Critical Care Medicine-Hematologic and Oncologic Disorders>>>>>Complications of Immunosuppressive Drugs and Chemotherapy
Question 2#

Which of the following statements about methotrexate toxicity is correct?

A. Folate supplementation prevents pulmonary toxicity
B. Approximately 15% of patients may experience an erythematous morbilliform drug rash
C. Hepatotoxicity is not a significant concern
D. The drug is primarily metabolized by the liver
E. Leucovorin is typically administered 72 to 96 hours after high-dose methotrexate

Correct Answer is B

Comment:

Correct Answer: B

Rapidly dividing cells require high amounts of folates for DNA synthesis. Methotrexate competitively inhibits an enzyme that reduces folate derivatives into molecules suitable for thymidine synthesis, thus preferentially affecting cells in s-phase. Up to 90% of methotrexate is excreted unchanged in the urine. Leucovorin is a reduced folate that bypasses the enzyme inhibited by methotrexate and can rescue cells that have not suffered severe DNA damage from high-dose methotrexate. To be effective, leucovorin must be initiated approximately 24 to 36 hours after methotrexate. In one study, up to 16% of patients receiving high-dose methotrexate develop an erythematous rash. Hepatotoxicity ranging from asymptomatic elevations in transaminases to cirrhosis can occur with highor low-dose methotrexate, and alcohol and other hepatotoxic medications should be avoided. Similarly, pulmonary toxicity that typically takes the form of hypersensitivity pneumonitis may occur with low-dose chronic use of methotrexate or after high doses of the drug, in which case leucovorin does not appear to reduce the risk.

References:

1. Howard SC, McCormick J, Pui C-H, Buddington RK, Harvey RD. Preventing and managing toxicities of high-dose methotrexate. Oncologist. 2016;21:1471-1482.
2. Hansen HH, Selawry OS, Holland JF, McCall CB. The variability of individual tolerance to methotrexate in cancer patients. Br J Cancer. 1971;25:298-305.
3. Bath RK, Brar NK, Forouhar FA, Wu GY. A review of methotrexate- associated hepatotoxicity. J Dig Dis. 2014;15:517-524.
4. Lateef O, Shakoor N, Balk RA. Methotrexate pulmonary toxicity. Expert Opin Drug Saf. 2005;4:723-730.