MTX is well absorbed orally below 25 mg/m2, but is usually administered IV, except in maintenance regimens and treatment of benign connective tissue diseases. It is eliminated in three phases, the second and third phases each taking 10-24 hours; elimination is considerably lengthened by renal dysfunction. There is some hepatic metabolism to the active drug 7-OH-MTX and approximately 10% of the drug is cleared by biliary excretion. Dose adjustments are not usually necessary with hepatic dysfunction. Significant third-space effects occur in the presence of fluid collections (e.g. ascites, pleural effusions) and can increase toxicity through reduced clearance. MTX excretion can also be inhibited by:

♦ Probenicid

♦ Penicillins (and cephalosporins)

♦ Non-steroidal anti-inflammatory agents

Evidence shows synergy with 5-fluorouracil (5-FU), which is maximal if given 24 hours before the 5-FU. Resistance occurs through:

♦ Impaired uptake

♦ Gene amplification of DHFR

♦ Decreased polyglutamation Toxicities include:

♦ Myelosuppression

♦ Nephrotoxicity

♦ Acute and chronic hepatotoxicity

♦ Self-limiting pneumonitis

♦ Arachnoiditis and chronic demyelination (when given intrathecally)

High-dose MTX has been used in sarcomas, has the advantage of some CSF penetration, and may overcome resistance. Folinic acid can be used to 'rescue' normal cells from undue toxicity, usually given 24 hours after MTX.

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