|Accession Number||DB01157 (APRD00268)|
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.
|External IDs||Not Available|
|Approved Prescription Products|
|Approved Generic Prescription Products||Not Available|
|Approved Over the Counter Products||Not Available|
|Unapproved/Other Products||Not Available|
|Brand mixtures||Not Available|
|Weight||Average: 369.4176 |
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.
|Structured Indications||Not Available|
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.
|Volume of distribution|
95% (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 elimination|
Ten to 30% of the administered dose is excreted unchanged in the urine.
11 to 20 hours
The LD50 of intravenous trimetrexate in mice is 62 mg/kg (186 mg/m2). Myelosuppression is a dose-limiting toxic effect.
|Pharmacogenomic Effects/ADRs||Not Available|
|Food Interactions||Not Available|
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||Not Available|
|ATC Codes||P01AX07 — Trimetrexate|
|AHFS Codes||Not Available|
|FDA label||Download (53.3 KB)|
|Predicted ADMET features|
|Mass Spec (NIST)||Not Available|
|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.|
|Super Class||Organoheterocyclic compounds|
|Alternative Parents||Methoxyanilines / Aminophenyl ethers / Phenylalkylamines / Phenoxy compounds / Methoxybenzenes / Anisoles / Secondary alkylarylamines / Aminopyrimidines and derivatives / Alkyl aryl ethers / Imidolactams / Heteroaromatic compounds / Azacyclic compounds / Primary amines / Organopnictogen compounds / Hydrocarbon derivatives|
|Substituents||Quinazolinamine / Methoxyaniline / Aminophenyl ether / Aniline or substituted anilines / Phenylalkylamine / Phenoxy compound / Methoxybenzene / Phenol ether / Anisole / Secondary aliphatic/aromatic amine/ Alkyl aryl ether / Aralkylamine / Aminopyrimidine / Pyrimidine / Benzenoid / Imidolactam / Monocyclic benzene moiety / Heteroaromatic compound / Ether / Azacycle / Secondary amine / Organooxygen compound / Organonitrogen compound / Organic nitrogen compound / Hydrocarbon derivative / Organopnictogen compound / Amine / Primary amine / Organic oxygen compound / Aromatic heteropolycyclic compound|
|Molecular Framework||Aromatic heteropolycyclic compounds|
|External Descriptors||Not Available|
- Pharmacological action
- 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 precursor synthesis. Binds its own mRNA and that of DHFRL1.
- Gene Name:
- Uniprot ID:
- Uniprot Name:
- Dihydrofolate reductase
- Molecular Weight:
- 21452.61 Da
- 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:10386066 ]
- 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:11448221 ]
- 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:11752096 ]
- 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:12416030 ]
- 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:12649191 ]
- 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:10091649 ]
- Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]