intravenous
dose: 30 mg/m²
route of administration: Intravenous
experiment type: STEADY-STATE
co-administered: LEUCOVORIN CALCIUM
LEUCOVORIN CALCIUM
 TRIMETREXATE plasma
Homo sapiens
population: UNHEALTHY
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
15.8 mg × h/L
REVIEW
https://www.ncbi.nlm.nih.gov/pubmed/7789290
30 mg/m² 1 times / day steady-state, intravenous
dose: 30 mg/m²
route of administration: Intravenous
experiment type: STEADY-STATE
co-administered: LEUCOVORIN CALCIUM
LEUCOVORIN CALCIUM
 TRIMETREXATE plasma
Homo sapiens
population: UNHEALTHY
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
11 h
REVIEW
https://www.ncbi.nlm.nih.gov/pubmed/7789290
30 mg/m² 1 times / day steady-state, intravenous
dose: 30 mg/m²
route of administration: Intravenous
experiment type: STEADY-STATE
co-administered: LEUCOVORIN CALCIUM
LEUCOVORIN CALCIUM
 TRIMETREXATE plasma
Homo sapiens
population: UNHEALTHY
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
100 mg/m2 1 times / week multiple, intravenous
MTD
Dose: 100 mg/m2, 1 times / week
Route: intravenous
Route: multiple
Dose: 100 mg/m2, 1 times / week
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
unhealthy, 49 years
Health Status: unhealthy
Age Group: 49 years
Sex: F
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
Disc. AE: Death...
AEs leading to
discontinuation/dose reduction:
Death (grade 5)
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
75 mg/m2 single, intravenous
MTD
Dose: 75 mg/m2
Route: intravenous
Route: single
Dose: 75 mg/m2
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
unhealthy, 63 years
Health Status: unhealthy
Age Group: 63 years
Sex: F
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
Disc. AE: Death...
AEs leading to
discontinuation/dose reduction:
Death (grade 5)
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
10 mg/m2 1 times / day steady, intravenous
MTD
Dose: 10 mg/m2, 1 times / day
Route: intravenous
Route: steady
Dose: 10 mg/m2, 1 times / day
Sources:
https://pubmed.ncbi.nlm.nih.gov/1831340/
unhealthy, adult
Health Status: unhealthy
Age Group: adult
Sex: unknown
Sources:
https://pubmed.ncbi.nlm.nih.gov/1831340/
Other AEs: Gastrointestinal signs and symptoms...
Other AEs:
Gastrointestinal signs and symptoms
Sources:
https://pubmed.ncbi.nlm.nih.gov/1831340/
100 mg/m2 1 times / week multiple, intravenous
MTD
Dose: 100 mg/m2, 1 times / week
Route: intravenous
Route: multiple
Dose: 100 mg/m2, 1 times / week
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
unhealthy, adult
Health Status: unhealthy
Age Group: adult
Sex: unknown
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
DLT: Myelosuppression...
Other AEs: Hematotoxicity...
Dose limiting toxicities:
Myelosuppression
Other AEs:
Hematotoxicity (grade 3, 2 patients)
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
110 mg/m2 1 times / week multiple, intravenous
MTD
Dose: 110 mg/m2, 1 times / week
Route: intravenous
Route: multiple
Dose: 110 mg/m2, 1 times / week
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
unhealthy, adult
Health Status: unhealthy
Age Group: adult
Sex: unknown
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
DLT: Myelosuppression...
Dose limiting toxicities:
Myelosuppression
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
130 mg/m2 1 times / week multiple, intravenous
MTD
