PMID- 28130685
OWN - NLM
STAT- MEDLINE
DCOM- 20180321
LR  - 20181113
IS  - 1434-9949 (Electronic)
IS  - 0770-3198 (Linking)
VI  - 36
IP  - 6
DP  - 2017 Jun
TI  - Metabolite monitoring to guide thiopurine therapy in systemic autoimmune 
      diseases.
PG  - 1341-1348
LID - 10.1007/s10067-017-3554-4 [doi]
AB  - 6-Thioguanine nucleotide (6-TGN) is the active metabolite of thiopurine drugs 
      azathioprine and 6-mercaptopurine. 6-Methylmercaptopurine (6-MMP) is an inactive 
      and potentially hepatotoxic metabolite. A subgroup of patients (shunters) 
      preferentially produce 6-MMP instead of 6-TGN, therefore displaying thiopurine 
      resistance and risk for hepatotoxicity. Outside inflammatory bowel disease 
      literature, few data exist regarding individualized thiopurine therapy based on 
      metabolite monitoring. This study sought to describe metabolite monitoring in 
      patients receiving weight-based thiopurine for systemic autoimmune diseases. 
      Patients were enrolled using a laboratory database, and data were retrospectively 
      collected. The correlation between the highest thiopurine dose (mg/kg) and the 
      6-TGN concentration (pmol/8 x 10(8) erythrocytes) was estimated with Pearson's 
      correlation coefficient. Seventy-one patients with various systemic autoimmune 
      conditions were enrolled. The correlation between the thiopurine dose and the 
      6-TGN level was weak for the overall patient sample (r = 0.201, p = 0.092) and 
      for the subgroup of non-shunters (r = 0.278, p = 0.053). Subjects with 6-MMP 
      levels >5700 pmol/8 x 10(8) erythrocytes had more hepatic cytolysis compared to 
      subjects with 6-MMP <5700, OR = 4.36 (CI 95% 1.18-16.13, p = 0.027). Twenty-two 
      patients (31%) were identified as shunters. Six shunters developed 
      hepatotoxicity, five of which had 6-MMP concentration >5700. Eleven non-shunters 
      had hepatotoxicity, one of which had 6-MMP >5700. Thiopurine metabolite 
      monitoring shows wide variability in 6-TGN levels among patients treated with 
      weight-based thiopurine for systemic autoimmune diseases. Thirty-one percent of 
      the patients in our series fulfilled the shunter definition. Thiopurine 
      metabolite monitoring and dose adjustment to improve maintenance of remission and 
      avoid hepatotoxicity should be studied prospectively.
FAU - Chapdelaine, Aurelie
AU  - Chapdelaine A
AD  - Department of Medicine, Hopital du Sacre-Coeur de Montreal, 5400 Gouin Ouest, 
      Montreal, Quebec, H4J 1C5, Canada. aurelie.chapdelaine@umontreal.ca.
FAU - Mansour, Anne-Marie
AU  - Mansour AM
AD  - Department of Medicine, Hopital du Sacre-Coeur de Montreal, 5400 Gouin Ouest, 
      Montreal, Quebec, H4J 1C5, Canada.
AD  - Faculty of Medicine, Universite de Montreal, 5400 Gouin Ouest, Montreal, Quebec, 
      H4J 1C5, Canada.
FAU - Troyanov, Yves
AU  - Troyanov Y
AD  - Department of Medicine, Hopital du Sacre-Coeur de Montreal, 5400 Gouin Ouest, 
      Montreal, Quebec, H4J 1C5, Canada.
FAU - Williamson, David R
AU  - Williamson DR
AD  - Department of Pharmacy, Hopital du Sacre-Coeur de Montreal, 5400 Gouin Ouest, 
      Montreal, Quebec, H4J 1C5, Canada.
AD  - Faculty of Pharmacy, Universite de Montreal, 5400 Gouin Ouest, Montreal, Quebec, 
      H4J 1C5, Canada.
FAU - Dore, Maxime
AU  - Dore M
AD  - Department of Pharmacy, Hopital du Sacre-Coeur de Montreal, 5400 Gouin Ouest, 
      Montreal, Quebec, H4J 1C5, Canada.
LA  - eng
PT  - Journal Article
PT  - Observational Study
DEP - 20170127
PL  - Germany
TA  - Clin Rheumatol
JT  - Clinical rheumatology
JID - 8211469
RN  - 0 (Antirheumatic Agents)
RN  - 0 (Guanine Nucleotides)
RN  - 0 (Thionucleotides)
RN  - 15867-02-4 (6-thioguanylic acid)
RN  - E7WED276I5 (Mercaptopurine)
RN  - EC 2.1.1.- (Methyltransferases)
RN  - EC 2.1.1.67 (thiopurine methyltransferase)
RN  - MRK240IY2L (Azathioprine)
RN  - Thiopurine S methyltranferase deficiency
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antirheumatic Agents/metabolism/*therapeutic use
MH  - Autoimmune Diseases/complications/*drug therapy
MH  - Azathioprine/metabolism/*therapeutic use
MH  - Chemical and Drug Induced Liver Injury/etiology
MH  - Drug Hypersensitivity/*blood/complications/diagnosis/epidemiology
MH  - Female
MH  - Guanine Nucleotides/*blood
MH  - Humans
MH  - Leukopenia
MH  - Male
MH  - Mercaptopurine/blood
MH  - Methyltransferases/blood
MH  - Middle Aged
MH  - Prevalence
MH  - Purine-Pyrimidine Metabolism, Inborn 
      Errors/*blood/complications/diagnosis/epidemiology
MH  - Quebec/epidemiology
MH  - Retrospective Studies
MH  - Thionucleotides/*blood
OTO - NOTNLM
OT  - Allopurinol
OT  - Azathioprine
OT  - Connective tissue disease
OT  - Dose-response relationship
OT  - Drug monitoring
OT  - Vasculitis
EDAT- 2017/01/29 06:00
MHDA- 2018/03/22 06:00
CRDT- 2017/01/29 06:00
PHST- 2016/09/01 00:00 [received]
PHST- 2017/01/18 00:00 [accepted]
PHST- 2016/12/22 00:00 [revised]
PHST- 2017/01/29 06:00 [pubmed]
PHST- 2018/03/22 06:00 [medline]
PHST- 2017/01/29 06:00 [entrez]
AID - 10.1007/s10067-017-3554-4 [pii]
AID - 10.1007/s10067-017-3554-4 [doi]
PST - ppublish
SO  - Clin Rheumatol. 2017 Jun;36(6):1341-1348. doi: 10.1007/s10067-017-3554-4. Epub 
      2017 Jan 27.