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Methotrexate

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Mechanism of Action
Dose Adjustments
Toxicities
Prevention & Overcoming Toxicities

Analogue of folic acid

1. Inhibits DIHYDROFOLATE REDUCTASE therefore decreasing the pool of REDUCED FOLATES in the cell
2. Inhibits PURINE & THYMIDYLATE synthesis
3. Inhibits DNA synthesis & function by misincorporating dUTP into DNA

TOXICITIES
1. Myelosuppression - Leukocytes nadir at 4-7 days & 12-21 days (biphasic), thrombocytpenia around day 7
2. Mucositis
3. Nephrotoxicity - ARF 2ndary to ppt MTX
4. Pneumonitis (interstitial changes)
5. Hepatotoxicity - transient elevation LFTs, fatal hepatic fibrosis/cirrhosis
6. Neurotoxicity with IT or high dose regimen
7. Mod-high potential N/V at high doses >250 mg/m2
8. Repro- reversible testicular dysfunction

To overcome & preven toxicities:
1. Leucovorin rescue - standard
start 24 hr after beginning HD MTX. Start dise is 10-15 mg/m2, continue until MTX level <0.05-0.1 uM. Check MTX levels at T=0, 24 hr, and then Q24 hr until MTX<0.05-0.1 uM.
2. Thymidine rescue- 72 hr infusion of 8 grams/m2/day
3. Carboxypeptidase G1 or G2 - removes glutamates from methotrexate

Dose
IT injection in adults: 12 mg Q2-5 days until CSF count is normal
IV: variable

Dose adjustments
--Hepatic: none needed
--renal: Creatinine Clearance:80-->use 75%; 60-79-->use 63%; 50-59-->use 56%
--increased t 1/2 in patients with bladder cancer who are s/p ileal conduit diversion.

Note: Methotrexate exits slowly from 3rd space. Fluid collections should be drained before methotrexate treatment.