The impact of high-dose methotrexate on intracellular 6-mercaptopurine disposition during interval therapy of childhood acute lymphoblastic leukemia.
OBJECTIVE
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/m(2) over 24 h) with daily oral 6-MP (25 mg/m(2)) 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.


CONCLUSIONS
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.
Adam  de Beaumais
T
T
Department of Pediatric Pharmacology and Pharmacogenetics, Robert Debre Hospital, 48 Boulevard Serurier, Paris, France.
Dervieux
T
T
Fakhoury
M
M
Medard
Y
Y
Azougagh
S
S
Zhang
D
D
Yakouben
K
K
Jacqz-Aigrain
E
E
D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001711:Biotransformation; D002648:Child; D002675:Child, Preschool; D004347:Drug Interactions; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D006801:Humans; D008658:Inactivation, Metabolic / Q000502:physiology; D007275:Injections, Intravenous; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008727:Methotrexate / Q000009:adverse effects* / Q000627:therapeutic use; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism*; D013866:Thioguanine / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D015122:Mercaptopurine; D013866:Thioguanine; D008727:Methotrexate