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Accession NumberDB01157  (APRD00268)
TypeSmall Molecule
GroupsApproved, Investigational

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. [PubChem]

CI-898Not AvailableNot Available
NeutrexinNot AvailableNot Available
SID26755046Not AvailableNot Available
SID50110873Not AvailableNot Available
TMQNot AvailableNot Available
TMXNot AvailableNot Available
TrimetrexateNot AvailableNot Available
Prescription ProductsNot Available
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International Brands
NeutrexinNot Available
Brand mixturesNot Available
SaltsNot Available
CAS number52128-35-5
WeightAverage: 369.4176
Monoisotopic: 369.180089627
Chemical FormulaC19H23N5O3
Mass SpecNot Available
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
Direct parentQuinazolinamines
Alternative parentsAnisoles; Aminopyrimidines and Derivatives; Toluenes; Alkyl Aryl Ethers; Primary Aromatic Amines; Secondary Amines; Polyamines
Substituentsphenol ether; anisole; aminopyrimidine; toluene; alkyl aryl ether; benzene; pyrimidine; primary aromatic amine; polyamine; secondary amine; ether; amine; primary amine; organonitrogen compound
Classification descriptionThis compound belongs to the quinazolinamines. These are heterocyclic aromatic compounds containing a quianazoline moiety substituted by one or more amine groups.
IndicationFor 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.
PharmacodynamicsTrimetrexate, 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 actionIn 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.
AbsorptionNot Available
Volume of distribution
  • 20 ± 8 L/m2
  • 36.9 ± 6 L/m2 [cancer patients]
Protein binding95% (over the concentration range of 18.75 to 1000 ng/mL)

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 eliminationTen to 30% of the administered dose is excreted unchanged in the urine.
Half life11 to 20 hours
  • 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]
ToxicityThe LD50 of intravenous trimetrexate in mice is 62 mg/kg (186 mg/m2). Myelosuppression is a dose-limiting toxic effect.
Affected organisms
  • Humans and other mammals
  • Bacteria and protozoa
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 1.0
Blood Brain Barrier + 0.9382
Caco-2 permeable + 0.6393
P-glycoprotein substrate Substrate 0.5758
P-glycoprotein inhibitor I Non-inhibitor 0.5948
P-glycoprotein inhibitor II Non-inhibitor 0.6545
Renal organic cation transporter Non-inhibitor 0.7837
CYP450 2C9 substrate Non-substrate 0.8668
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Non-substrate 0.5206
CYP450 1A2 substrate Non-inhibitor 0.5
CYP450 2C9 substrate Non-inhibitor 0.7037
CYP450 2D6 substrate Non-inhibitor 0.7397
CYP450 2C19 substrate Non-inhibitor 0.6512
CYP450 3A4 substrate Non-inhibitor 0.8614
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.6235
Ames test Non AMES toxic 0.6339
Carcinogenicity Non-carcinogens 0.9136
Biodegradation Not ready biodegradable 0.9968
Rat acute toxicity 2.3340 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9027
hERG inhibition (predictor II) Non-inhibitor 0.6892
ManufacturersNot Available
Dosage formsNot Available
PricesNot Available
CountryPatent NumberApprovedExpires (estimated)
United States60179221998-05-182018-05-18
Experimental Properties
melting point215-217 °CPhysProp
water solubility31.4 mg/LNot Available
logP2.55HANSCH,C ET AL. (1995)
pKa8.0Not Available
Predicted Properties
Water Solubility0.0309ALOGPS
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
Polarizability40.24 Å3ChemAxon
Number of Rings3ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
SpectraNot Available
Synthesis Reference

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

General ReferenceNot Available
External Links
KEGG DrugD06238
KEGG CompoundC11154
PubChem Compound5583
PubChem Substance46505247
Therapeutic Targets DatabaseDAP000635
ATC CodesP01AX07
AHFS CodesNot Available
PDB Entries
FDA labelshow(53.3 KB)
MSDSNot Available
Drug Interactions
AcenocoumarolThe anticoagulant effect of Acenocoumarol, a Vitamin K antagonist, may be altered by antineoplastics such as Trimetrexate. Monitor for changes in the anticoagulant effects of warfarin and other coumarin derivatives during concomitant use.
DigoxinThe absorption of Digoxin, a cardiac glycoside, may be decreased by antineoplastic agents such as Trimetrexate. Liquid forms of Digoxin do not appear to be significantly affected. Monitor Digoxin tablet efficacy if Trimetrexate therapy is initiated, discontinued or if the dose is altered.
WarfarinThe anticoagulant effect of Warfarin, a Vitamin K antagonist, may be altered by antineoplastics such as Trimetrexate. Monitor for changes in the anticoagulant effects of warfarin and other coumarin derivatives during concomitant use.
Food InteractionsNot Available


1. Dihydrofolate reductase

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor


Name UniProt ID Details
Dihydrofolate reductase P00374 Details


  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. Pubmed
  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. Pubmed
  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. Pubmed
  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. Pubmed
  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. Pubmed
  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. Pubmed
  7. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on March 26, 2014 12:27