Dose: 130 mg/m2, 1 times / week
Route: intravenous
Route: multiple
Dose: 130 mg/m2, 1 times / week
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
unhealthy, adult
Health Status: unhealthy
Age Group: adult
Sex: unknown
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
DLT: Myelosuppression...
Disc. AE: Hematotoxicity...
Dose limiting toxicities:
Myelosuppression
AEs leading to
discontinuation/dose reduction:
Hematotoxicity (grade 2, 2 patients)
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
15 mg/m2 single, intravenous
MTD
Dose: 15 mg/m2
Route: intravenous
Route: single
Dose: 15 mg/m2
Sources:
https://pubmed.ncbi.nlm.nih.gov/1831340/
unhealthy, adult
Health Status: unhealthy
Age Group: adult
Sex: unknown
Sources:
https://pubmed.ncbi.nlm.nih.gov/1831340/
Other AEs: Gastrointestinal signs and symptoms...
Other AEs:
Gastrointestinal signs and symptoms
Sources:
https://pubmed.ncbi.nlm.nih.gov/1831340/
155 mg/m2 1 times / week multiple, intravenous
MTD
Dose: 155 mg/m2, 1 times / week
Route: intravenous
Route: multiple
Dose: 155 mg/m2, 1 times / week
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
unhealthy, adult
Health Status: unhealthy
Age Group: adult
Sex: unknown
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
DLT: Myelosuppression...
Dose limiting toxicities:
Myelosuppression
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
155 mg/m2 1 times / week multiple, intravenous
MTD
Dose: 155 mg/m2, 1 times / week
Route: intravenous
Route: multiple
Dose: 155 mg/m2, 1 times / week
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
unhealthy, adult
Health Status: unhealthy
Age Group: adult
Sex: unknown
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
Disc. AE: Hematotoxicity...
AEs leading to
discontinuation/dose reduction:
Hematotoxicity (grade 2, 12 patients)
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
50 mg/m2 1 times / week multiple, intravenous
MTD
Dose: 50 mg/m2, 1 times / week
Route: intravenous
Route: multiple
Dose: 50 mg/m2, 1 times / week
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
unhealthy, adult
Health Status: unhealthy
Age Group: adult
Sex: unknown
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
DLT: Myelosuppression...
Dose limiting toxicities:
Myelosuppression
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
75 mg/m2 1 times / week multiple, intravenous
MTD
Dose: 75 mg/m2, 1 times / week
Route: intravenous
Route: multiple
Dose: 75 mg/m2, 1 times / week
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
unhealthy, adult
Health Status: unhealthy
Age Group: adult
Sex: unknown
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
DLT: Myelosuppression...
Dose limiting toxicities:
Myelosuppression
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
90 mg/m2 1 times / week multiple, intravenous
MTD
Dose: 90 mg/m2, 1 times / week
Route: intravenous
Route: multiple
Dose: 90 mg/m2, 1 times / week
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
unhealthy, adult
Health Status: unhealthy
Age Group: adult
Sex: unknown
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
DLT: Myelosuppression...
Disc. AE: Hematotoxicity...
Dose limiting toxicities:
Myelosuppression
AEs leading to
discontinuation/dose reduction:
Hematotoxicity (grade 2, 1 patient)
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
AEs

