(S)-2-(4-(((2,4-diaminopteridin-6-yl)methyl) (methyl)amino)benzamido)pentanedioic acid

Absorption
Oral absorption is dose dependent. T max is 1 to 2 h (oral) and 30 to 60 min (IM). The mean bioavailability is 60%. Absorption of doses more than 80 mg/m 2 is significantly less, possibly because of a saturation effect. Food delays absorption and reduces peak concentration.

Distribution
Initial Vd is 0.18 L/kg (18% of body weight); steady state Vd is approximately 0.4 to 0.8 L/kg (40% to 80% of body weight). Approximately 50% is protein bound. Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given orally or parenterally, but it has been detected in breast milk.

Metabolism
Methotrexate undergoes hepatic and intracellular metabolism to active polyglutamated forms and is partially metabolized by intestinal flora after oral administration. Major metabolite is 7-hydroxymethotrexate.

Elimination
Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. With IV administration, 80% to 90% is excreted unchanged in urine within 24 h and less than 10% through biliary excretion. The t½ for doses less than 30 mg/m 2 is approximately 3 to 10 h; 8 to 15 h for high doses.

Special Populations
Renal Function Impairment
An increase in serum levels occurs because of decreased elimination in patients with renal function impairment.

Acitretin, etretinate, NSAIDs, penicillins, probenecid, salicylates, sulfonamides, tetracyclines
May increase methotrexate blood levels and toxicity.

Antibiotics (oral) such as chloramphenicol, nonabsorbable broad spectrum antibiotics (eg, neomycin), and tetracycline
May decrease intestinal absorption of methotrexate or interfere with enterohepatic circulation.

Charcoal
May reduce methotrexate efficacy.

Digoxin
May reduce serum digoxin levels and actions.

Folic acid
May decrease responses to systemically administered methotrexate.

Hydantoins
May reduce plasma levels.

Mercaptopurine
Plasma concentrations may be increased by methotrexate.

Theophylline
Methotrexate decreases Cl of theophylline.

Trimethoprim
May increase risk of methotrexate-induced bone marrow suppression and megaloblastic anemia.