Myelosuppression with methotrexate

Methotrexate Inhibits DHFR inhibits TS inhibits de novo purine nucleotide synthesis Breast cancer, head and neck cancer, osteogenic sarcoma, primary central nervous system lymphoma, non-Hodgkin s lymphoma, bladder cancer, chorioca rcinoma Mucositis, diarrhea, myelosuppression with neutropenia and thrombocytopenia... 

Purine analogs and antimetabolites, eg, 6-mercaptopurine, methotrexate Mechanism uncertain may promote apoptosis of immune cells Generalized suppression of immune processes Moderately severe to severe Crohn s disease and ulcerative colitis GI upset, mucositis myelosuppression purine analogs may cause hepatotoxicity, but rare with methotrexate at the low doses used... 

Increased risk of myelosuppression with clozapine, azathioprine, cisplatin, methotrexate... 

METHOTREXATE PENICILLINS t plasma concentrations of methotrexate and risk of toxic effects of methotrexate, e.g. myelosuppression, liver cirrhosis, pulmonary toxicity Penicillins 1 renal elimination of methotrexate by renal tubular secretion, which is the main route of elimination of methotrexate. Penicillins compete with methotrexate for renal elimination. Displacement from proteinbinding sites may occur and is only a minor contribution to the interaction Avoid concurrent use. If concurrent use is necessary, monitor clinically and biochemically for blood dyscrasia, liver toxicity and pulmonary toxicity. Do FBCs and LFTs prior to concurrent treatment... 

Pemetrexed toxicity mirrors that of methotrexate, with the additional feature of a prominent erythematous and pruritic rash in 40% of patients. Dexamethasone, 4 mg twice-daily on days —1, 0, and +1, markedly diminishes this toxicity. Unpredictably severe myelosuppression with pemetrexed, seen especially in patients with preexisting homocystinemia and possibly reflecting folate deficiency, is largely eliminated by concurrent administration of low doses o/folic acid, 0.35—1 mg/day beginning 1—2 weeks prior to pemetrexed and continuing while the drug is administered. Intramuscular vitamin Bj2(I mg) is given with the first dose of pemetrexed to correct possible Bj2 deficiency. There is no evidence that these small doses of folate and Bj compromise the therapeutic effect. 

A study in 9 patients found that neither furosemide nor hydroflumethiazide had any effect on the clearance of methotrexate in the urine. However, a study in women with breast cancer, treated with methotrexate, cyclophosphamide and fluorouracil found that the concurrent use of a thiazide diuretic appeared to increase the myelosuppressant effects, but it is not clear which of the antineoplastics might have been affected. ... 

Nephrotoxicity can be a problem with high doses of methotrexate, but it is less likely to occur than myelosuppression, especially if the patient is well hydrated and the urine is alkalinized. MTX is a weak acid and is more water-soluble at alkaline pH it is thus eliminated more rapidly in alkaline urine. The answer is (D). 

Methotrexate (MTX), a folate antagonist, enjoys limited efficacy against brain tumors due to BBB impermeability and systemic toxicities including myelosuppression and gastrointestinal necrosis (126). Though cisternal or intraventricular MTX infusion offered poor drug dissemination (19,146), broad parenchymal distribution with direct MTX injection (147) suggested promise for local MTX delivery. 

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