Neutrexin: Full Drug Profile
Neutrexin - General Information
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]
Pharmacology of Neutrexin
Neutrexin, 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.
Neutrexin for patients
While you are being treated with trimetrexate, and after you stop treatment, do not have any immunizations (vaccinations) without your doctor’s okay. Try to avoid contact with people who have recently taken the oral polio vaccine. Check with your doctor about this. Trimetrexate can lower your blood counts (white blood cells, red blood cells, platelets). Your doctor will check your blood counts before and after each treatment to see its effect. Your doctor or nurse will give you specific instructions if your blood counts are low. Trimetrexate can decrease your white blood cell count. This can increase your risk of getting an infection. Report fever of 100.5°F or higher, or signs of infection such as pain in passing your urine, coughing, and bringing up sputum. Trimetrexate can decrease your platelet count. This can increase your risk of bleeding. DO NOT take any aspirin or aspirin–containing medicines. Report unusual bruising, or bleeding such as nosebleeds, bleeding gums when you brush your teeth, or black, tarry stools. Getting a wig before starting treatment may make it easier to deal with hair loss. Talk to your nurse or doctor about this. If your insurance does not cover it, there may be other resources to help you. Hair loss is temporary, and your hair will grow back after treatment.
Neutrexin 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.
Neutrexin Contraindications
Neutrexin (trimetrexate glucuronate for injection) is contraindicated in patients with clinically significant sensitivity to trimetrexate, leucovorin, or methotrexate.
Additional information about Neutrexin
Neutrexin 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. 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. Drug Interactions: Not Available Food Interactions: Not Available Generic Name: Trimetrexate Synonyms: TMQ; TMX; Trimetrexato [INN-Spanish]; Trimetrexatum [INN-Latin] Drug Category: Antibiotics; Antimetabolites, Antineoplastic; Antifungal Agents; Folic Acid Antagonists; Antiprotozoals Drug Type: Small Molecule; Approved Other Brand Names containing Trimetrexate: Neutrexin; Absorption: Not Available Toxicity (Overdose): The LD50 of intravenous trimetrexate in mice is 62 mg/kg (186 mg/m2). Myelosuppression is a dose-limiting toxic effect. 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. Half Life: 11 to 20 hours Dosage Forms of Neutrexin: Powder, for solution Intravenous Chemical IUPAC Name: 5-methyl-6-[[(3,4,5-trimethoxyphenyl)amino]methyl]quinazoline-2,4-diamine Chemical Formula: C19H23N5O3 Trimetrexate on Wikipedia: https://en.wikipedia.org/wiki/Trimetrexate Organisms Affected: Bacteria and protozoa; Humans and other mammals