Methotrexate

Mechanism

Pharmacological Class and Group

Antimetabolite of the class of Folic Acid Antagonists for systemic use.

Mechanism of Action

Methotrexate has a structure analogous to folic acid, which allows it to competitively bind to multiple key enzymes of monocarbon metabolism.

Mechanism of Enzyme Inhibition and Adenosine Release

1. Inhibition of Dihydrofolate Reductase (DHFR): Methotrexate binds almost irreversibly to the enzyme DHFR, preventing the conversion of dihydrofolate into its reduced active form: tetrahydrofolate (THF):

Methotrexate DHFR ↓ THF Blocking Thymidylate and Purine Synthesis

2. Inhibition of Thymidylate Synthase (TS): By depleting the pool of methylated folates, it indirectly blocks the limiting step in the cellular replication of the hyperproliferative keratinocyte in the psoriasis plaque.

3. Inhibition of AICAR Transformylase (Key Anti-inflammatory Mechanism): At low doses (immunosuppressive/dermatological), it inhibits the enzyme AICAR transformylase, inducing the intracellular accumulation of AICAR. This promotes massive cellular release into the extracellular space of adenosine, a potent anti-inflammatory that binds to the A2a receptors of macrophages and lymphocytes, robustly suppressing the release of TNF-α, IL-12 and IL-23.

Pharmacokinetics

High Resolution Pharmacokinetics

• Absorption: Rapid but saturable oral absorption at high doses by active transport mediated by the reduced folate transporter (RFC-1). Subcutaneous (SC) administration provides 100% bioavailability and significantly reduces adverse digestive effects.
• Distribution: Moderate apparent volume of distribution. Binding to plasma albumin by 50%. It enters the target cells actively and undergoes a process of intracellular polyglutamination (addition of glutamic acid chains), which retains the drug for a long time inside the cells for weeks, preventing its exit.
• Metabolism: Intracellular metabolism to active polyglutamine forms and minor metabolite 7-hydroxymethotrexate. It does not have hepatic clearance significantly mediated by CYP450.
• Excretion: Predominant renal excretion (>80-90%) in unchanged form through glomerular filtration and active tubular secretion mediated by organic anion transporters (OAT1 and OAT3).
• Half-life (t_1/2): Plasma half-life of 3 to 10 hours, but the biological half-life of intracellular polyglutamine metabolites exceeds 7-14 days.

Indicators and dose

Clinical Indications and Off-Label Uses

• Moderate to Severe Plaque Psoriasis: One of the most prescribed classic first-line systemic drugs globally.
• Psoriatic Arthritis: Controls both the skin component and peripheral and axial joint involvement.
• Severe Atopic Dermatitis (off-label / refractory): As a corticosteroid-sparing agent in patients refractory to local therapies.
• Subacute Cutaneous or Systemic Lupus Erythematosus (off-label): Control of refractory discoid and erythematous lesions.

Dosage and Clinical Adjustment

• Recommended Starting Dose: 7.5 mg to 15 mg administered strictly orally or subcutaneously once a week (e.g., every Monday as a single dose).
• Titration: Progressively increase in steps from 2.5 mg to 5 mg weekly according to tolerance and clinical response, up to a usual therapeutic maximum of 20 mg to 25 mg per week.
• Rescue Supplementation with Folic Acid (Mandatory): Administer 5 mg of folic acid orally once a week, strictly setting the intake 24 to 48 hours after the weekly dose of methotrexate (to reduce nausea, stomatitis and prevent macrocytic anemia without reducing the effectiveness of the chemotherapy dose).

Adjustment in Kidney Failure:

• eGFR 60-89 mL/min/1.73 m²: Use with caution, consider reducing dose by 25%.
• eGFR 30-59 mL/min/1.73 m²: Mandatory dose reduction to 50%.
• eGFR < 30 mL/min/1.73 m²: Absolute contraindication for use.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• Pregnancy and Breastfeeding: Proven major teratogen (mutagenic, abortive of medical choice).
• Moderate to severe renal failure (eGFR < 30-45 mL/min/1.73 m²).
• Pre-existing severe liver dysfunction, active non-alcoholic hepatic steatosis or Child-Pugh B or C cirrhosis.
• Serious active chronic infections (active Tuberculosis, decompensated HIV, active Hepatitis B or C).
• Basal myelosuppression (Leukopenia < 3000/mm³, Thrombocytopenia < 100,000/mm³).

Relative Contraindications

• Active and frequent alcohol consumption (high risk of enhancing liver cirrhosis).
• Concomitant use with nephrotoxic drugs or drugs with high plasma protein binding.

Adverse Effects (ADR) and Specific Toxicity

• Very common (>20%): Immediate digestive intolerance (morning sickness, colicky epigastric pain, diarrhea and painful mucosal ulcerative stomatitis).
• Frequent (1%-10%): Transient elevation of transaminases (AST/ALT), fatigue, headache.
• Uncommon (0.1%-1%): Myelosuppression (leukopenia, extreme neutropenia predisposing to sepsis, megaloblastic anemia due to interference with erythropoiesis, thrombocytopenia), Chronic hepatotoxicity with a tendency to cirrhosis, Acute interstitial pneumonitis due to hypersensitivity (potentially fatal, regardless of dose).

Critical Toxicity: Acute Overdosage and the Use of Folinic Acid

Methotrexate in dermatology is administered strictly on a single weekly dose regimen. Prescription errors or accidental daily intake by the patient cause massive acute toxicity with rapid onset that compromises life. It manifests with severe pancytopenia, neutropenic sepsis, diffuse generalized skin peeling (epidermal necrobiosis) and gastrointestinal bleeding mucosal ulcerations.

Accidental Daily Intake Absolute depletion of active folates Total cellular arrest in the Bone Marrow and Intestine

Given clinical suspicion of acute overdose, the use of standard folic acid is ineffective since the DHFR enzyme is blocked. Folinic Acid (Leucovorin / Calcium Folinate) should be administered immediately and as a priority intravenously or intramuscularly, which metabolically bypasses the enzymatic blockade of DHFR by directly providing the necessary reduced tetrahydrofolate.

Drug Interactions of Clinical Relevance

• Nonsteroidal Anti-Inflammatories (NSAIDs) and Salicylates: NSAIDs competitively reduce the active tubular secretion of metextrexate mediated by OAT1/OAT3, dramatically increasing the free plasma concentration and the risk of severe pancytopenia. Avoid or monitor with extreme rigor.
• Sulfamethoxazole/Trimethoprim (Cotrimoxazole): Trimethoprim also acts as a weak inhibitor of bacterial and eukaryotic DHFR. Their joint use synergistically multiplies hematological toxicity, potentially triggering acute spinal cord aplasia.

Safety in Pregnancy and Breastfeeding

• Pregnancy: FDA Category Absolute contraindication. It causes craniofacial, CNS and extremity malformations. Both men and women undergoing treatment must use effective contraception during treatment and maintain it for a minimum of 6 months after definitive discontinuation of methotrexate (due to the intracellular retention time of polyglutamine metabolites).
• Breastfeeding: Absolutely contraindicated due to the excretion of active metabolites that induce immunosuppression and mitotic cell arrest in the infant.