PMID- 10594482
OWN - NLM
STAT- MEDLINE
DCOM- 20000127
LR  - 20190513
IS  - 0306-5251 (Print)
IS  - 1365-2125 (Electronic)
IS  - 0306-5251 (Linking)
VI  - 48
IP  - 6
DP  - 1999 Dec
TI  - Thiopurine methyltransferase activity and its relationship to the occurrence of 
      rejection episodes in paediatric renal transplant recipients treated with 
      azathioprine.
PG  - 793-800
AB  - AIMS: Azathioprine is a prodrug commonly used in combination therapy to prevent 
      allograft rejection after renal transplantation. After conversion to 
      6-mercaptopurine, the drug is metabolized into 6-thioguanine nucleotides (6-TGN) 
      and catabolized by thiopurine methyltransferase (TPMT), an enzyme under monogenic 
      control. The aim of this study was to evaluate the inter- and intraindividual 
      variability of red blood cell thiopurine methyltransferase and 6-TGN 
      concentrations and their relationship to the clinical effects of azathioprine in 
      paediatric patients. METHODS: In the present study, the inter- and 
      intraindividual variations in red blood cell TPMT activity and 6-TGN 
      concentrations and their relationship to the actions of azathioprine were 
      evaluated during the first year after renal transplantation in 22 paediatric 
      patients. RESULTS: 6-TGN concentration reached steady-state values after 6 months 
      and correlated negatively with TPMT activity (P=0.004). Initial TPMT activity 
      (median: 20.8 nmol h-1 ml-1, range 7.8-34.6) and 6-TGN concentration at 
      steady-state (median: 80 pmol 8 x 10(8-1) cells, range not detected to 366) were 
      not related to the occurrence of rejection episodes during the period of the 
      study. In contrast, TPMT activity and the percentage difference in TPMT activity 
      from the day of transplantation determined at month 1 were higher in the patients 
      with rejection episodes by comparison with those that did not reject during the 
      first 3 months or the first year following transplantation (P<0.005). 
      CONCLUSIONS: We report a relationship between TPMT activity and occurrence of 
      rejection in paediatric kidney transplant patients undergoing azathioprine 
      therapy. These data suggest a link between high red blood cell TPMT activity and 
      poor clinical outcome probably caused by rapid azathioprine catabolism.
FAU - Dervieux, T
AU  - Dervieux T
AD  - Unite de Pharmacologie Pediatrique, Hopital Robert Debre, Paris, France.
FAU - Medard, Y
AU  - Medard Y
FAU - Baudouin, V
AU  - Baudouin V
FAU - Maisin, A
AU  - Maisin A
FAU - Zhang, D
AU  - Zhang D
FAU - Broly, F
AU  - Broly F
FAU - Loirat, C
AU  - Loirat C
FAU - Jacqz-Aigrain, E
AU  - Jacqz-Aigrain E
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Br J Clin Pharmacol
JT  - British journal of clinical pharmacology
JID - 7503323
RN  - 0 (Antimetabolites)
RN  - 0 (Guanine Nucleotides)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Prodrugs)
RN  - 0 (Thionucleotides)
RN  - 15867-02-4 (6-thioguanylic acid)
RN  - EC 2.1.1.- (Methyltransferases)
RN  - EC 2.1.1.67 (thiopurine methyltransferase)
RN  - MRK240IY2L (Azathioprine)
SB  - IM
MH  - Antimetabolites/*pharmacology
MH  - Azathioprine/*pharmacology
MH  - Child
MH  - Chromatography, High Pressure Liquid
MH  - Female
MH  - Genotype
MH  - Graft Rejection/*metabolism
MH  - Guanine Nucleotides/blood/metabolism
MH  - Humans
MH  - Immunosuppressive Agents/*pharmacology
MH  - *Kidney Transplantation/physiology
MH  - Male
MH  - Methyltransferases/blood/genetics/*metabolism
MH  - Prodrugs/*pharmacology
MH  - Thionucleotides/blood/metabolism
PMC - PMC2014314
EDAT- 1999/12/14 00:00
MHDA- 1999/12/14 00:01
PMCR- 2000/06/01
CRDT- 1999/12/14 00:00
PHST- 1999/12/14 00:00 [pubmed]
PHST- 1999/12/14 00:01 [medline]
PHST- 1999/12/14 00:00 [entrez]
PHST- 2000/06/01 00:00 [pmc-release]
AID - bcp087 [pii]
AID - 10.1046/j.1365-2125.1999.00087.x [doi]
PST - ppublish
SO  - Br J Clin Pharmacol. 1999 Dec;48(6):793-800. doi: 
      10.1046/j.1365-2125.1999.00087.x.