Mechanism of Action of Pemetrexed
Pemetrexed is a multitargeted antifolate that inhibits at least three key enzymes in folate metabolism: thymidylate synthase (TYMS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), thereby disrupting both pyrimidine and purine synthesis required for DNA replication and cell division. 1
Primary Enzymatic Targets
Thymidylate synthase (TYMS) is the most clinically relevant target of pemetrexed, as this enzyme catalyzes the formation of thymidine nucleotides essential for DNA synthesis 2, 3
Dihydrofolate reductase (DHFR) is inhibited by pemetrexed, blocking the reduction of dihydrofolate to tetrahydrofolate, which is necessary for one-carbon transfer reactions in nucleotide biosynthesis 3, 4
Glycinamide ribonucleotide formyltransferase (GARFT) inhibition by pemetrexed disrupts de novo purine synthesis, further impairing DNA and RNA production 3, 5
A fourth enzyme, aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT), is also inhibited by pemetrexed, contributing to its antiproliferative effects through additional disruption of purine synthesis 4, 6
Intracellular Activation and Retention
Pemetrexed requires intracellular polyglutamylation to exert its full antiproliferative activity, with polyglutamate derivatives being the active forms that inhibit the target enzymes 2, 6
Polyglutamylation enhances intracellular retention of pemetrexed and increases its binding affinity to target enzymes, particularly TYMS, making the polyglutamate forms significantly more potent than the parent compound 2, 6
The extent of polyglutamylation varies by tissue type and may contribute to differential sensitivity across tumor histologies 2
Mechanism-Based Clinical Implications
Pegargiminase sensitizes mesothelioma to pemetrexed by suppressing de novo synthesis and salvage of thymidine, as arginine deprivation in ASS1-deficient tumors enhances pemetrexed's inhibition of TYMS 1
Histological subtype predicts pemetrexed efficacy, with non-squamous NSCLC showing superior response compared to squamous-cell histology, likely due to differential intratumoral TYMS expression levels 2
Vitamin supplementation (folic acid and vitamin B12) is mandatory to reduce bone marrow and mucosal toxicity without compromising antitumor efficacy, as these vitamins prevent folate depletion in normal tissues while tumor cells remain sensitive due to their higher proliferative rate 1, 3, 4
Pharmacokinetics Relevant to Mechanism
Pemetrexed undergoes rapid renal elimination as unchanged parent compound with a terminal half-life of 2-5 hours, requiring dose adjustment in renal impairment 2
The drug's rapid clearance necessitates repeated dosing (typically every 21 days at 500 mg/m²) to maintain sustained inhibition of target enzymes 2, 3