May 27, 2017
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Discontinued Warning IconPlease Note: This Brand Name drug is no longer available in the US.
(Generic versions may still be available.)


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 purine biosynthesis. The end result is disruption of DNA, RNA, and protein synthesis, with consequent cell death. Leucovorin (folinic acid) is readily transported into mammalian cells by an active, carrier-mediated process and can be assimilated into cellular folate pools following its metabolism. In vitro studies have shown that leucovorin provides a source of reduced folates necessary for normal cellular biosynthetic processes. Because the Pneumocystis carinii organism lacks the reduced folate carrier-mediated transport system, leucovorin is prevented from entering the organism. Therefore, at concentrations achieved with therapeutic doses of trimetrexate plus leucovorin, the selective transport of trimetrexate, but not leucovorin, into the Pneumocystis carinii organism allows the concurrent administration of leucovorin to protect normal host cells from the cytotoxicity of trimetrexate without inhibiting the antifolate's inhibition of Pneumocystis carinii. It is not known if considerably higher doses of leucovorin would affect trimetrexate's effect on Pneumocystis carinii.


Trimetrexate inhibits, in a dose-related manner, in vitro growth of the trophozoite stage of rat Pneumocystis carinii cultured on human embryonic lung fibroblast cells. Trimetrexate concentrations between 3 and 54.1 M were shown to inhibit the growth of trophozoites. Leucovorin alone at a concentration of 10 M did not alter either the growth of the trophozoites or the anti-pneumocystis activity of trimetrexate. Resistance to trimetrexate's antimicrobial activity against Pneumocystis carinii has not been studied.


Trimetrexate pharmacokinetics were assessed in six 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. Trimetrexate clearance (mean ± SD) was 38 ± 15 mL/min/m2 and volume of distribution at steady state (Vdss) was 20 ± 8 L/m2. The plasma concentration time profile declined in a biphasic manner over 24 hours with a terminal half-life of 11 ± 4 hours.

The pharmacokinetics of trimetrexate without the concomitant administration of leucovorin have been evaluated in cancer patients with advanced solid tumors using various dosage regimens. The decline in plasma concentrations over time has been described by either biexponential or triexponential equations. Following the single-dose administration of 10 to 130 mg/m2 to 37 patients, plasma concentrations were obtained for 72 hours. Nine plasma concentration time profiles were described as biexponential. The alpha phase half-life was 57 ± 28 minutes, followed by a terminal phase with a half-life of 16 ± 3 hours. The plasma concentrations in the remaining patients exhibited a triphasic decline with half-lives of 8.6 ± 6.5 minutes, 2.4 ± 1.3 hours, and 17.8 ± 8.2 hours.

Trimetrexate clearance in cancer patients has been reported as 53 ± 41 mL/min (14 patients) and 32 ± 18 mL/min/m2 (23 patients) following single-dose administration. After a five-day infusion of trimetrexate to 16 patients, plasma clearance was 30 ± 8 mL/min/m2.

Renal clearance of trimetrexate in cancer patients has varied from about 4 ± 2 mL/min/m2 to 10 ± 6 mL/min/m2. Ten to 30% of the administered dose is excreted unchanged in the urine. Considering the free fraction of trimetrexate, active tubular secretion may possibly contribute to the renal clearance of trimetrexate. Renal clearance has been associated with urine flow, suggesting the possibility of tubular reabsorption as well.

The Vdss of trimetrexate in cancer patients after single-dose administration and for whom plasma concentrations were obtained for 72 hours was 36.9 ± 17.6 L/m2 (n=23) and 0.62 ± 0.24 L/kg (n=14). Following a constant infusion of trimetrexate for five days, Vdss was 32.8 ± 16.6 L/m2. The volume of the central compartment has been estimated as 0.17 ± 0.08 L/kg and 4.0 ± 2.9 L/m2.

There have been inconsistencies in the reporting of trimetrexate protein binding. The in vitro plasma protein binding of trimetrexate using ultrafiltration is approximately 95% over the concentration range of 18.75 to 1000 ng/mL. There is a suggestion of capacity limited binding (saturable binding) at concentrations greater than about 1000 ng/mL, with free fraction progressively increasing to about 9.3% as concentration is increased to 15 g/mL. Other reports have declared trimetrexate to be greater than 98% bound at concentrations of 0.1 to 10 g/mL; however, specific free fractions were not stated. The free fraction of trimetrexate also has been reported to be about 15 to 16% at a concentration of 60 ng/mL, increasing to about 20% at a trimetrexate concentration of 6 g/mL.

Trimetrexate metabolism in man has not been characterized. Preclinical data strongly suggest that the major metabolic pathway is oxidative O-demethylation, followed by conjugation to either glucuronide or the sulfate. N-demethylation and oxidation is a related minor pathway. Preliminary findings in humans indicate the presence of a glucuronide conjugate with DHFR inhibition and a demethylated metabolite in urine.

The presence of metabolite(s) in human plasma following the administration of trimetrexate is suggested by the differences seen in trimetrexate plasma concentrations when measured by HPLC and a nonspecific DHFR inhibition assay. The profiles are similar initially, but diverge with time; concentrations determined by DHFR being higher than those determined by HPLC. This suggests the presence of one or more metabolites with DHFR inhibition activity. After intravenous administration of trimetrexate to humans, urinary recovery averaged about 40%, using a DHFR assay, in comparison to 10% urinary recovery as determined by HPLC, suggesting the presence of one or more metabolites that retain inhibitory activity against DHFR. Fecal recovery of trimetrexate over 48 hours after intravenous administration ranged from 0.09 to 7.6% of the dose as determined by DHFR inhibition and 0.02 to 5.2% of the dose as determined by HPLC.

The pharmacokinetics of trimetrexate have not been determined in patients with renal insufficiency or hepatic dysfunction.

Last reviewed on RxList: 1/11/2017
This monograph has been modified to include the generic and brand name in many instances.

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