New Findings in Methotrexate Pharmacology – Diagnostic Possibilities and Impact on Clinical Care
Authors:
Řiháček M. 1 3; Pilátová K. 1 3; J. Štěrba 1,3; Pilný R. 1 3; Valík D. 1 3
Authors‘ workplace:
Klinika dětské onkologie LF MU a FN Brno
1; Oddělení laboratorní medicíny, Masarykův onkologický ústav, Brno
2; Regionální centrum aplikované molekulární onkologie, Masarykův onkologický ústav, Brno
3
Published in:
Klin Onkol 2015; 28(3): 163-170
Category:
Reviews
doi:
https://doi.org/10.14735/amko2015163
Overview
Methotrexate is an anti-cancer drug used to treat several malignancies including pediatric acute lymphoblastic leukemia and choriocarcinoma. Despite recent advances in cancer chemotherapy, it remains a mainstay of therapy since its discovery in the early second half of the previous century. Moreover, low-dose methotrexate is a gold standard antirheumatic drug in the treatment of rheumatoid arthritis, psoriasis, systemic scleroderma and other autoimmune disorders. Side effects of methotrexate treatment are well known and described; however, their occurrence may often be unpredictable due to lack of specific biomarkers of toxicity. Methotrexate plasma levels are routinely monitored by therapeutic drug monitoring, nevertheless, occurrence and concentrations of its metabolites are not measured. During methotrexate treatment 7- hydroxymethotrexate and 2,4- diamino- N10- mehylpteroic acid appear in plasma. The latter can further be hydroxylated and glucuronidated resulting in five possible extracellular methotrexate metabolites. In addition, methotrexate is intracellularly converted to its active polyglutamylated forms. Therapeutic efficacy is dependent on formation of methotrexate polyglutamates as it keeps intracellular pool of the drug and enhances its affinity towards various target enzymes. In this study, we describe pharmacokinetic and pharmacodynamic characteristics of methotrexate metabolites. We also review methotrexate blood brain barrier transport to cerebrospinal fluid regarding its use in the prevention of leukemic central nervous system involvement and management of methotrexate toxicity with the use of carboxypeptidase- G2. Finally, we discuss laboratory methods for monitoring methotrexate metabolites and benefits of simultaneous determination of methotrexate and metabolites as possible biomarkers of therapeutic efficacy and clinical toxicity.
Key words:
methotrexate – 7- hydroxymethotrexate – toxicity – pharmacokinetics – drug monitoring – polyglutamates
This study was supported by European Regional Development Fund and the State budget of the Czech Republic for Regional Centre of Applied Molecular Oncology (RECAMO, CZ.1.05/2.1.00/03.0101), by the project MEYS – NPS I – LO1413 and by IGA Czech Ministry of Health NT14327.
The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.
The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.
Submitted:
27. 3. 2015
Accepted:
28. 4. 2015
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Labels
Paediatric clinical oncology Surgery Clinical oncologyArticle was published in
Clinical Oncology
2015 Issue 3
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