AEs

AESignificanceDosePopulation
Death grade 5
Disc. AE
100 mg/m2 1 times / week multiple, intravenous
MTD
Dose: 100 mg/m2, 1 times / week
Route: intravenous
Route: multiple
Dose: 100 mg/m2, 1 times / week
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
unhealthy, 49 years
Health Status: unhealthy
Age Group: 49 years
Sex: F
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
Death grade 5
Disc. AE
75 mg/m2 single, intravenous
MTD
Dose: 75 mg/m2
Route: intravenous
Route: single
Dose: 75 mg/m2
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
unhealthy, 63 years
Health Status: unhealthy
Age Group: 63 years
Sex: F
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
Gastrointestinal signs and symptoms
10 mg/m2 1 times / day steady, intravenous
MTD
Dose: 10 mg/m2, 1 times / day
Route: intravenous
Route: steady
Dose: 10 mg/m2, 1 times / day
Sources:
https://pubmed.ncbi.nlm.nih.gov/1831340/
unhealthy, adult
Health Status: unhealthy
Age Group: adult
Sex: unknown
Sources:
https://pubmed.ncbi.nlm.nih.gov/1831340/
Myelosuppression DLT
100 mg/m2 1 times / week multiple, intravenous
MTD
Dose: 100 mg/m2, 1 times / week
Route: intravenous
Route: multiple
Dose: 100 mg/m2, 1 times / week
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
unhealthy, adult
Health Status: unhealthy
Age Group: adult
Sex: unknown
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
Hematotoxicity grade 3, 2 patients
100 mg/m2 1 times / week multiple, intravenous
MTD
Dose: 100 mg/m2, 1 times / week
Route: intravenous
Route: multiple
Dose: 100 mg/m2, 1 times / week
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
unhealthy, adult
Health Status: unhealthy
Age Group: adult
Sex: unknown
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
Myelosuppression DLT
110 mg/m2 1 times / week multiple, intravenous
MTD
Dose: 110 mg/m2, 1 times / week
Route: intravenous
Route: multiple
Dose: 110 mg/m2, 1 times / week
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
unhealthy, adult
Health Status: unhealthy
Age Group: adult
Sex: unknown
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
Myelosuppression DLT
130 mg/m2 1 times / week multiple, intravenous
MTD
Dose: 130 mg/m2, 1 times / week
Route: intravenous
Route: multiple
Dose: 130 mg/m2, 1 times / week
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
unhealthy, adult
Health Status: unhealthy
Age Group: adult
Sex: unknown
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
Hematotoxicity grade 2, 2 patients
Disc. AE
130 mg/m2 1 times / week multiple, intravenous
MTD
Dose: 130 mg/m2, 1 times / week
Route: intravenous
Route: multiple
Dose: 130 mg/m2, 1 times / week
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
unhealthy, adult
Health Status: unhealthy
Age Group: adult
Sex: unknown
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
Gastrointestinal signs and symptoms
15 mg/m2 single, intravenous
MTD
Dose: 15 mg/m2
Route: intravenous
Route: single
Dose: 15 mg/m2
Sources:
https://pubmed.ncbi.nlm.nih.gov/1831340/
unhealthy, adult
Health Status: unhealthy
Age Group: adult
Sex: unknown
Sources:
https://pubmed.ncbi.nlm.nih.gov/1831340/
Myelosuppression DLT
155 mg/m2 1 times / week multiple, intravenous
MTD
Dose: 155 mg/m2, 1 times / week
Route: intravenous
Route: multiple
Dose: 155 mg/m2, 1 times / week
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
unhealthy, adult
Health Status: unhealthy
Age Group: adult
Sex: unknown
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
Hematotoxicity grade 2, 12 patients
Disc. AE
155 mg/m2 1 times / week multiple, intravenous
MTD
Dose: 155 mg/m2, 1 times / week
Route: intravenous
Route: multiple
Dose: 155 mg/m2, 1 times / week
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
unhealthy, adult
Health Status: unhealthy
Age Group: adult
Sex: unknown
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
Myelosuppression DLT
50 mg/m2 1 times / week multiple, intravenous
MTD
Dose: 50 mg/m2, 1 times / week
Route: intravenous
Route: multiple
Dose: 50 mg/m2, 1 times / week
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
unhealthy, adult
Health Status: unhealthy
Age Group: adult
Sex: unknown
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
Myelosuppression DLT
75 mg/m2 1 times / week multiple, intravenous
MTD
Dose: 75 mg/m2, 1 times / week
Route: intravenous
Route: multiple
Dose: 75 mg/m2, 1 times / week
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
unhealthy, adult
Health Status: unhealthy
Age Group: adult
Sex: unknown
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
Myelosuppression DLT
90 mg/m2 1 times / week multiple, intravenous
MTD
Dose: 90 mg/m2, 1 times / week
Route: intravenous
Route: multiple
Dose: 90 mg/m2, 1 times / week
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
unhealthy, adult
Health Status: unhealthy
Age Group: adult
Sex: unknown
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
Hematotoxicity grade 2, 1 patient
Disc. AE
90 mg/m2 1 times / week multiple, intravenous
MTD
Dose: 90 mg/m2, 1 times / week
Route: intravenous
Route: multiple
Dose: 90 mg/m2, 1 times / week
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
unhealthy, adult
Health Status: unhealthy
Age Group: adult
Sex: unknown
Sources:
https://pubmed.ncbi.nlm.nih.gov/2953412/
Overview

