PMID- 19086961
OWN - NLM
STAT- MEDLINE
DCOM- 20090108
LR  - 20131121
IS  - 1572-0241 (Electronic)
IS  - 0002-9270 (Linking)
VI  - 103
IP  - 12
DP  - 2008 Dec
TI  - A 6-thioguanine nucleotide threshold level of 400 pmol/8 x 10(8) erythrocytes 
      predicts azathioprine refractoriness in patients with inflammatory bowel disease 
      and normal TPMT activity.
PG  - 3115-22
LID - 10.1111/j.1572-0241.2008.01743.x [doi]
AB  - BACKGROUND AND AIMS: A therapeutic level of 6-thioguanine nucleotides (6-TGN) has 
      been reported in inflammatory bowel disease (IBD) patients under azathioprine 
      (AZA). We investigated the threshold value of 6-TGN that may be predictive of AZA 
      refractoriness and its impact on safety profile. METHODS: Patients with normal 
      thiopurine methyltransferase (TPMT) activity (7.5-14 U/mL erythrocytes), 
      suffering from steroid-dependent or active IBD despite AZA use for at least 6 
      months, were prospectively included. Clinical efficacy, adverse events, and 
      thiopurine metabolite levels were recorded at baseline, 1 month after each dose 
      escalation, and thereafter every 3 months. RESULTS: Fifty-five patients were 
      included (43 with Crohn's disease, 12 with ulcerative colitis). After a mean 
      follow-up of 12 months, 31 patients (56.3%) did not reach clinical remission 
      despite a gradual increase in AZA dose and 6-TGN level of >400 pmol/8 x 10(8) 
      erythrocytes, and were considered refractory to AZA (sensitivity 45%, specificity 
      100%). Adverse events occurred more frequently in these patients than in 
      responders (42%vs 25%, respectively, P= 0.02). Among 55 patients, 15 cases of 
      myelotoxicity associated with elevated levels of total methylated metabolites 
      (14,500 pmol/8 x 10(8) erythrocytes vs 5,230 pmol/8 x 10(8) erythrocytes in 
      patients without myelotoxicity, P= 0.03) were observed. Patients with total 
      methylated metabolites of >11,100 pmol/8 x 10(8) erythrocytes had an increased 
      risk of developing myelotoxicity (odds ratio [OR] 11.0, 95% confidence interval 
      [CI] 1.1-250, P= 0.05). CONCLUSION: A 6-TGN level of >400 pmol/8 x 10(8) 
      erythrocytes in IBD patients with normal TPMT activity and steroid-dependent or 
      active disease despite an optimal AZA regimen may predict refractoriness to this 
      drug. Furthermore, high levels of methylated derivatives are associated with an 
      increased risk of myelotoxicity.
FAU - Roblin, Xavier
AU  - Roblin X
AD  - Department of Gastroenterology, CHU Grenoble, Grenoble, France.
FAU - Peyrin-Biroulet, Laurent
AU  - Peyrin-Biroulet L
FAU - Phelip, Jean M
AU  - Phelip JM
FAU - Nancey, Stephane
AU  - Nancey S
FAU - Flourie, Bernard
AU  - Flourie B
LA  - eng
PT  - Clinical Trial
PT  - Journal Article
PT  - Retracted Publication
PL  - United States
TA  - Am J Gastroenterol
JT  - The American journal of gastroenterology
JID - 0421030
RN  - 0 (Guanine Nucleotides)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Thionucleotides)
RN  - EC 2.1.1.- (Methyltransferases)
RN  - EC 2.1.1.67 (thiopurine methyltransferase)
RN  - FTK8U1GZNX (Thioguanine)
RN  - MRK240IY2L (Azathioprine)
SB  - IM
EIN - Am J Gastroenterol. 2009 Apr;104(4):1072. Biroulet, Laurent P [corrected to 
      Peyrin-Biroulet, Laurent]
RIN - Am J Gastroenterol. 2009 Mar;104(3):801. PMID: 19262535
CIN - Am J Gastroenterol. 2009 May;104(5):1334. PMID: 19367265
MH  - Adult
MH  - Azathioprine/*therapeutic use
MH  - Drug Resistance
MH  - Erythrocytes/*metabolism
MH  - Female
MH  - Guanine Nucleotides/metabolism
MH  - Humans
MH  - Immunosuppressive Agents/*therapeutic use
MH  - Inflammatory Bowel Diseases/drug therapy/*metabolism
MH  - Male
MH  - Methyltransferases/*metabolism
MH  - Middle Aged
MH  - Prospective Studies
MH  - Thioguanine/metabolism
MH  - Thionucleotides/*metabolism
MH  - Treatment Outcome
EDAT- 2008/12/18 09:00
MHDA- 2009/01/09 09:00
CRDT- 2008/12/18 09:00
PHST- 2008/12/18 09:00 [entrez]
PHST- 2008/12/18 09:00 [pubmed]
PHST- 2009/01/09 09:00 [medline]
AID - AJG1743 [pii]
AID - 10.1111/j.1572-0241.2008.01743.x [doi]
PST - ppublish
SO  - Am J Gastroenterol. 2008 Dec;103(12):3115-22. doi: 
      10.1111/j.1572-0241.2008.01743.x.