Citterio-Quentin Antony, Moulsma Mustapha, Gustin Marie-Paule, Boulieu Roselyne
*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.
Ther Drug Monit. 2017 Oct;39(5):483-491. doi: 10.1097/FTD.0000000000000430.
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.
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.
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).
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.
已对肌苷三磷酸焦磷酸酶（ITPA）对硫嘌呤类药物反应变异性的影响进行了研究，但关于其在硫嘌呤类代谢产物方面作用的数据尚少。目前利用ITPA改变硫嘌呤类代谢产物水平的能力，根据硫嘌呤甲基转移酶（TPMT）活性来优化硫唑嘌呤（AZA）治疗，本研究的目的是在一大群人中研究ITPA表型，并评估ITPA与TPMT活性及硫嘌呤类代谢产物之间的关系。
测定了183名成人和138名儿童（无论是否接受AZA治疗）的ITPA活性。在红细胞中测量了6-硫鸟嘌呤核苷酸（6-TGN）、6-甲基巯基嘌呤核苷酸（6-MeMPN）水平以及ITPA和TPMT活性。使用高斯混合模型评估ITPA活性的分布。还评估了个体内变异性以及年龄、性别、AZA治疗和相关联合用药对ITPA活性的影响。
这项回顾性研究显示ITPA活性呈四峰分布。未发现年龄、性别、AZA治疗和联合用药有影响。在成人中，ITPA活性与6-TGN或6-MeMPN浓度无显著相关性，而在儿童人群中观察到与6-MeMPN水平呈弱负相关（rs = -0.261；P = 0.024）。在儿童中观察到ITPA与TPMT活性之间呈弱正相关（rs = 0.289；P = 0.001）。
ITPA活性受非遗传参数的影响较小，对成人的6-TGN和6-MeMPN浓度无影响，在儿童中仅与6-MeMPN和TPMT活性有弱相关性。这些结果表明ITPA不是6-TGN形成中的限速酶，但提示儿童ITPA活性降低可能是细胞中6-MeMPN积累的一个危险因素。
