Generic placeholder image

Current Drug Metabolism


ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

Intracellular Disposition of Methotrexate in Acute Lymphoblastic Leukemia in Children

Author(s): Tiphaine Adam de Beaumais and Evelyne Jacqz-Aigrain

Volume 13, Issue 6, 2012

Page: [822 - 834] Pages: 13

DOI: 10.2174/138920012800840400

Price: $65


Methotrexate (MTX) is a key agent for the treatment of acute lymphoblastic leukemia in children and the benefit of high-dose MTX is well established as it significantly increases cure rates and improves patients’ prognosis. However, the determinants of MTX therapeutic effect are not clearly identified, although intracellular polyglutamation is essential. MTX, the monoglutamate form (MTXG1) inhibits the dihydrofolate reductase (DHFR) implicated in the folate cycle. MTXG1 is metabolized to active methotrexate polyglutamates (MTXPG) with sequential gamma-linkage of 2 to 6 glutamyl residues by the folylpolyglutamate synthetase (FPGS). Long chain MTXPG have higher affinity than MTX for the enzymes involved in de novo purine synthesis such as 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (ATIC) and thymidilate synthase (TS), which results in a reinforcement of MTX inhibition. Thus, intracellular formation of MTXPG enhances the cytotoxic and antileukemic effect of MTX. Different pharmacogenetic polymorphisms contribute to interindividual variability in MTX response to treatment. In addition, pharmacokinetic interactions with 6-mercaptopurine (6-MP), frequently co-administered, have been reported. And factors affecting intracellular MTX disposition and 6-MP/MTX interactions, including pharmacogenetic polymorphisms affecting MTX disposition are reviewed.

Keywords: Methotrexate, acute lymphoblastic leukemia, transport, metabolism, pharmacogenetics, pediatrics

Rights & Permissions Print Export Cite as
© 2023 Bentham Science Publishers | Privacy Policy