Trimetrexate is a dihydrofolate reductase inhibitor used primarily as an alternative for treatment of the fungus Pneumocystis jirovecii (carinii) and has also been used in the treatment of cerebral toxoplasmosis. Trimetrexate (as trimetrexate glucuronate) is marketed under the brand name Neutrexins. 

Use

Trimetrexate's potential use as an antiparasitic agent in treating malaria and protozoan disease such as trypanosomiasis (Chagas'disease) is currently being investigated. Trimetrexate has been increasingly investigated for use in a variety of solid tumors, including colorectal cancer, demonstrating some benefit in advanced disease in multicenter trials, as well as, in early studies, in hematologic malignancies. Trimetrexate should be co-administered with leucovorin (5-formyltetrahydrofolate) to ameliorate the risk of myelotoxicity when used for infections.

Mechanism of action

Trimetrexate is a nonclassical DHFR inhibitor. It is 100–1500 times more potent than trimethoprim in inhibiting the DHFR of Pneumocystis jirovecii, but is less selective than trimethoprim in its effects on mammalian DHFR, therefore resulting in more toxicity. DHFR is an important folate coenzyme – by inhibiting DHFR, trimetrexate prevents the biosynthesis of thymidylate. Trimetrexate also indirectly inhibits purine biosynthesis through depletion of reduced folates. 

As a consequence, both DNA and RNA synthesis is affected. Trimetrexate and leucovorin co-administration results in therapeutic activity against Pneumocystis jirovecii since this organism lacks a folate transport system and is dependent upon its ability to synthesize folates. In comparison, human cells are able to use leucovorin as a preformed folate with resultant reduced toxicity. Trimetrexate is lipophilic and is thought to enter cells generally by passive diffusion, although some facilitated transport systems may also be involved. 

Side-effects

Although dermatological side-effects are common with trimetrexate, no hypersensitivity reactions have been reported in infection treatment trials (mainly PCP). Trimetrexate should be avoided in patients who have had hypersensitivity reactions to methotrexate or leucovorin.