PMID- 20033410
OWN - NLM
STAT- MEDLINE
DCOM- 20100803
LR  - 20171116
IS  - 1432-0843 (Electronic)
IS  - 0344-5704 (Linking)
VI  - 66
IP  - 4
DP  - 2010 Sep
TI  - The impact of high-dose methotrexate on intracellular 6-mercaptopurine 
      disposition during interval therapy of childhood acute lymphoblastic leukemia.
PG  - 653-8
LID - 10.1007/s00280-009-1205-4 [doi]
AB  - 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/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. 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.
FAU - Adam de Beaumais, T
AU  - Adam de Beaumais T
AD  - Department of Pediatric Pharmacology and Pharmacogenetics, Robert Debre Hospital, 
      48 Boulevard Serurier, Paris, France.
FAU - Dervieux, T
AU  - Dervieux T
FAU - Fakhoury, M
AU  - Fakhoury M
FAU - Medard, Y
AU  - Medard Y
FAU - Azougagh, S
AU  - Azougagh S
FAU - Zhang, D
AU  - Zhang D
FAU - Yakouben, K
AU  - Yakouben K
FAU - Jacqz-Aigrain, E
AU  - Jacqz-Aigrain E
LA  - eng
PT  - Journal Article
DEP - 20091223
PL  - Germany
TA  - Cancer Chemother Pharmacol
JT  - Cancer chemotherapy and pharmacology
JID - 7806519
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - E7WED276I5 (Mercaptopurine)
RN  - FTK8U1GZNX (Thioguanine)
RN  - YL5FZ2Y5U1 (Methotrexate)
SB  - IM
MH  - Adolescent
MH  - Antimetabolites, Antineoplastic/*adverse effects/*pharmacokinetics/therapeutic 
      use
MH  - Biotransformation
MH  - Child
MH  - Child, Preschool
MH  - Drug Interactions
MH  - Erythrocytes/metabolism
MH  - Female
MH  - Humans
MH  - Inactivation, Metabolic/physiology
MH  - Injections, Intravenous
MH  - Male
MH  - Mercaptopurine/administration & dosage/*pharmacokinetics/therapeutic use
MH  - Methotrexate/*adverse effects/therapeutic use
MH  - Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/*metabolism
MH  - Thioguanine/metabolism
EDAT- 2009/12/25 06:00
MHDA- 2010/08/04 06:00
CRDT- 2009/12/25 06:00
PHST- 2009/08/27 00:00 [received]
PHST- 2009/11/27 00:00 [accepted]
PHST- 2009/12/25 06:00 [entrez]
PHST- 2009/12/25 06:00 [pubmed]
PHST- 2010/08/04 06:00 [medline]
AID - 10.1007/s00280-009-1205-4 [doi]
PST - ppublish
SO  - Cancer Chemother Pharmacol. 2010 Sep;66(4):653-8. doi: 10.1007/s00280-009-1205-4. 
      Epub 2009 Dec 23.