Brands, Medical Use, Clinical Data
Drug Category
- Antibiotics
- Antimetabolites, Antineoplastic
- Antifungal Agents
- Folic Acid Antagonists
- Antiprotozoals
Dosage Forms
- Powder for solution (containing trimetrexate glucuronate equivalent to either 200 mg or 25 mg of trimetrexate)
Brands / Synonyms
Neutrexin; TMQ; TMX; Trimetrexate (USAN); Trimetrexate [USAN:BAN:INN]; Trimetrexato [INN-Spanish]; Trimetrexatum [INN-Latin]
Indications
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.
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 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
Toxicity
The LD50 of intravenous trimetrexate in mice is 62 mg/kg (186 mg/m2). Myelosuppression is a dose-limiting toxic effect.
Biotrnasformation / Drug Metabolism
Hepatic. Preclinical data strongly suggest that the major metabolic pathway is oxidative O-demethylation, followed by conjugation to either glucuronide or the sulfate.
Contraindications
Neutrexin (trimetrexate glucuronate for injection) is contraindicated in patients with clinically significant
sensitivity to trimetrexate, leucovorin, or methotrexate.
Drug Interactions
Since trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug metabolizing
enzyme system may elicit important drug-drug interactions that may alter trimetrexate plasma concentrations. Agents
that might be coadministered with trimetrexate in AIDS patients for other indications that could elicit this activity
include erythromycin, rifampin, rifabutin, ketoconazole, and fluconazole. In vitro perfusion of isolated rat liver
has shown that cimetidine caused a significant reduction in trimetrexate metabolism and that acetaminophen altered
the relative concentration of trimetrexate metabolites possibly by competing for sulfate metabolites. Based on an in
vitro rat liver model, nitrogen substituted imidazole drugs (clotrimazole, ketoconazole, miconazole) were potent,
non-competitive inhibitors of trimetrexate metabolism. Patients medicated with these drugs and trimetrexate should be
carefully monitored.
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