Polyglutamation is a time- and concentration-dependent process that occurs in tumor cells and, to a lesser extent, in normal tissues. The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT. Once in the cell, pemetrexed is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. Pempro is transported into cells by both the reduced folate carrier and membrane folate binding protein transport systems. In vitro studies have shown that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), all folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Pempro is an antifolate containing the pyrrolopyrimidine-based nucleus that exerts its antineoplastic activity by disrupting folate-dependent metabolic processes essential for cell replication.
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