Methotrexate (MTX)
- Often used with IBD therapies as prevention of HACA (antibody)
formation to biologics
- Risk of hepatotoxicity
- Monitor Transaminases
- Every 2wks for the first 6wks on MTX
- Then every 2-3mo (or with infusions)
- Elevations common (10% of patients), usually transient
- If transaminase levels remain >3x ULN on serial exams,
methotrexate should be discontinued due to risk of
developing progressive fibrosis
- Restarting methotrexate can be attempted at a lower dose
after the labs have normalized
- The use of folate with methotrexate significantly
reduces the risk of hepatotoxicity
- Reduces incidence of nausea and vomiting while taking
methotrexate
- No advantage to daily or weekly dosing of folate
Risk factors for methotrexate hepatotoxicity include:
-
Obesity
-
Diabetes mellitus
-
Lack of folate supplementation
-
Alcohol use
-
Preexisting liver disease
Mechanism of action: not fully understood
Methotrexate inhibits dihydrofolate reductase, inhibiting purine
synthesis, thereby inhibiting DNA and RNA replication
Methotrexate alters multiple cellular pathways, including increased
adenosine signaling as well as down-regulation of cytokines,
eicosanoids, and adhesion molecules.
Methotrexate is metabolized by the liver (first-pass hepatic
metabolism) and about 10% is excreted in bile.
After methotrexate enters peripheral blood cells, it undergoes
polyglutamylation, (varying chain lengths of glutamate metabolites
are made). The enzymatic processes of these glutamate metabolites
contribute to the steady state of the drug