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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Molecular, biochemical, and cellular pharmacology of pemetrexed.

Pemetrexed is a new-generation antifolate that in its higher polyglutamyl forms is a potent, direct inhibitor of thymidylate synthase and, to a lesser extent, glycinamide ribonucleotide transformylase. Activity of the drug may be partially preserved under conditions in which cells are highly resistant to other thymidylate synthase inhibitors, possibly because of premetrexed's secondary inhibitory effects on purine synthesis. Pemetrexed inhibition of dihydrofolate reductase is not of pharmacologic importance. Pemetrexed has high affinity for the reduced folate carrier and folate receptor and is among the most potent substrates for folylpolyglutamate synthetase. These properties result in rapid accumulation of the free drug in cells with the rapid formation of high levels of the active polyglutamyl congeners. Pemetrexed activity is modulated by natural folates within cells that compete for polyglutamation at the level of folylpolyglutamate synthetase. Cells resistant to methotrexate because of impaired transport via the reduced folate carrier may retain partial sensitivity to pemetrexed. This is due to concurrent diminished transport of physiologic reduced folates and contraction of the cellular folate pool, thereby relaxing the usual level of suppression of pemetrexed polyglutamation. The risk of pemetrexed toxicity is increased when cellular folates are suboptimal. This is best monitored by assessment of blood homocysteine levels, and can be diminished by the coadministration of folic acid.[1]


  1. Molecular, biochemical, and cellular pharmacology of pemetrexed. Goldman, I.D., Zhao, R. Semin. Oncol. (2002) [Pubmed]
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