트라이메트렉세이트

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.

Side effects have been noted to occur less often with trimetrexate than with methotrexate. Hematologic toxicity has been the primary as well as the dose-limiting side effect seen to date in clinical studies in patients being treated for pneumocystis carinii pneumonia. These patients have had manageable decreases in neutrophil and platelet counts. Adverse effects reported in AIDS patients have included nausea, vomiting, diarrhea, reversible liver function abnormalities, skin rash, and fever. In cancer patients treated with trimetrexate (without leucovorin), hematologic toxicities have also been observed. Mild to moderate mucositis and stomatitis have occurred in some cancer patients, but this is rare in pneumocystis carinii pneumonia patients.

Recommended method to remove /methotrexate/: charcoal hemoperfusion. /Methotrexate/

Leucovorin preferably should be given within the first hour after overdose; therefore, the initial route should be iv using a dose equal to amount of folic acid antagonist consumed. Thereafter, oral doses (15 mg) should be given every 6 hr for methotrexate. /Methotrexate/

Inadvertent intrathecal overdosage of methotrexate constitutes a medical emergency, requiring prompt treatment and management. Although data are limited, management may be guided by the dose administered, time elapsed since administration, and anticipated severity of neurotoxicity. Regardless of the dose administered, as soon as the overdose is recognized, a repeat lumbar puncture should be performed immediately and CSF allowed to drain to gravity. The efficacy of CSF drainage alone as a means for removing the drug is a function of the dose administered and time elapsed since administration, and decreases as these factors increase. If the dose exceeds 100 mg, prompt neurosurgical intervention with ventriculolumbar perfusion following immediate CSF drainage should be considered; continuous CSF drainage or multiple CSF exchanges may also be considered but are not likely to be as effective. Other treatment measures may include high-dose parenteral leucovorin calcium therapy to minimize systemic toxicity, corticosteroids to minimize CNS inflammatory reactions, and other supportive therapy as necessary. While the addition of leucovorin to the ventriculolumbar perfusion fluid has been suggested and employed, its value is not known and the possibility that it may be epileptogenic via this route of administration should be considered. The possible benefits of prophylactic anticonvulsant therapy are probably outweighed by the potential for obscuring acute neurologic symptoms and causing additional adverse effects. /Methotrexate/

In cases of overdosage of methotrexate, leucovorin calcium, a potent folic acid antagonist antidote, should be administered as soon as possible, preferably within the first hr. Use of leucovorin calcium after an hr's delay is much less effective. In general, the dose of leucovorin calcium should be equal to or greater than that of methotrexate. When large doses or overdoses of methotrexateare given, leucovorin calcium may be administered by iv infusion in doses up to 75 mg within 12 hr, followed by 12 mg im every 6 hr for 4 doses. Other leucovorin calcium dosage regimens are also recommended. When average doses of methotrexate appear to have an adverse effect, 6-12 mg of leucovorin calcium may be given im every 6 hr for 4 doses. Leucovorin calcium has been administered several hr following high-dose methotrexate therapy in an effort to control the duration of exposure of sensitive cells to methotrexate ("leucovorin rescue"); the manufacturers warn that this procedure is considered investigational and hazardous. /Methotrexate/

Substances that destroy fungi by suppressing their ability to grow or reproduce. They differ from FUNGICIDES, INDUSTRIAL because they defend against fungi present in human or animal tissues.

Antimetabolites that are useful in cancer chemotherapy.

Inhibitors of the enzyme, dihydrofolate reductase (TETRAHYDROFOLATE DEHYDROGENASE), which converts dihydrofolate (FH2) to tetrahydrofolate (FH4). They are frequently used in cancer chemotherapy. (From AMA, Drug Evaluations Annual, 1994, p2033)

Ten to 30% of the administered dose is excreted unchanged in the urine.

20 ± 8 L/m2

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]

Clinical pharmacokinetic studies in cancer patients show that trimetrexate plasma concentration-time curves are biphasic or triphasic in form. The terminal elimination half-life averages 13.6 hr. Mean total plasma clearance and volume of distribution as steady-state values were 27.9 ml/min/sq m and 21.1 l/sq m, respectively. Cerebrospinal fluid concentration was 3.4% of that in plasma, which shows that trimetrexate does not cross the blood-brain barrier well. Trimetrexate is 86 to 94% bound to plasma proteins.

Mean oral bioavailability of the parenteral solution (glucuronate) in AIDS patients was 42%, with a mean maximum plasma concentration of 1182 ng/ml (3.2 umole/l) achieved 1.8 hr postdose. /Trimetrexate glucuromate/