PMID- 28650902
OWN - NLM
STAT- MEDLINE
DCOM- 20180516
LR  - 20181211
IS  - 1536-3694 (Electronic)
IS  - 0163-4356 (Linking)
VI  - 39
IP  - 5
DP  - 2017 Oct
TI  - ITPA Activity in Adults and Children Treated With or Without Azathioprine: 
      Relationship Between TPMT Activity, Thiopurine Metabolites, and Co-medications.
PG  - 483-491
LID - 10.1097/FTD.0000000000000430 [doi]
AB  - BACKGROUND: The implication of inosine triphosphate pyrophosphatase (ITPA) on 
      thiopurine drug response variability has been investigated but little data are 
      available on its role on thiopurine metabolites. The ability of ITPA to modify 
      the thiopurine metabolite levels is currently used to optimize azathioprine (AZA) 
      therapy in relation to thiopurine S-methyltransferase (TPMT) activity, the aim of 
      this study is to investigate ITPA phenotype in a large population and to evaluate 
      the relation between ITPA and TPMT activities and thiopurine metabolites. 
      METHODS: ITPA activity was determined in 183 adults and 138 children with or 
      without AZA therapy. 6-thioguanine nucleotides (6-TGN), 6-methylmercaptopurine 
      nucleotides (6-MeMPN) levels, and ITPA as well as TPMT activities were measured 
      in red blood cells. Using the Gaussian mixture model, distribution of ITPA 
      activity was evaluated. Intraindividual variability and influence of age, sex, 
      AZA treatment and associated co-medications on ITPA activity were also assessed. 
      RESULTS: This retrospective study shows a quadrimodal distribution in ITPA 
      activity. No influence of age, sex, AZA therapy, and co-medications was found. In 
      adults, ITPA activity was not significantly associated with 6-TGN or 6-MeMPN 
      concentrations, whereas a weak negative correlation was observed with 6-MeMPN 
      levels in pediatric populations (rs = -0.261; P = 0.024). A weak positive 
      correlation was observed between ITPA and TPMT activities in children (rs = 
      0.289; P = 0.001). CONCLUSIONS: ITPA activity was poorly influenced by nongenetic 
      parameters and has no influence on 6-TGN and 6-MeMPN concentrations in adults and 
      only a weak correlation with 6-MeMPN and TPMT activity in children. These results 
      demonstrate that ITPA is not a rate-limiting enzyme in the formation of 6-TGN but 
      suggest that a decrease in ITPA activity in children may be a risk factor for 
      accumulation of 6-MeMPN in cells.
FAU - Citterio-Quentin, Antony
AU  - Citterio-Quentin A
AD  - *Universite de Lyon, Universite Lyon 1, UMR CNRS 5305, Pharmacie Clinique, 
      Pharmacocinetique et Evaluation du Medicament; daggerHospices Civils de Lyon, 
      Groupement Hospitalier Edouard Herriot, Laboratoire de Biologie Medicale Multi 
      Sites du CHU de Lyon, unite de Pharmacocinetique Clinique; double daggerHospices Civils de 
      Lyon, Groupement Hospitalier Edouard Herriot, Laboratoire de Biologie Medicale 
      Multi Sites du CHU de Lyon, unite de Pharmacologie, Toxicologie et Elements 
      trace; and  section signLaboratoire des Pathogenes Emergents-Fondation Merieux, Centre 
      International de Recherche en Infectiologie (CIRI), Inserm U1111, CNRS UMR5308, 
      ENS de Lyon, UCBL1, Lyon, France.
FAU - Moulsma, Mustapha
AU  - Moulsma M
FAU - Gustin, Marie-Paule
AU  - Gustin MP
FAU - Boulieu, Roselyne
AU  - Boulieu R
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  - EC 2.1.1.- (Methyltransferases)
RN  - EC 2.1.1.67 (thiopurine methyltransferase)
RN  - EC 3.6.1.- (Pyrophosphatases)
RN  - EC 3.6.1.9 (ITPA protein, human)
RN  - MRK240IY2L (Azathioprine)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Azathioprine/*therapeutic use
MH  - Child
MH  - Child, Preschool
MH  - Female
MH  - Guanine Nucleotides/metabolism
MH  - Humans
MH  - Immunosuppressive Agents/*therapeutic use
MH  - Infant
MH  - Male
MH  - Methyltransferases/*metabolism
MH  - Middle Aged
MH  - Phenotype
MH  - Pyrophosphatases/*metabolism
MH  - Retrospective Studies
MH  - Thioinosine/analogs & derivatives/metabolism
MH  - Thionucleotides/metabolism
MH  - Young Adult
EDAT- 2017/06/27 06:00
MHDA- 2018/05/17 06:00
CRDT- 2017/06/27 06:00
PHST- 2017/06/27 06:00 [pubmed]
PHST- 2018/05/17 06:00 [medline]
PHST- 2017/06/27 06:00 [entrez]
AID - 10.1097/FTD.0000000000000430 [doi]
PST - ppublish
SO  - Ther Drug Monit. 2017 Oct;39(5):483-491. doi: 10.1097/FTD.0000000000000430.