ITPA Activity in Adults and Children Treated With or Without Azathioprine: Relationship Between TPMT Activity, Thiopurine Metabolites, and Co-medications.

Ther Drug Monit

*Université de Lyon, Université Lyon 1, UMR CNRS 5305, Pharmacie Clinique, Pharmacocinétique et Evaluation du Médicament; †Hospices Civils de Lyon, Groupement Hospitalier Edouard Herriot, Laboratoire de Biologie Médicale Multi Sites du CHU de Lyon, unité de Pharmacocinétique Clinique; ‡Hospices Civils de Lyon, Groupement Hospitalier Edouard Herriot, Laboratoire de Biologie Médicale Multi Sites du CHU de Lyon, unité de Pharmacologie, Toxicologie et Eléments trace; and §Laboratoire des Pathogènes Emergents-Fondation Mérieux, Centre International de Recherche en Infectiologie (CIRI), Inserm U1111, CNRS UMR5308, ENS de Lyon, UCBL1, Lyon, France.

Published: October 2017

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.

Download full-text PDF

Source
http://dx.doi.org/10.1097/FTD.0000000000000430DOI Listing

Publication Analysis

Top Keywords

itpa activity
32
itpa
15
tpmt activity
12
aza therapy
12
tpmt activities
12
activity
10
thiopurine metabolites
8
itpa tpmt
8
6-mempn levels
8
distribution itpa
8

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!