Methotrexate
Methotrexate (MTX) is a potent **folic acid antagonist** used in veterinary oncology primarily for the treatment of **lymphoproliferative disorders** (such as lymphoma) and certain solid tumors in dogs and cats. Beyond its antineoplastic properties, it possesses significant **immunosuppressive** capabilities, making it a valuable option for refractory immune-mediated conditions, such as feline non-suppurative cholangitis/cholangiohepatitis that has not responded to standard prednisolone or chlorambucil therapy. **Clinical Pearl:** Because MTX has a very narrow therapeutic index and relies heavily on renal clearance, patient hydration and kidney function are paramount to preventing severe toxicity. It is highly toxic to rapidly dividing cells, meaning the gastrointestinal epithelium and bone marrow are particularly susceptible to collateral damage.
Mechanism: Methotrexate is an **S-phase specific antimetabolite**. It acts by competitively and irreversibly inhibiting the enzyme **dihydrofolate reductase (DHFR)**. * Folic acid โ (via DHFR) โ Dihydrofolate โ (via DHFR) โ **Tetrahydrofolate** (active form). * By blocking DHFR, MTX prevents the reduction of dihydrofolate to tetrahydrofolate. * Tetrahydrofolate is an essential cofactor for the synthesis of purines and pyrimidines (specifically thymidylate). * The depletion of these precursors halts DNA, RNA, and protein synthesis, ultimately leading to apoptosis in rapidly proliferating cells (e.g., neoplasms, bone marrow, GI tract epithelium). > **Note:** DHFR has a much greater affinity for MTX than for folic acid. Therefore, coadministration of folic acid will not reverse MTX toxicity. **Leucovorin calcium** (a derivative of tetrahydrofolic acid that bypasses the blocked enzyme) is required as a rescue agent.
Dosing by species
- For susceptible neoplastic diseases (usually as part of a multi-drug protocol) ยท 2.5 mg/m2 PO 2-3 times weekly; 0.3-0.8 mg/m2 IV every 7 days ยท PO/IV ยท 2-3 times weekly (PO) or every 7 days (IV)
- For non-suppurative cholangitis/cholangiohepatitis (CCHC) syndrome with fibrosis ยท A total dose of 0.4 mg per cat total dose given on one day in three divided doses: 0.26 mg at hour zero, 0.13 mg at the 12 and 24 hour dosing. Repeat every 7-10 days. ยท PO ยท Divided over 24 hours, repeated every 7-10 days ยท Use in conjunction with ursodeoxycholic acid (15 mg/kg PO q24h) and folate (0.25 mg/kg PO q24h).
- As part of the LMP protocol for maintenance of canine lymphoma ยท 2.5-5 mg/m2 PO twice a week ยท PO ยท twice a week ยท Given with Chlorambucil 20 mg/m2 PO every 15 days and Prednisone 20 mg/m2 PO every other day. When Vincristine is added it is at a dose of 0.5-0.7 mg/m2 and is given every 15 days alternating weeks with the chlorambucil.
- In combination with other antineoplastics (per protocol) ยท 5 mg/m2 PO twice weekly or 0.8 mg/kg IV every 21 days; alternatively 2.5 mg/m2 PO daily ยท PO/IV ยท twice weekly, every 21 days, or daily
Doses are a clinical reference for licensed veterinary professionals. Always confirm against the current label and the individual patient.
Routes of administration
Contraindications
- Preexisting bone marrow depression
- Severe hepatic insufficiency
- Severe renal insufficiency
- Hypersensitivity to the drug
- Pregnancy (Teratogenic/Embryotoxic - FDA Category X)
- Nursing mothers
- Pre-existing severe bone marrow suppression
- Severe renal impairment
- Severe hepatic impairment
- Pregnancy and lactation (teratogenic and embryotoxic)
- Patients with significant third-space fluid accumulations (e.g., ascites, pleural effusion)
Adverse effects
- Diarrhea
- Nausea
- Vomiting
- Inappetence (especially in cats)
- GI toxicity (ulcers, mucosal sloughing, stomatitis)
- Hematopoietic toxicity / Myelosuppression (nadir at 4-6 days)
- Hepatopathy
- Renal tubular necrosis
- Alopecia
- Depigmentation
- Pulmonary infiltrates and fibrosis
- CNS toxicity (encephalopathy) if given intrathecally
- Anaphylaxis (rare)
- Myelosuppression (neutropenia, thrombocytopenia, anemia)
- Gastrointestinal toxicity (anorexia, vomiting, diarrhea, stomatitis)
- Hepatotoxicity (elevated liver enzymes)
Drug interactions
- Amiodarone ยท Prolonged PO administration (>2 weeks) may inhibit MTX metabolism
- Asparaginase ยท Given concomitantly with MTX may decrease MTX efficacy
- Azathioprine ยท Potential for increased risk for hepatic toxicity
- Chloramphenicol ยท May displace MTX from plasma proteins increasing risk for toxicity, but also may reduce MTX absorption and enterohepatic recirculation
- Cisplatin ยท May have synergistic action with MTX, but alter the renal elimination of MTX
- Cyclosporine ยท May increase MTX levels
- Folic Acid ยท May reduce MTX efficacy, but folate deficiency increases MTX toxicity
- Neomycin (oral) ยท May decrease the absorption of oral methotrexate if given concomitantly
- NSAIDs / Salicylates ยท Severe hematologic and GI toxicity risk; use caution in dogs also on MTX
- Penicillins ยท May decrease MTX renal elimination ยท moderate
- Probenecid ยท May inhibit the tubular secretion of MTX and increase its half-life ยท major
- Pyrimethamine ยท A similar folic acid antagonist; may increase MTX toxicity and should not be given to patients receiving MTX
Monitoring
- Efficacy of treatment
- Clinical signs of GI irritation and ulceration
- Complete blood counts (with platelets) weekly early in therapy, then every 4-6 weeks (Discontinue if WBC <4000/mm3 or platelets <100,000/mm3)
- Baseline and ongoing renal function tests
- Baseline and ongoing hepatic function tests (liver enzymes)
- Complete Blood Count (CBC) - baseline and prior to each dose (monitor for nadir)
- Renal function panel (BUN, Creatinine, Urinalysis)
- Hepatic enzymes (ALT, AST, ALP, Bilirubin)
- Clinical signs of gastrointestinal toxicity (vomiting, diarrhea, anorexia)
- Hydration status
Overdose
Acute overdosage in dogs is associated with severe exacerbations of adverse effects, particularly **myelosuppression** and **acute renal failure**. Acute tubular necrosis occurs secondary to drug precipitation in the renal tubules. * **Toxicity Thresholds:** In dogs, the maximally tolerated dose is reported to be 0.12 mg/kg q24h for 5 days. A dose of 10 mg/kg is considered lethal if leucovorin rescue is not performed. * **Decontamination:** Empty the gut and prevent absorption using standard protocols if ingestion is recent. Oral neomycin has been suggested to help prevent intestinal absorption. * **Renal Protection:** Forced alkaline diuresis should be considered to minimize renal damage. Maintain urine pH between 7.5-8 by adding 0.5-1 mEq/kg of sodium bicarbonate per 500 mL of IV fluid. * **Antidote:** **Leucovorin calcium** is the specific therapy for MTX overdoses. It must be given as soon as possible (preferably within the first hour, definitely within 48 hours). Dogs treated with leucovorin at 15 mg/m2 every 3 hours IV for 8 doses, then IM q6h for 8 doses were able to tolerate very high MTX doses.
VetSheet drug reference is intended for licensed veterinary professionals as a clinical decision-support aid, not a substitute for professional judgement or the manufacturerโs current label.