Overview

CYP3A4CYP2C9CYP2D6hERG

OverviewOther

Other InhibitorOther SubstrateOther Inducer
CYP 450
32
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
CYP 450
32
 yes
likely (co-administration study)
Comment: concomitant administration of SPORANOX (itraconazole) and trimetrexate may inhibit the metabolism of trimetrexate
Sourcing

Sourcing

Vendor/AggregatorIDURL
001 Chemical
DY558210
https://www.001chemical.com/chem/52128-35-5
AA Blocks
AA00DB6L
https://www.aablocks.com/goods/Goods/detail?id=AA00DB6L
Achemtek
0101-002318
http://www.achemtek.com/52128-35-5
Adooq BioScience
A12796
https://www.adooq.com/trimetrexate.html
Ambinter
Amb22731961
http://www.ambinter.com/reference/22731961
Angel Pharmatech
AG302845
http://www.angelpharmatech.com/52128-35-5.html
BioChemPartner
BCP15515
http://www.biochempartner.com/52128-35-5-BCP15515
BLD Pharm
BD155583
http://www.bldpharm.com/products/52128-35-5.html
Chem Scene
CS-4063
http://www.chemscene.com/52128-35-5.html
Chemspace
CSSB00020617805
https://chem-space.com/CSSB00020617805
CSNpharm
CSN12149
https://www.csnpharm.com/products/trimetrexate.html
DC Chemicals
DC23932
http://www.dcchemicals.com/product_show-DC23932.html
eNovation Chemicals
D673579
https://www.enovationchem.com/ProductDetails.asp?ProductID=D673579
Finetech
FT-0649497
http://www.finetechnology-ind.com/prod/detail/pub/52128-35-5.html
Lab Network
LN01342098
https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN01342098
MedChem Express
HY-10373
https://www.medchemexpress.com/Trimetrexate.html
Molcore
MC558210
https://www.molcore.com/product/52128-35-5
Parchem
30218
http://www.parchem.com/chemical-supplier-distributor/Trimetrexate-020218.aspx
Smolecule
S545904
http://www.smolecule.com/products/s545904
Smolecule
S772620
https://www.smolecule.com/products/s772620
THE BioTek
bt-287020
https://www.thebiotek.com/product/inhibitors/bt-287020
PubMed

