Methotrexate - Pharmacokinetics

Pharmacokinetics

Methotrexate is a weak dicarboxylic acid with pKa 4.8 and 5.5, and thus it is mostly ionized at physiologic pH. Oral absorption is saturatable and thus dose-dependent, with doses less than 40 mg/m2 having 42% bioavailability and doses greater than 40 mg/m2 only 18%. Mean oral bioavailability is 33% (13-76% range), and there is no clear benefit to subdividing an oral dose. Mean intramuscular bioavailability is 76%.

Methotrexate is metabolized by intestinal bacteria to the inactive metabolite 4-amino-4-deoxy-N-methylpteroic acid (DAMPA), which accounts for less than 5% loss of the oral dose.

Factors that decrease absorption include food, oral nonabsorbable antibiotics (e.g. vancomycin, neomycin, and bacitracin), and more rapid transit through the gastrointestinal tract (GI) tract, such as diarrhea, while slower transit time in the GI tract from constipation will increase absorption. Methotrexate is also administered in the placenta accreta, inhibiting the blood circulation to the target site.