| 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. |
| Pharmacodynamics |
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. |
| 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. |
| Absorption |
Not Available |
| Volume of distribution |
- 20 ± 8 L/m2
- 36.9 ± 6 L/m2 [cancer patients]
|
| Protein binding |
95% (over the concentration range of 18.75 to 1000 ng/mL) |
| Metabolism |
Hepatic. Preclinical data strongly suggest that the major
metabolic pathway is oxidative O-demethylation, followed by conjugation
to either glucuronide or the sulfate. |
| Route of elimination |
Ten to 30% of the administered dose is excreted unchanged in the urine. |
| 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]
|
| Toxicity |
The LD50 of intravenous trimetrexate in mice is 62 mg/kg (186 mg/m2). Myelosuppression is a dose-limiting toxic effect. |
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