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QuickView for Trimetrexate (compound)

Summary
General Info

PubChem

PubChem Compound 332299

PubChem Compound 332299

Name:	Trimetrexate
PubChem Compound ID:	332299
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.
Molecular formula:	C₂₁H₂₉N₅O₇S
Molecular weight:	495.55 g/mol
Synonyms:	117052-25-2; Ethanesulfonic acid, 2-hydroxy-, compd. with 5-methyl-6-[[ (3,4, 5-trimethoxyphenyl)amino]methyl]-2,4-quinazolinediamine (1:1); Ethanesulfonic acid, 2-hydroxy-, compd. with 5-methyl-6-(((3,4,5-trimethoxyphenyl)amino)methyl)-2,4-quinazolinediamine; NSC 328564; JB-11 isethionate; NSC328564; 82935-04-4; Trimetrexate isethionate salt; Ethanesulfonic acid, 2-hydroxy-, compd. with 5-methyl-6-(((3,4,5-trimethoxyphenyl)amino)methyl)-2,4-quinazolinediamine (1:1)

DrugBank

Identification

Name:	Trimetrexate
Name (isomeric):	DB01157
Drug Type:	small molecule
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.
Synonyms:	Trimetrexatum [INN-Latin]; Trimetrexato [INN-Spanish]; TMQ; TMX
Brand:	Neutrexin
Category:	Antimetabolites, Antineoplastic, Antifungal Agents, Antiprotozoals, Antibiotics, Folic Acid Antagonists
CAS number:	52128-35-5

Pharmacology

Indication:	For use, with concurrent leucovorin administration (leucovorin protection), as an alternative therapy for the treatment of moderate-to-severe <i>Pneumocystis carinii</i> pneumonia (PCP) in immunocompromised patients, including patients with the acquired immunodeficiency syndrome (AIDS). Also used to treat several types of cancer including colon cancer.
Pharmacology:	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 reproducti... show more » 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. show less «
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 interferen... show more » 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. show less «
Protein binding:	95% (over the concentration range of 18.75 to 1000 ng/mL)
Biotransformation:	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:	Bacteria and protozoa\|\|Humans and other mammals

Interactions

Drug interaction:

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.
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.

Targets

Dihydrofolate reductase