Trimetrexate

Identification

Summary

Trimetrexate is a folate antagonist used for the treatment of moderate-to-severe Pneumocystis carinii pneumonia (PCP) in immunocompromised patients as an alternative therapy in combination with leucovorin.

Brand Names
Neutrexin
Generic Name
Trimetrexate
DrugBank Accession Number
DB01157
Background

A nonclassical folic acid inhibitor through its inhibition of the enzyme dihydrofolate reductase. It is being tested for efficacy as an antineoplastic agent and as an antiparasitic agent against pneumocystis pneumonia in AIDS patients. Myelosuppression is its dose-limiting toxic effect.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 369.4176
Monoisotopic: 369.180089627
Chemical Formula
C19H23N5O3
Synonyms
  • Trimetrexate
  • Trimetrexato
  • Trimetrexatum

Pharmacology

Indication

For use, with concurrent leucovorin administration (leucovorin protection), 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). Also used to treat several types of cancer including colon cancer.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used in combination to treatPneumocystis jirovecii pneumoniaRegimen in combination with: Leucovorin (DB00650)•••••••••••••••••••••
Used in combination to treatPneumocystis jirovecii pneumoniaRegimen in combination with: Leucovorin (DB00650)•••••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Trimetrexate, a non-classical folate antagonist, is a synthetic inhibitor of the enzyme dihydrofolate reductase (DHFR). During DNA synthesis and cellular reproduction, folic acid is reduced to tetrahydrofolic acid by the enzyme folic acid reductase. By interfering with the reduction of folic acid, trimetrexate interferes with tissue cell reproduction. Generally, the most sensitive cells to the antimetabolite effect of trimetrexate are those cells which are most actively proliferating such as malignant cells, dermal epithelium, buccal and intestinal mucosa, bone marrow, fetal cells, and cells of the urinary bladder. Because the proliferation of cells in malignant tissues is greater than in most normal tissues, trimetrexate may impair the growth of the malignant tissues without causing irreversible damage to normal tissues. Due to very serious and potentially life-threatening side-effects of this drug, leucovorin must be co-administered for at least 72 hours after the last dose.

Mechanism of action

In vitro studies have shown that 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 p.r.n. biosynthesis. The end result is disruption of DNA, RNA, and protein synthesis, with consequent cell death.

TargetActionsOrganism
ADihydrofolate reductase
inhibitor
Humans
Absorption

Not Available

Volume of distribution
  • 20 ± 8 L/m2
  • 36.9 ± 6 L/m2 [cancer patients]
Protein binding

95% (over the concentration range of 18.75 to 1000 ng/mL)

Metabolism

Hepatic. Preclinical data strongly suggest that the major metabolic pathway is oxidative O-demethylation, followed by conjugation to either glucuronide or the sulfate.

Route of elimination

Ten to 30% of the administered dose is excreted unchanged in the urine.

Half-life

11 to 20 hours

Clearance
  • 38 +/- 15 mL/min/m2 [patients with acquired immunodeficiency syndrome (AIDS) who had Pneumocystis carinii pneumonia (4 patients) or toxoplasmosis (2 patients). Trimetrexate was administered intravenously as a bolus injection at a dose of 30 mg/m2/day along with leucovorin 20 mg/m2 every 6 hours for 21 days]
  • 53 +/- 41 mL/min/m2 [Cancer patients with advanced solid tumors using various dosage regimensreceiving a single-dose administration of 10 to 130 mg/m2]
  • 30 +/- 8 mL/min/m2 [Cancer patients with advanced solid tumors using various dosage regimensafter a five-day infusion]
Adverse Effects
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Toxicity

The LD50 of intravenous trimetrexate in mice is 62 mg/kg (186 mg/m2). Myelosuppression is a dose-limiting toxic effect.

Pathways
Not Available
Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
Not Available

Interactions

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This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Trimetrexate which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Trimetrexate which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Trimetrexate which could result in a higher serum level.
AcetaminophenAcetaminophen may decrease the excretion rate of Trimetrexate which could result in a higher serum level.
AcetazolamideThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Acetazolamide.
Food Interactions
No interactions found.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Trimetrexate glucuronateL137U4A79K82952-64-5ZCJXQWYMBJYJNB-LRDBBFHQSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
NeutrexinInjection, powder, lyophilized, for solution25 mg/2mLIntravenousMedimmune Oncology, Inc.2006-05-11Not applicableUS flag
NeutrexinInjection, powder, lyophilized, for solution200 mg/16mLIntravenousMedimmune Oncology, Inc.2006-05-11Not applicableUS flag
Neutrexin Pws IV 25mg/vialPowder, for solution25 mg / vialIntravenousMedimmune Oncology, Inc.1994-12-312007-02-21Canada flag