PubMed

TitleDatePubMed
The immunobiology of cord blood transplantation.
2010-12
Gateways to clinical trials.
2010-12
High-resolution structures of Trypanosoma brucei pteridine reductase ligand complexes inform on the placement of new molecular entities in the active site of a potential drug target.
2010-12
Cancer chemotherapy: targeting folic acid synthesis.
2010-11-19
Synthesis and biological evaluation of biguanide and dihydrotriazine derivatives as potential inhibitors of dihydrofolate reductase of opportunistic microorganisms.
2010-06
S9511: a Southwest Oncology Group phase II study of trimetrexate, 5-fluorouracil, and leucovorin in unresectable or metastatic adenocarcinoma of the stomach.
2010-04
Anticancer agents against malaria: time to revisit?
2010-03
A review of synergy concepts of nonlinear blending and dose-reduction profiles.
2010-01-01
Emax model and interaction index for assessing drug interaction in combination studies.
2010-01-01
Applying Emax model and bivariate thin plate splines to assess drug interactions.
2010-01-01
Application and review of the separate ray model to investigate interaction effects.
2010-01-01
Efficient experimental design and nonparametric modeling of drug interaction.
2010-01-01
Comparison of methods for statistical analysis of combination studies.
2010-01-01
Comparison of methods for evaluating drug-drug interaction.
2010-01-01
Radiation recall with anticancer agents.
2010
Academia-pharma intersect: providing a broader perspective on drug development synergies between academia and industry.
2010
Interpretable correlation descriptors for quantitative structure-activity relationships.
2009-12-24
Clinical efficacy of first- and second-line treatments for HIV-associated Pneumocystis jirovecii pneumonia: a tri-centre cohort study.
2009-12
A mapping of drug space from the viewpoint of small molecule metabolism.
2009-08
Structures of dihydrofolate reductase-thymidylate synthase of Trypanosoma cruzi in the folate-free state and in complex with two antifolate drugs, trimetrexate and methotrexate.
2009-07
Trimetrexate and folinic acid: a valuable salvage option for Pneumocystis jirovecii pneumonia.
2009-06-19
Current status and perspectives regarding the treatment of osteo-sarcoma: chemotherapy.
2008-09
Epigenetic mechanisms involved in differential MDR1 mRNA expression between gastric and colon cancer cell lines and rationales for clinical chemotherapy.
2008-08-01
Chemical and genetic validation of dihydrofolate reductase-thymidylate synthase as a drug target in African trypanosomes.
2008-07
Quantitative correlation between promoter methylation and messenger RNA levels of the reduced folate carrier.
2008-05-01
Effect of folate derivatives on the activity of antifolate drugs used against malaria and cancer.
2008-05
Impairments in antifolate transport are common in retinoblastoma tumor samples.
2008-03
Radiation recall dermatitis: case report and review of the literature.
2008-01
Effects of folate and folylpolyglutamyl synthase modulation on chemosensitivity of breast cancer cells.
2007-11
Commentary: a case for minimizing folate supplementation in clinical regimens with pemetrexed based on the marked sensitivity of the drug to folate availability.
2007-07
Raloxifene and selective cell cycle specific agents: a case for the inclusion of raloxifene in current breast cancer treatment therapies.
2007-06-29
The protection against trimetrexate cytotoxicity in human bone marrow by sequence-dependent administration of raloxifene, 5-fluorouracil/trimetrexate.
2007-01-05
Dihydrofolate reductase as a target for chemotherapy in parasites.
2007
A phase II trial of S-1 monotherapy in metastatic colorectal cancer after failure of irinotecan- and oxaliplatin-containing regimens.
2006-12-18
Mutant Gly482 and Thr482 ABCG2 mediate high-level resistance to lipophilic antifolates.
2006-12
Complete regression of large solid tumors using engineered drug-resistant hematopoietic cells and anti-CD137 immunotherapy.
2006-08
The inverse relationship between reduced folate carrier function and pemetrexed activity in a human colon cancer cell line.
2006-02
Towards species-specific antifolates.
2006
A phase I/II study of trimetrexate and capecitabine in patients with advanced refractory colorectal cancer.
2005-10
Tolerance by selective in vivo expansion of foreign major histocompatibility complex-transduced autologous bone marrow.
2005-08-15
Prediction of genotoxicity of chemical compounds by statistical learning methods.
2005-06
Highly efficient transduction of repopulating bone marrow cells using rapidly concentrated polymer-complexed retrovirus.
2005-05-13
Superior depletion of alloreactive T cells from peripheral blood stem cell and umbilical cord blood grafts by the combined use of trimetrexate and interleukin-2 immunotoxin.
2004-11
Dihydropteroate synthase gene mutations in Pneumocystis and sulfa resistance.
2004-10
Characterization of a folate transporter in HeLa cells with a low pH optimum and high affinity for pemetrexed distinct from the reduced folate carrier.
2004-09-15
Design, synthesis, and biological evaluation of 2,4-diamino-5-methyl-6-substituted-pyrrolo[2,3-d]pyrimidines as dihydrofolate reductase inhibitors.
2004-07-01
p14ARF expression increases dihydrofolate reductase degradation and paradoxically results in resistance to folate antagonists in cells with nonfunctional p53.
2004-06-15
Phase II clinical trial of 5-fluorouracil, trimetrexate, and leucovorin (NFL) in patients with advanced pancreatic cancer.
2003
Pneumocystis carinii dihydrofolate reductase used to screen potential antipneumocystis drugs.
1991-07
Metabolic disposition of trimetrexate, a nonclassical dihydrofolate reductase inhibitor, in rat and dog.
1990-11-01
Patents

