Trimetrexate Uses, Dosage, Side Effects and more
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.
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.
| Trade Name | Trimetrexate |
| Availability | Discontinued |
| Generic | Trimetrexate |
| Trimetrexate Other Names | Trimetrexate, Trimetrexato, Trimetrexatum |
| Related Drugs | clindamycin, sulfamethoxazole / trimethoprim, Bactrim, Bactrim DS, dapsone |
| Type | |
| Formula | C19H23N5O3 |
| Weight | Average: 369.4176 Monoisotopic: 369.180089627 |
| Protein binding | 95% (over the concentration range of 18.75 to 1000 ng/mL) |
| Groups | Approved, Investigational |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | |
| Last Updated: | January 7, 2025 at 1:49 am |
Uses
Trimetrexate is a folate antagonist used for the treatment of moderate-to-severe Pneumocystis carinii pneumonia (PCP) in immunocompromised patients as an alternative therapy in combination with leucovorin.
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.
Trimetrexate is also used to associated treatment for these conditions: Pneumocystis Jirovecii Pneumonia
How Trimetrexate works
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.
Toxicity
The LD50 of intravenous trimetrexate in mice is 62 mg/kg (186 mg/m2). Myelosuppression is a dose-limiting toxic effect.
Food Interaction
No interactions found.Drug Interaction
Unknown: fluticasone / salmeterol, ibuprofen, erenumab, fremanezumab, aspirin, azithromycin, sulfamethoxazole / trimethoprim, onabotulinumtoxinA, multivitamin with minerals, ciprofloxacin, loratadine, sulfamethoxazole / trimethoprim, docusate, ubiquinone, acetaminophen / hydrocodone, levothyroxine, valacyclovir, cholecalciferol, alprazolam, sertraline
Disease Interaction
Major: colitis, bone marrow suppression, renal/liver disease
Volume of Distribution
- 20 ± 8 L/m2
- 36.9 ± 6 L/m2 [cancer patients]
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]
Elimination Route
Ten to 30% of the administered dose is excreted unchanged in the urine.