Categories

ATC Codes
P01AX07 — Trimetrexate
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as quinazolinamines. These are heterocyclic aromatic compounds containing a quianazoline moiety substituted by one or more amine groups.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazanaphthalenes
Sub Class
Benzodiazines
Direct Parent
Quinazolinamines
Alternative Parents
Methoxyanilines / Aminophenyl ethers / Phenylalkylamines / Phenoxy compounds / Methoxybenzenes / Anisoles / Secondary alkylarylamines / Aminopyrimidines and derivatives / Alkyl aryl ethers / Imidolactams
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Substituents
Alkyl aryl ether / Amine / Aminophenyl ether / Aminopyrimidine / Aniline or substituted anilines / Anisole / Aralkylamine / Aromatic heteropolycyclic compound / Azacycle / Benzenoid
show 20 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals
  • Pneumocystis carinii
  • Bacteria and protozoa

Chemical Identifiers

UNII
UPN4ITI8T4
CAS number
52128-35-5
InChI Key
NOYPYLRCIDNJJB-UHFFFAOYSA-N
InChI
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)
IUPAC Name
5-methyl-6-{[(3,4,5-trimethoxyphenyl)amino]methyl}quinazoline-2,4-diamine
SMILES
COC1=CC(NCC2=C(C)C3=C(C=C2)N=C(N)N=C3N)=CC(OC)=C1OC

References

Synthesis Reference

Martin Stogniew, Javad M. Zadei, "Compositions comprising trimetrexate and methods of their synthesis and use." U.S. Patent US6258821, issued January, 1974.

US6258821
General References
  1. FDA Approved Products: Neutrexin (trimetrexate glucuronate) for injection [Link]
Human Metabolome Database
HMDB0015288
KEGG Drug
D06238
KEGG Compound
C11154
PubChem Compound
5583
PubChem Substance
46505247
ChemSpider
5381
BindingDB
18268
RxNav
42333
ChEBI
9737
ChEMBL
CHEMBL119
ZINC
ZINC000000598852
Therapeutic Targets Database
DAP000635
PharmGKB
PA451790
PDBe Ligand
TMQ
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Trimetrexate
FDA label
Download (53.3 KB)

Clinical Trials

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Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Ben Venue Laboratories Inc.
  • Medimmune Inc.
Dosage Forms
FormRouteStrength
Injection, powder, lyophilized, for solutionIntravenous200 mg/16mL
Injection, powder, lyophilized, for solutionIntravenous25 mg/2mL
Powder, for solutionIntravenous25 mg / vial
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US6017922No2000-01-252018-05-18US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)215-217 °CPhysProp
water solubility31.4 mg/LNot Available
logP2.55HANSCH,C ET AL. (1995)
pKa8.0Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0309 mg/mLALOGPS
logP2.36ALOGPS
logP2.28Chemaxon
logS-4.1ALOGPS
pKa (Strongest Acidic)17.04Chemaxon
pKa (Strongest Basic)7.54Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count8Chemaxon
Hydrogen Donor Count3Chemaxon
Polar Surface Area117.54 Å2Chemaxon
Rotatable Bond Count6Chemaxon
Refractivity107.7 m3·mol-1Chemaxon
Polarizability40.22 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9382
Caco-2 permeable+0.6393
P-glycoprotein substrateSubstrate0.5758
P-glycoprotein inhibitor INon-inhibitor0.5948
P-glycoprotein inhibitor IINon-inhibitor0.6545
Renal organic cation transporterNon-inhibitor0.7837
CYP450 2C9 substrateNon-substrate0.8668
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateNon-substrate0.5206
CYP450 1A2 substrateNon-inhibitor0.5
CYP450 2C9 inhibitorNon-inhibitor0.7037
CYP450 2D6 inhibitorNon-inhibitor0.7397
CYP450 2C19 inhibitorNon-inhibitor0.6512
CYP450 3A4 inhibitorNon-inhibitor0.8614
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.6235
Ames testNon AMES toxic0.6339
CarcinogenicityNon-carcinogens0.9136
BiodegradationNot ready biodegradable0.9968
Rat acute toxicity2.3340 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9027
hERG inhibition (predictor II)Non-inhibitor0.6892
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-0ugj-0409000000-97a2080cda5a33464953
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-00di-0009000000-44304d384ebef5e4664d
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-014i-0009000000-059012d3f7519ee12780
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-00di-0009000000-e788b5cf8c3c3f6dc8f6
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0gi9-0039000000-266da0eb6eb34859ca31
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-00di-0901000000-3483f705b925478499d2
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-00vi-0392000000-d042ddaffecb9c5df560
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-209.0054296
predicted
DarkChem Lite v0.1.0
[M-H]-186.24498
predicted
DeepCCS 1.0 (2019)
[M+H]+208.5924296
predicted
DarkChem Lite v0.1.0
[M+H]+188.603
predicted
DeepCCS 1.0 (2019)
[M+Na]+209.3178296
predicted
DarkChem Lite v0.1.0
[M+Na]+195.57784
predicted
DeepCCS 1.0 (2019)

