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

Details

Stereochemistry ABSOLUTE
Molecular Formula C19H23N5O3.C6H10O7
Molecular Weight 563.557
Optical Activity UNSPECIFIED
Defined Stereocenters 4 / 4
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of TRIMETREXATE GLUCURONATE

SMILES

O[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O.COC1=CC(NCC2=C(C)C3=C(N)N=C(N)N=C3C=C2)=CC(OC)=C1OC

InChI

InChIKey=ZCJXQWYMBJYJNB-LRDBBFHQSA-N
InChI=1S/C19H23N5O3.C6H10O7/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;7-1-2(8)3(9)4(10)5(11)6(12)13/h5-8,22H,9H2,1-4H3,(H4,20,21,23,24);1-5,8-11H,(H,12,13)/t;2-,3+,4-,5-/m.0/s1

HIDE SMILES / InChI

Molecular Formula C6H10O7
Molecular Weight 194.1394
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 4 / 4
E/Z Centers 0
Optical Activity UNSPECIFIED

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

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

Curator's Comment: # Pfizer

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
Target ID: P00374
Gene ID: 1719.0
Gene Symbol: DHFR
Target Organism: Homo sapiens (Human)
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Curative
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
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
3.1 mg/L
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
TRIMETREXATE plasma
Homo sapiens
population: UNHEALTHY
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
15.8 mg × h/L
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
TRIMETREXATE plasma
Homo sapiens
population: UNHEALTHY
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
11 h
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
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:
unhealthy, 49 years
n = 1
Health Status: unhealthy
Condition: pulmonary and pleural metastasis from cutaneous angiosarcoma
Age Group: 49 years
Sex: F
Population Size: 1
Sources:
Disc. AE: Death...
AEs leading to
discontinuation/dose reduction:
Death (grade 5)
Sources:
75 mg/m2 single, intravenous
MTD
Dose: 75 mg/m2
Route: intravenous
Route: single
Dose: 75 mg/m2
Sources:
unhealthy, 63 years
n = 1
Health Status: unhealthy
Condition: adenocarcinoma of the lung
Age Group: 63 years
Sex: F
Population Size: 1
Sources:
Disc. AE: Death...
AEs leading to
discontinuation/dose reduction:
Death (grade 5)
Sources:
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:
unhealthy, adult
n = 17
Health Status: unhealthy
Condition: solid cancer
Age Group: adult
Sex: unknown
Population Size: 17
Sources:
Other AEs: Gastrointestinal signs and symptoms...
Other AEs:
Gastrointestinal signs and symptoms
Sources:
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:
unhealthy, adult
n = 4
Health Status: unhealthy
Condition: solid cancer
Age Group: adult
Sex: unknown
Population Size: 4
Sources:
DLT: Myelosuppression...
Other AEs: Hematotoxicity...
Dose limiting toxicities:
Myelosuppression
Other AEs:
Hematotoxicity (grade 3, 2 patients)
Sources:
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:
unhealthy, adult
n = 3
Health Status: unhealthy
Condition: solid cancer
Age Group: adult
Sex: unknown
Population Size: 3
Sources:
DLT: Myelosuppression...
Dose limiting toxicities:
Myelosuppression
Sources:
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:
unhealthy, adult
n = 7
Health Status: unhealthy
Condition: solid cancer
Age Group: adult
Sex: unknown
Population Size: 7
Sources:
DLT: Myelosuppression...
Disc. AE: Hematotoxicity...
Dose limiting toxicities:
Myelosuppression
AEs leading to
discontinuation/dose reduction:
Hematotoxicity (grade 2, 2 patients)
Sources:
15 mg/m2 single, intravenous
MTD
Dose: 15 mg/m2
Route: intravenous
Route: single
Dose: 15 mg/m2
Sources:
unhealthy, adult
n = 18
Health Status: unhealthy
Condition: solid cancer
Age Group: adult
Sex: unknown
Population Size: 18
Sources:
Other AEs: Gastrointestinal signs and symptoms...
Other AEs:
Gastrointestinal signs and symptoms
Sources:
155 mg/m2 1 times / week multiple, intravenous (max)
MTD
Dose: 155 mg/m2, 1 times / week
Route: intravenous
Route: multiple
Dose: 155 mg/m2, 1 times / week
Sources:
unhealthy, adult
n = 29
Health Status: unhealthy
Condition: solid cancer
Age Group: adult
Sex: unknown
Population Size: 29
Sources:
Disc. AE: Hematotoxicity...
AEs leading to
discontinuation/dose reduction:
Hematotoxicity (grade 2, 12 patients)
Sources:
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:
unhealthy, adult
n = 2
Health Status: unhealthy
Condition: solid cancer
Age Group: adult
Sex: unknown
Population Size: 2
Sources:
