PMID- 25853923
OWN - NLM
STAT- MEDLINE
DCOM- 20160906
LR  - 20171116
IS  - 1536-3694 (Electronic)
IS  - 0163-4356 (Linking)
VI  - 37
IP  - 6
DP  - 2015 Dec
TI  - Routinely Established Skewed Thiopurine Metabolism Leads to a Strikingly High 
      Rate of Early Therapeutic Failure in Patients With Inflammatory Bowel Disease.
PG  - 797-804
LID - 10.1097/FTD.0000000000000213 [doi]
AB  - BACKGROUND: The conventional thiopurines azathioprine and mercaptopurine are 
      considered maintenance immunosuppressive drugs of choice in the treatment of 
      inflammatory bowel disease (IBD). Unfortunately, treatment is often discontinued 
      because of adverse events (AEs) or refractoriness, retrospectively associated 
      with the high levels of the thiopurine metabolites 6-methylmercaptopurine 
      ribonucleotides (6-MMPR). Patients with a clinically "skewed" thiopurine 
      metabolism may be particularly at risk for therapy failure. We determined the 
      predictive value of this pharmacological phenomenon in patients with IBD during 
      regular thiopurine therapy. METHODS: Clinical effectiveness and tolerability of 
      weight-based thiopurine therapy were determined in all patients with IBD 
      displaying a skewed metabolism [ratio 6-MMPR/6-thioguanine nucleotide (6-TGN) 
      >20]. All samples were routinely assessed between 2008 and 2012, as part of 
      standard clinical follow-up after initiation of conventional thiopurine therapy. 
      RESULTS: Forty-one (84%) of 49 included patients with IBD discontinued 
      thiopurines (55% female, 53% with Crohn disease) with a median duration of 14 
      weeks (range, 7-155). The majority of patients with a skewed metabolism 
      discontinued thiopurines because of adverse events (55%) or refractoriness (12%). 
      The most commonly observed adverse event was hepatotoxicity (18 patients, 37%). 
      Median 6-TGN level was 159 pmol/8 x 10 RBC (range, 46-419), median 6-MMPR level 
      was 11,020 pmol/8 x 10 RBC (range, 3610-43,670), and the median 6-MMPR/6-TGN 
      ratio was 72 (range, 29-367). Thiopurine therapy failure was associated with a 
      ratio above 50 (P < 0.03). Hepatotoxicity occurred more frequently in patients 
      with an extremely skewed metabolism (6-MMPR/6-TGN ratio >100) (P < 0.01). 
      CONCLUSIONS: This study demonstrates that a routinely established skewed 
      metabolism is a major risk factor for future thiopurine failure in patients with 
      IBD. These observations imply that routine thiopurine metabolite measurements may 
      be used as a prognostic tool to identify those patients with an aberrant-skewed 
      metabolism at an early stage, possibly benefitting from therapy adjustments.
FAU - Kreijne, Joany E
AU  - Kreijne JE
AD  - Departments of *Gastroenterology and Hepatology, and daggerPharmacy, VU University 
      Medical Center, Amsterdam; and double daggerDepartment of Internal Medicine, Geriatrics, and 
      Gastroenterology, Atrium-ORBIS Medical Center, Heerlen-Sittard-Geleen, the 
      Netherlands.
FAU - Seinen, Margien L
AU  - Seinen ML
FAU - Wilhelm, Abraham J
AU  - Wilhelm AJ
FAU - Bouma, Gerd
AU  - Bouma G
FAU - Mulder, Chris J
AU  - Mulder CJ
FAU - van Bodegraven, Adriaan A
AU  - van Bodegraven AA
FAU - de Boer, Nanne K H
AU  - de Boer NK
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Ther Drug Monit
JT  - Therapeutic drug monitoring
JID - 7909660
RN  - 0 (Guanine Nucleotides)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Thionucleotides)
RN  - 15867-02-4 (6-thioguanylic acid)
RN  - 46S541971T (Thioinosine)
RN  - 7021-52-5 (6-methylthiopurine ribonucleoside-5'-phosphate)
RN  - E7WED276I5 (Mercaptopurine)
RN  - MRK240IY2L (Azathioprine)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Azathioprine/adverse effects/*metabolism/therapeutic use
MH  - Cohort Studies
MH  - Colitis, Ulcerative/*drug therapy
MH  - Crohn Disease/*drug therapy
MH  - Female
MH  - Follow-Up Studies
MH  - Guanine Nucleotides/metabolism
MH  - Humans
MH  - Immunosuppressive Agents/adverse effects/metabolism/therapeutic use
MH  - Male
MH  - Mercaptopurine/adverse effects/*metabolism/therapeutic use
MH  - Middle Aged
MH  - Retrospective Studies
MH  - Risk Factors
MH  - Thioinosine/analogs & derivatives/metabolism
MH  - Thionucleotides/metabolism
MH  - Treatment Failure
MH  - Young Adult
EDAT- 2015/04/09 06:00
MHDA- 2016/09/07 06:00
CRDT- 2015/04/09 06:00
PHST- 2015/04/09 06:00 [entrez]
PHST- 2015/04/09 06:00 [pubmed]
PHST- 2016/09/07 06:00 [medline]
AID - 10.1097/FTD.0000000000000213 [doi]
PST - ppublish
SO  - Ther Drug Monit. 2015 Dec;37(6):797-804. doi: 10.1097/FTD.0000000000000213.