Targets

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Details
1. Dihydrofolate reductase
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
Curator comments
Competitive inhibitor
General Function
Nadph binding
Specific Function
Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA pre...
Gene Name
DHFR
Uniprot ID
P00374
Uniprot Name
Dihydrofolate reductase
Molecular Weight
21452.61 Da
References
  1. Bertino JR, Zhao SC, Mineishi S, Ercikan-Abali EA, Banerjee D: Use of variants of dihydrofolate reductase in gene transfer to produce resistance to methotrexate and trimetrexate. Prog Exp Tumor Res. 1999;36:82-94. [Article]
  2. Graffner-Nordberg M, Kolmodin K, Aqvist J, Queener SF, Hallberg A: Design, synthesis, computational prediction, and biological evaluation of ester soft drugs as inhibitors of dihydrofolate reductase from Pneumocystis carinii. J Med Chem. 2001 Jul 19;44(15):2391-402. [Article]
  3. Warlick CA, Diers MD, Wagner JE, McIvor RS: In vivo selection of antifolate-resistant transgenic hematopoietic stem cells in a murine bone marrow transplant model. J Pharmacol Exp Ther. 2002 Jan;300(1):50-6. [Article]
  4. Zhu WY, Bunni M, Priest DG, DiCapua JL, Dressler JM, Chen Z, Melera PW: Severe folate restriction results in depletion of and alteration in the composition of the intracellular folate pool, moderate sensitization to methotrexate and trimetrexate, upregulation of endogenous DHFR activity, and overexpression of metallothionein II and folate receptor alpha that, upon folate repletion, confer drug resistance to CHL cells. J Exp Ther Oncol. 2002 Sep-Oct;2(5):264-77. [Article]
  5. Sweeney CL, Frandsen JL, Verfaillie CM, McIvor RS: Trimetrexate inhibits progression of the murine 32Dp210 model of chronic myeloid leukemia in animals expressing drug-resistant dihydrofolate reductase. Cancer Res. 2003 Mar 15;63(6):1304-10. [Article]
  6. Polshakov VI, Birdsall B, Frenkiel TA, Gargaro AR, Feeney J: Structure and dynamics in solution of the complex of Lactobacillus casei dihydrofolate reductase with the new lipophilic antifolate drug trimetrexate. Protein Sci. 1999 Mar;8(3):467-81. [Article]
  7. Sowers R, Wenzel BD, Richardson C, Meyers PA, Healey JH, Levy AS, Gorlick R: Impairment of methotrexate transport is common in osteosarcoma tumor samples. Sarcoma. 2011;2011:834170. doi: 10.1155/2011/834170. Epub 2010 Dec 22. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Reduced folate carrier activity
Specific Function
Transporter for the intake of folate. Uptake of folate in human placental choriocarcinoma cells occurs by a novel mechanism called potocytosis which functionally couples three components, namely th...
Gene Name
SLC19A1
Uniprot ID
P41440
Uniprot Name
Folate transporter 1
Molecular Weight
64867.62 Da
References
  1. Wang Y, Zhao R, Goldman ID: Characterization of a folate transporter in HeLa cells with a low pH optimum and high affinity for pemetrexed distinct from the reduced folate carrier. Clin Cancer Res. 2004 Sep 15;10(18 Pt 1):6256-64. doi: 10.1158/1078-0432.CCR-04-0645. [Article]
  2. Sowers R, Wenzel BD, Richardson C, Meyers PA, Healey JH, Levy AS, Gorlick R: Impairment of methotrexate transport is common in osteosarcoma tumor samples. Sarcoma. 2011;2011:834170. doi: 10.1155/2011/834170. Epub 2010 Dec 22. [Article]
  3. Jackson RC, Fry DW, Boritzki TJ, Besserer JA, Leopold WR, Sloan BJ, Elslager EF: Biochemical pharmacology of the lipophilic antifolate, trimetrexate. Adv Enzyme Regul. 1984;22:187-206. doi: 10.1016/0065-2571(84)90014-1. [Article]

Drug created at June 13, 2005 13:24 / Updated at October 09, 2021 02:48