DLT: Myelosuppression...
Dose limiting toxicities:
Myelosuppression
Sources:
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:
unhealthy, adult
n = 7
Health Status: unhealthy
Condition: solid cancer
Age Group: adult
Sex: unknown
Population Size: 7
Sources:
DLT: Myelosuppression...
Dose limiting toxicities:
Myelosuppression
Sources:
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:
unhealthy, adult
n = 8
Health Status: unhealthy
Condition: solid cancer
Age Group: adult
Sex: unknown
Population Size: 8
Sources:
DLT: Myelosuppression...
Dose limiting toxicities:
Myelosuppression
Sources:
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:
unhealthy, adult
n = 6
Health Status: unhealthy
Condition: solid cancer
Age Group: adult
Sex: unknown
Population Size: 6
Sources:
DLT: Myelosuppression...
Disc. AE: Hematotoxicity...
Dose limiting toxicities:
Myelosuppression
AEs leading to
discontinuation/dose reduction:
Hematotoxicity (grade 2, 1 patient)
Sources:
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:
unhealthy, 49 years
n = 1
Health Status: unhealthy
Condition: pulmonary and pleural metastasis from cutaneous angiosarcoma
Age Group: 49 years
Sex: F
Population Size: 1
Sources:
Death grade 5
Disc. AE
75 mg/m2 single, intravenous
MTD
Dose: 75 mg/m2
Route: intravenous
Route: single
Dose: 75 mg/m2
Sources:
unhealthy, 63 years
n = 1
Health Status: unhealthy
Condition: adenocarcinoma of the lung
Age Group: 63 years
Sex: F
Population Size: 1
Sources:
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:
unhealthy, adult
n = 17
Health Status: unhealthy
Condition: solid cancer
Age Group: adult
Sex: unknown
Population Size: 17
Sources:
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:
unhealthy, adult
n = 4
Health Status: unhealthy
Condition: solid cancer
Age Group: adult
Sex: unknown
Population Size: 4
Sources:
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:
unhealthy, adult
n = 4
Health Status: unhealthy
Condition: solid cancer
Age Group: adult
Sex: unknown
Population Size: 4
Sources:
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:
unhealthy, adult
n = 3
Health Status: unhealthy
Condition: solid cancer
Age Group: adult
Sex: unknown
Population Size: 3
Sources:
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:
unhealthy, adult
n = 7
Health Status: unhealthy
Condition: solid cancer
Age Group: adult
Sex: unknown
Population Size: 7
Sources:
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:
unhealthy, adult
n = 7
Health Status: unhealthy
Condition: solid cancer
Age Group: adult
Sex: unknown
Population Size: 7
Sources:
Gastrointestinal signs and symptoms
15 mg/m2 single, intravenous
MTD
Dose: 15 mg/m2
Route: intravenous
Route: single
Dose: 15 mg/m2
Sources:
unhealthy, adult
n = 18
Health Status: unhealthy
Condition: solid cancer
Age Group: adult
Sex: unknown
Population Size: 18
Sources:
Hematotoxicity grade 2, 12 patients
Disc. AE
155 mg/m2 1 times / week multiple, intravenous (max)
MTD
Dose: 155 mg/m2, 1 times / week
Route: intravenous
Route: multiple
Dose: 155 mg/m2, 1 times / week
Sources:
unhealthy, adult
n = 29
Health Status: unhealthy
Condition: solid cancer
Age Group: adult
Sex: unknown
Population Size: 29
Sources:
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:
unhealthy, adult
n = 2
Health Status: unhealthy
Condition: solid cancer
Age Group: adult
Sex: unknown
Population Size: 2
Sources:
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:
unhealthy, adult
n = 7
Health Status: unhealthy
Condition: solid cancer
Age Group: adult
Sex: unknown
Population Size: 7
Sources:
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:
unhealthy, adult
n = 8
Health Status: unhealthy
Condition: solid cancer
Age Group: adult
Sex: unknown
Population Size: 8
Sources:
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:
unhealthy, adult
n = 6
Health Status: unhealthy
Condition: solid cancer
Age Group: adult
Sex: unknown
Population Size: 6
Sources:
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:
unhealthy, adult
n = 6
Health Status: unhealthy
Condition: solid cancer
Age Group: adult
Sex: unknown
Population Size: 6
Sources:
Overview

Overview

CYP3A4CYP2C9CYP2D6hERG

OverviewOther

Other InhibitorOther SubstrateOther Inducer

Drug as victim

Drug as victim

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

Sourcing

Vendor/AggregatorIDURL
PubMed

PubMed

TitleDatePubMed
Prediction of genotoxicity of chemical compounds by statistical learning methods.
2005 Jun
Cancer chemotherapy: targeting folic acid synthesis.
2010 Nov 19
Patents