Patents

05534518
7
JP2005520795A
26
JP3775780B2
14
JP4787165B2
104

Sample Use Guides

In Vivo Use Guide
Neutrexin (trimetrexate glucuronate for injection) is administered at a dose of 45 mg/m2 once daily by intravenous infusion over 60 minutes. Leucovorin must be administered daily during treatment with Neutrexin and for 72 hours past the last dose of Neutrexin. Leucovorin may be administered intravenously at a dose of 20 mg/m2 over 5 to 10 minutes every 6 hours for a total daily dose of 80 mg/m2, or orally as 4 doses of 20 mg/m2 spaced equally throughout the day. The oral dose should be rounded up to the next higher 25 mg increment. The recommended course of therapy is 21 days of Neutrexin and 24 days of leucovorin.
Route of Administration: Intravenous
In Vitro Use Guide
Carboxypeptidase G2 (CPG2), an enzyme produced by Pseudomonas strain RS-16, hydrolyzes the glutamate residue from methotrexate and other folates. The possibility of enhancing trimetrexate cytotoxicity by CPG2 induced folate depletion was investigated in vitro in a human leukemia cell line, CCRF-CEM, and in three sublines of these cells each with a different methotrexate resistance phenotype. Trimetrexate alone was cytotoxic against the parent and all the resistant cell lines with the drug concentrations required to decrease the cell count to 50% of control in the nanomolar range (1.4, 1.6, 1.5, and 0.7 nM in CCRF-CEM, CCRF-CEM/E, CCRF-CEM/P, and CCRF-CEM/T, respectively) following 5 days of exposure.
Substance Class Chemical
Created
by admin
on Mon Mar 31 18:13:10 GMT 2025
Edited
by admin
on Mon Mar 31 18:13:10 GMT 2025
Record UNII
UPN4ITI8T4
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
NSC-249008
Preferred Name English
TRIMETREXATE
HSDB   INN   MI   USAN   VANDF   WHO-DD  
USAN   INN  
Official Name English
Trimetrexate [WHO-DD]
Common Name English
TRIMETREXATE [USAN]
Common Name English
2,4-Diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl]quinazoline
Systematic Name English
2,4-QUINAZOLINEDIAMINE, 5-METHYL-6-(((3,4,5-TRIMETHOXYPHENYL)AMINO)METHYL)-
Systematic Name English
TRIMETREXATE [HSDB]
Common Name English
TRIMETREXATE [VANDF]
Common Name English
TRIMETREXATE [MI]
Common Name English
trimetrexate [INN]
Common Name English
Classification Tree Code System Code
WHO-ATC P01AX07
Created by admin on Mon Mar 31 18:13:11 GMT 2025 , Edited by admin on Mon Mar 31 18:13:11 GMT 2025
LIVERTOX NBK548765
Created by admin on Mon Mar 31 18:13:11 GMT 2025 , Edited by admin on Mon Mar 31 18:13:11 GMT 2025
FDA ORPHAN DRUG 132299
Created by admin on Mon Mar 31 18:13:11 GMT 2025 , Edited by admin on Mon Mar 31 18:13:11 GMT 2025
NCI_THESAURUS C2153
Created by admin on Mon Mar 31 18:13:11 GMT 2025 , Edited by admin on Mon Mar 31 18:13:11 GMT 2025
NCI_THESAURUS C511
Created by admin on Mon Mar 31 18:13:11 GMT 2025 , Edited by admin on Mon Mar 31 18:13:11 GMT 2025
