impact of high-dose methotrexate on intracellular 6-mercaptopurine disposition during interval therapy of childhood acute lymphoblastic leukemia

• Published in: Cancer chemotherapy and pharmacology 2010-09, Vol.66 (4), p.653-658
• Main Authors: Adam de Beaumais, T, Dervieux, T, Fakhoury, M, Medard, Y, Azougagh, S, Zhang, D, Yakouben, K, Jacqz-Aigrain, E
• Format: Article
• Language: English
• Subjects: Adolescent; Antimetabolites, Antineoplastic - adverse effects; Antimetabolites, Antineoplastic - pharmacokinetics; Antimetabolites, Antineoplastic - therapeutic use; Antineoplastic agents; Biological and medical sciences; Biotransformation; Cancer Research; Child; Child, Preschool; Drug Interactions; Erythrocytes - metabolism; Female; Hematologic and hematopoietic diseases; Humans; Inactivation, Metabolic - physiology; Injections, Intravenous; leukemia; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Medicine; Medicine & Public Health; Mercaptopurine; Mercaptopurine - administration & dosage; Mercaptopurine - pharmacokinetics; Mercaptopurine - therapeutic use; methotrexate; Methotrexate - adverse effects; Methotrexate - therapeutic use; Methotrexate polyglutamates; Oncology; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Thioguanine - metabolism; Thioguanine nucleotides
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-009-1205-4

Purpose Low-dose methotrexate (MTX) therapy is the cornerstone treatment of acute lymphoblastic leukemia (ALL) and may enhance the activation of 6-mercaptopurine (6-MP) to 6-thioguanine nucleotides (6-TGN). Yet, data have established that high-dose MTX (HDMTX) hampers the accumulation of 6-TGN in red blood cells (RBC) and lymphoblasts. Methods To clarify the pharmacokinetic interactions between these two antimetabolites, we serially measured RBC 6-TGN and MTX polyglutamates (MTXPG) levels following repeated courses of HDMTX (5 g/m² over 24 h) with daily oral 6-MP (25 mg/m²) during interval therapy in 20 children with ALL. Results HDMTX produced a rapid reduction in RBC 6-TGN 24 h after the start of MTX, and this effect was sustained at least by the third day (median decrease −21%; P < 0.001). However, a return to pre-infusion of 6-TGN levels was observed by the time of the following HDMTX course 14 days later (P < 0.001). RBC MTX polyglutamates accumulation followed Michaelis-Menten kinetics but was not associated with the change in pre-infusion 6-TGN levels which remained stable during the interval period. Conclusion HDMTX does not appear to enhance 6-MP activation to 6-TGN. Moreover, given that the deleterious effect of HDMTX on intracellular 6-MP disposition has been shown to be several folds greater in lymphoblasts than in RBC. Our data warrant additional studies elucidating the optimal MTX dose synergizing with 6-MP.