Sample Use Guides

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 Fri Dec 15 15:31:02 GMT 2023
Edited
by admin
on Fri Dec 15 15:31:02 GMT 2023
Record UNII
L137U4A79K
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
TRIMETREXATE GLUCURONATE
MART.   ORANGE BOOK   USAN   VANDF   WHO-DD  
USAN  
Official Name English
2,4-QUINAZOLINEDIAMINE, 5-METHYL-6-(((3,4,5-TRIMETHOXYPHENYL)AMINO)METHYL)-, MONO-D-GLUCURONATE
Common Name English
TRIMETREXATE GLUCURONATE [MART.]
Common Name English
Trimetrexate glucuronate [WHO-DD]
Common Name English
TRIMETREXATE GLUCURONATE [ORANGE BOOK]
Common Name English
TRIMETREXATE D-GLUCURONATE
MI  
Common Name English
CI-898
Code English
NEUTREXIN
Brand Name English
D-GLUCURONIC ACID, COMPD. WITH 5-METHYL-6-(((3,4,5-TRIMETHOXYPHENYL)AMINO)METHYL)-2,4-QUINAZOLINEDIAMINE (1:1)
Systematic Name English
NSC-352122
Code English
2,4-DIAMINO-5-METHYL-6-((3,4,5-TRIMETHOXYANILINO)METHYL)QUINAZOLINE MONO-D-GLUCURONATE
Common Name English
TRIMETREXATE GLUCURONATE [VANDF]
Common Name English
TRIMETREXATE GLUCURONATE [USAN]
Common Name English
TRIMETREXATE D-GLUCURONATE [MI]
Common Name English
Classification Tree Code System Code
FDA ORPHAN DRUG 14286
Created by admin on Fri Dec 15 15:31:02 GMT 2023 , Edited by admin on Fri Dec 15 15:31:02 GMT 2023
FDA ORPHAN DRUG 14686
Created by admin on Fri Dec 15 15:31:02 GMT 2023 , Edited by admin on Fri Dec 15 15:31:02 GMT 2023
FDA ORPHAN DRUG 8385
Created by admin on Fri Dec 15 15:31:02 GMT 2023 , Edited by admin on Fri Dec 15 15:31:02 GMT 2023
NCI_THESAURUS C2153
Created by admin on Fri Dec 15 15:31:02 GMT 2023 , Edited by admin on Fri Dec 15 15:31:02 GMT 2023
Code System Code Type Description
EPA CompTox
DTXSID90273968
Created by admin on Fri Dec 15 15:31:02 GMT 2023 , Edited by admin on Fri Dec 15 15:31:02 GMT 2023
PRIMARY
PUBCHEM
54949
Created by admin on Fri Dec 15 15:31:02 GMT 2023 , Edited by admin on Fri Dec 15 15:31:02 GMT 2023
PRIMARY
NCI_THESAURUS
C1265
Created by admin on Fri Dec 15 15:31:02 GMT 2023 , Edited by admin on Fri Dec 15 15:31:02 GMT 2023
PRIMARY
RXCUI
38725
Created by admin on Fri Dec 15 15:31:02 GMT 2023 , Edited by admin on Fri Dec 15 15:31:02 GMT 2023
PRIMARY RxNorm
NSC
352122
Created by admin on Fri Dec 15 15:31:02 GMT 2023 , Edited by admin on Fri Dec 15 15:31:02 GMT 2023
PRIMARY
CAS
82952-64-5
Created by admin on Fri Dec 15 15:31:02 GMT 2023 , Edited by admin on Fri Dec 15 15:31:02 GMT 2023
PRIMARY
MERCK INDEX
m11163
Created by admin on Fri Dec 15 15:31:02 GMT 2023 , Edited by admin on Fri Dec 15 15:31:02 GMT 2023
PRIMARY Merck Index
EVMPD
SUB04976MIG
Created by admin on Fri Dec 15 15:31:02 GMT 2023 , Edited by admin on Fri Dec 15 15:31:02 GMT 2023
PRIMARY
SMS_ID
100000084647
Created by admin on Fri Dec 15 15:31:02 GMT 2023 , Edited by admin on Fri Dec 15 15:31:02 GMT 2023
PRIMARY
FDA UNII
L137U4A79K
Created by admin on Fri Dec 15 15:31:02 GMT 2023 , Edited by admin on Fri Dec 15 15:31:02 GMT 2023
PRIMARY
DRUG BANK
DBSALT002433
Created by admin on Fri Dec 15 15:31:02 GMT 2023 , Edited by admin on Fri Dec 15 15:31:02 GMT 2023
PRIMARY
ChEMBL
CHEMBL119
Created by admin on Fri Dec 15 15:31:02 GMT 2023 , Edited by admin on Fri Dec 15 15:31:02 GMT 2023
PRIMARY
MESH
C056321
Created by admin on Fri Dec 15 15:31:02 GMT 2023 , Edited by admin on Fri Dec 15 15:31:02 GMT 2023
PRIMARY
USAN
AA-34
Created by admin on Fri Dec 15 15:31:02 GMT 2023 , Edited by admin on Fri Dec 15 15:31:02 GMT 2023
PRIMARY
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