METHOTREXATE-FOLATE INTERPLAY: FROM PHARMACOLOGICAL MECHANISMS TO CLINICAL TOXICITY MANAGEMENT

Methotrexate (MTX) is an established therapeutic agent used extensively in oncology and the management of chronic inflammatory and autoimmune disorders. Despite its clinical effectiveness, MTX may produce adverse effects involving the gastrointestinal tract, liver, bone marrow, and other rapidly dividing tissues. Many of these toxicities are associated with interference with folate-dependent metabolic pathways. Folate supplementation has therefore become an important strategy for improving the safety and tolerability of MTX therapy. This review examines the pharmacological basis of the interaction between MTX and folate, the clinical benefits of folic acid supplementation, and the role of folinic acid in the management of MTX toxicity. MTX inhibits dihydrofolate reductase and, following intracellular polyglutamation, affects several folate-dependent pathways involved in nucleotide synthesis and cellular metabolism. In low-dose MTX therapy, additional mechanisms, including altered purine metabolism and adenosine signalling, contribute to its anti-inflammatory effects. Evidence from clinical studies and systematic reviews indicates that folic acid supplementation can reduce several MTX-associated adverse effects, particularly gastrointestinal symptoms, oral mucosal toxicity, and elevations in hepatic enzymes, without substantially compromising the therapeutic efficacy of low-dose MTX. In contrast, folinic acid (leucovorin) has a distinct role as rescue therapy following high-dose MTX treatment and in clinically significant MTX toxicity. Management of severe toxicity may also require hydration, urinary alkalinisation, monitoring of serum MTX concentrations and renal function, and, in selected cases, glucarpidase. Recent research has further explored oxidative stress, intestinal injury, and pharmacogenetic factors as potential contributors to MTX toxicity, although their clinical applications require further validation. Overall, appropriate folate supplementation represents an important component of safe MTX therapy, while individualized monitoring and timely rescue remain essential for preventing and managing serious toxicity.