Trimetrexate is a parenterally administered folate antagonist that is used as a second line therapy for severe Pneumocystis jirovecii (previously carinii) pneumonia. Trimetrexate therapy has been associated with transient, mild serum enzyme elevations during therapy, but has not been convincingly linked to instances of acute, clinically apparent liver injury.


Trimetrexate (trye" me trex' ate) is a folic acid analogue which acts as an antagonist inhibiting the enzymes involved in folate dependent synthetic pathways such as thymidine synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase. Inhibition of these enzymes leads to decrease in intracellular thymidine and purine which interferes with RNA and DNA synthesis and leads to apoptotic cell death in rapidly dividing cells. Trimetrexate is a nonclassical folate antagonist and, unlike methotrexate, is lipid soluble which leads to different pharmacokinetics and tissue distribution. Trimetrexate was developed as an antineoplastic agent and showed some activity against breast, lung and head and neck cancer, but had difficult toxicities and never received approval for these uses in the United States. Trimetrexate is also taken up by pathogens including Pneumocystis jirovecii where it blocks the folate dependent synthetic pathways and causes their death. At the same time, folate being water soluble can partially block the systemic effects of trimetrexate, but is not taken up by the pathogens. For this reason, high doses of trimetrexate combined with leucovorin “rescue” were evaluated as therapy of Pneumocystis jirovecii in patients who were resistant or intolerant of first line anti-Pneumocystis therapies. Trimetrexate was approved for use as a second line therapy of moderate-to-severe Pneumocystis jirovecii pneumonia in immunodeficient patients in the United States in 1993. It remains available as a second line drug for this indication, but has not been widely used. Trimetrexate is available in single use vials of 25 or 200 mg as a powder for reconstitution under the brand name Neutrexin. The recommended dose is 45 mg/m2 once daily for 21 days concurrent with leucovorin, orally or intravenously, four times daily for 24 days. When given with leucovorin, trimetrexate is well tolerated, but can cause many of the common side effects of other folate antagonists such as fatigue, nausea, vomiting, anorexia, diarrhea, alopecia, anemia, neutropenia and rash. Uncommon, but potentially serious adverse events include febrile neutropenia, infections, dehydration, renal failure, arrhythmias and peripheral neuropathy.


When given without leucovorin protection, trimetrexate therapy is associated with a moderate rate of serum enzyme elevations, serum ALT or AST elevations above 5 times ULN in up to 20% of patients. When given with leucovorin, however, trimetrexate has fewer side effects although serum enzyme elevations can still occur. In clinical trials in patients with HIV infection and Pneumocystis jirovecii pneumonia, ALT elevations above 5 times ULN occurred in 1% to 8% of patients, but were usually no more frequent than with standard therapy using trimethoprim with sulfamethoxazole. The elevations were typically transient, without accompanying symptoms or jaundice and resolved or improved despite continuation of therapy. No instances of clinically apparent acute liver injury attributed to trimetrexate have been reported in the literature. In addition, trimetrexate has not been linked to sinusoidal obstruction syndrome or to reactivation of hepatitis B. Nevertheless, trimetrexate probably has hepatotoxic potential, but because it has limited use, is given for short periods of time and is administered with leucovorin, it has not been convincingly linked to cases of clinically apparent liver injury with jaundice.

Likelihood score: E* (unproven but suspected cause of liver injury).

Mechanism of Injury

The cause of the serum enzyme elevations that may occur during trimetrexate use is probably direct hepatotoxicity from the folate antagonism. Its hepatic metabolism has not been well defined.

Outcome and Management

Trimetrexate therapy has been linked to serum enzyme elevations in a small-to-moderate proportion of patients, but these elevations rarely require dose modifications or early discontinuation of treatment. The elevations often decrease even with continuation of treatment. There have been no instances of idiosyncratic liver injury, acute liver failure, chronic hepatitis or vanishing bile duct syndrome linked to trimetrexate therapy.

Drug Class: Antineoplastic Agents, Antifolate Agents



Trimetrexate – Neutrexin®


Antineoplastic Agents


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 18 April 2016

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  • Helweg-Larsen J, Benfield T, Atzori C, Miller RF. Clinical efficacy of first- and second-line treatments for HIV-associated Pneumocystis jirovecii pneumonia: a tri-centre cohort study. J Antimicrob Chemother 2009; 64: 1282-90. [PMC free article: PMC2775667] [PubMed: 19858161]
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