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Identification
Name Trimetrexate
Accession Number DB01157 (APRD00268)
Type small molecule
Groups approved
Description

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]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
TMQ
TMX
Trimetrexato [INN-Spanish]
Trimetrexatum [INN-Latin]
Salts Not Available
Brand names
Name Company
Neutrexin
Brand mixtures Not Available
Categories
  • Antiprotozoals
  • Folic Acid Antagonists
  • Antifungal Agents
  • Antibiotics
  • Antimetabolites, Antineoplastic
CAS number 52128-35-5
Weight Average: 369.4176
Monoisotopic: 369.180089627
Chemical Formula C19H23N5O3
InChI Key InChIKey=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)
Plain Text
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
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Quinazolines
Substructures
  • Quinazolines
  • Aliphatic and Aryl Amines
  • Phenols and Derivatives
  • Ethers
  • Benzene and Derivatives
  • Pyrimidines and Derivatives
  • Catechols
  • Heterocyclic compounds
  • Aromatic compounds
  • Anisoles
  • Cyanamides
  • Phenyl Esters
  • Anilines
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.
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.
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]
Toxicity The 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
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Medimmune oncology inc
Packagers
Dosage forms
Form Route Strength
Powder, for solution Intravenous
Prices Not Available
Patents
Country Patent Number Approved Expires (estimated)
United States 6017922 1998-05-18 2018-05-18
Properties
State solid
Experimental Properties
Property Value Source
melting point 215-217 °C PhysProp
water solubility 31.4 mg/L Not Available
logP 2.55 HANSCH,C ET AL. (1995)
pKa 8.0 Not Available
Predicted Properties
Property Value Source
water solubility 3.09e-02 g/l ALOGPS
logP 2.36 ALOGPS
logP 2.28 ChemAxon
logS -4.1 ALOGPS
pKa (strongest acidic) 17.04 ChemAxon
pKa (strongest basic) 7.54 ChemAxon
physiological charge 1 ChemAxon
hydrogen acceptor count 8 ChemAxon
hydrogen donor count 3 ChemAxon
polar surface area 117.54 ChemAxon
rotatable bond count 6 ChemAxon
refractivity 107.7 ChemAxon
polarizability 40.24 ChemAxon
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D06238 Link_out
KEGG Compound C11154 Link_out
PubChem Compound 5583 Link_out
PubChem Substance 46505247 Link_out
ChemSpider 5381 Link_out
BindingDB 18268 Link_out
Therapeutic Targets Database DAP000635 Link_out
PharmGKB PA451790 Link_out
HET TMQ Link_out
Drug Product Database 2065770 Link_out
RxList http://www.rxlist.com/cgi/generic2/trimetrexate.htm Link_out
Drugs.com http://www.drugs.com/cdi/trimetrexate.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Trimetrexate Link_out
ATC Codes
  • P01AX07
AHFS Codes Not Available
PDB Entries
FDA label show (53.3 KB)
MSDS Not Available
Interactions
Drug Interactions
Drug Interaction
Acenocoumarol The 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.
Digoxin The 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.
Warfarin The 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 Interactions Not Available
Targets

1. Dihydrofolate reductase

Pharmacological action: yes
Actions: inhibitor
Organism class: human
UniProt ID: P00374 Link_out
Gene: DHFR Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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. 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
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19