Code System Code Type Description
EVMPD
SUB11312MIG
Created by admin on Mon Mar 31 18:13:11 GMT 2025 , Edited by admin on Mon Mar 31 18:13:11 GMT 2025
PRIMARY
INN
5103
Created by admin on Mon Mar 31 18:13:11 GMT 2025 , Edited by admin on Mon Mar 31 18:13:11 GMT 2025
PRIMARY
NCI_THESAURUS
C1314
Created by admin on Mon Mar 31 18:13:11 GMT 2025 , Edited by admin on Mon Mar 31 18:13:11 GMT 2025
PRIMARY
HSDB
6545
Created by admin on Mon Mar 31 18:13:11 GMT 2025 , Edited by admin on Mon Mar 31 18:13:11 GMT 2025
PRIMARY
CAS
52128-35-5
Created by admin on Mon Mar 31 18:13:11 GMT 2025 , Edited by admin on Mon Mar 31 18:13:11 GMT 2025
PRIMARY
RXCUI
42333
Created by admin on Mon Mar 31 18:13:11 GMT 2025 , Edited by admin on Mon Mar 31 18:13:11 GMT 2025
PRIMARY RxNorm
MESH
D016597
Created by admin on Mon Mar 31 18:13:11 GMT 2025 , Edited by admin on Mon Mar 31 18:13:11 GMT 2025
PRIMARY
SMS_ID
100000076926
Created by admin on Mon Mar 31 18:13:11 GMT 2025 , Edited by admin on Mon Mar 31 18:13:11 GMT 2025
PRIMARY
DAILYMED
UPN4ITI8T4
Created by admin on Mon Mar 31 18:13:11 GMT 2025 , Edited by admin on Mon Mar 31 18:13:11 GMT 2025
PRIMARY
IUPHAR
7613
Created by admin on Mon Mar 31 18:13:11 GMT 2025 , Edited by admin on Mon Mar 31 18:13:11 GMT 2025
PRIMARY
PUBCHEM
5583
Created by admin on Mon Mar 31 18:13:11 GMT 2025 , Edited by admin on Mon Mar 31 18:13:11 GMT 2025
PRIMARY
DRUG BANK
DB01157
Created by admin on Mon Mar 31 18:13:11 GMT 2025 , Edited by admin on Mon Mar 31 18:13:11 GMT 2025
PRIMARY
ChEMBL
CHEMBL119
Created by admin on Mon Mar 31 18:13:11 GMT 2025 , Edited by admin on Mon Mar 31 18:13:11 GMT 2025
PRIMARY
MERCK INDEX
m11163
Created by admin on Mon Mar 31 18:13:11 GMT 2025 , Edited by admin on Mon Mar 31 18:13:11 GMT 2025
PRIMARY Merck Index
NSC
249008
Created by admin on Mon Mar 31 18:13:11 GMT 2025 , Edited by admin on Mon Mar 31 18:13:11 GMT 2025
PRIMARY
EPA CompTox
DTXSID3023714
Created by admin on Mon Mar 31 18:13:11 GMT 2025 , Edited by admin on Mon Mar 31 18:13:11 GMT 2025
PRIMARY
DRUG CENTRAL
2757
Created by admin on Mon Mar 31 18:13:11 GMT 2025 , Edited by admin on Mon Mar 31 18:13:11 GMT 2025
PRIMARY
WIKIPEDIA
TRIMETREXATE
Created by admin on Mon Mar 31 18:13:11 GMT 2025 , Edited by admin on Mon Mar 31 18:13:11 GMT 2025
PRIMARY
FDA UNII
UPN4ITI8T4
Created by admin on Mon Mar 31 18:13:11 GMT 2025 , Edited by admin on Mon Mar 31 18:13:11 GMT 2025
PRIMARY
Related Record Type Details
DIHYDROFOLATE REDUCTASE
TARGET -> INHIBITOR
PLASMA PROTEIN FRACTION (HUMAN)
BINDER->LIGAND
BINDING
Structure of TRIMETREXATE GLUCURONATE
SALT/SOLVATE -> PARENT
Structure of TRIMETREXATE MONOACETATE MONOHYDRATE
SALT/SOLVATE -> PARENT
Related Record Type Details
Structure of TRIMETREXATE
ACTIVE MOIETY
Name Property Type Amount Referenced Substance Defining Parameters References
Biological Half-life PHARMACOKINETIC
NIH
NCATS
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