Methotrexate
Methotrexate. Folate antagonist — inhibits DHFR → reduces tetrahydrofolate → impairs thymidine + purine synthesis. Low-dose immunosuppressive… Oral half-life 6 h.
Folate antagonist — inhibits DHFR → reduces tetrahydrofolate → impairs thymidine + purine synthesis. Low-dose immunosuppressive mechanism is AICAR accumulation → adenosine release → anti-inflammatory. Leucovorin (folinic acid) is the antidote for overdose.
PK: zero-content on the whole oral block, and the intravenous row hung on an oral-only study. Re-sourced to Herman 1989 (PMID:2715941), 41 patients dosed 10 mg/m2 orally and intravenously a week apart: "the oral bioavailability was 0.70", "The terminal half-life was approximately 6 h", and "The volumes of distribution at steady state and for the central compartment were 22.2 and 13.5 L/m2" — the steady-state figure scaled at 1.73 m2 gives 38 L, an intravenous-derived TRUE volume. The stored 8 h was the upper endpoint of a review "5 to 8 hours". F 0.70 IS VALID ONLY AT LOW DOSE: absorption is saturable, and a 50 mg oral dose yields only 1.1 to 2.7 times the exposure of 15 mg, so above roughly 25 mg this over-predicts. The subcutaneous and intramuscular routes on this record ARE supportable — "Intramuscular and subcutaneous injections of methotrexate result in comparable pharmacokinetics, suggesting that these routes of administration are interchangeable" — though no absorption rate exists for either. EFFECT IS DECOUPLED: "No clear relationship between pharmacokinetic parameters and clinical response has been demonstrated", and the active polyglutamates are retained inside cells.
Pharmacokinetics
- Oral — t½ 6 h · F 70% · Vd 38 L
- IV — t½ 6 h · F 100% · Vd 38 L
Related compounds
- Folic Acid — caution
Sources: PMID:8882301, PMID:27496039, PMID:2715941, PMID:3199396