布洛芬在PDA早产儿中手性药代动力学/药效学及其相关联的CYP2C8/9基因多态性研究

Patent ductus arteriosus (PDA) is one of the most common congenital heart diseases in premature neonates. Ibuprofen has been widely used for the treatment of PDA during the neonatal period f for many years. However, the optimal ibuprofen treatment regimen or protocol for managing a persistent PDA in infants has not been well established. And the dark side of the coin is the potential side effects. CYP2C8 and CYP2C9 is the major enzyme involved in the Ibuprofen hydroxylation metabolism. Their genes exhibit highest degrees of polymorphism and remarkable ethnic differences in their allele and haplotype frequencies. What's more, the impact of neonatal ontogenetic genetic polymorphism factors and physiological factors for drug metabolism and the exact mechanism have not been elucidated. The present study intends to establish the pharmacogenomics oriented PG-PK-PD model to explore chiral ibuprofen metabolic transformation mechanism, reduce drug toxicity and enhance efficacy. The study is conducted with aims of : ① Screening of 900 neonatal patients to study CYP2C8/9 polymorphism, induce blood stem cells to generate liver cells in vitro, analyze the enzyme activity and define the relationship between gene polymorphism and the enzyme. ②Studying pharmacokinetic characteristics and chiral transformation under CYP2C8/9 mutation by a quantitative analysis. ③ Applying PK-PD model to individualized ibuprofen treatment . This study aims to reveal the mechanism of IBP in preterm neonates andestablish individualized treatment strategies to improve the clinical therapy.

动脉导管开放（PDA）是早产儿最常见的先心病之一，严重时甚至危及生命。口服布洛芬（IBP）关闭PDA使用方便，疗效佳，但早产儿中个体差异大，风险未知。CYP2C8和2C9 是IBP的主要代谢酶，具有高度基因多态性。当前早产儿CYP2C8/9基因多态性与生理因素对IBP代谢影响的确切机制尚未阐明，推测其可能是IBP个体差异大的重要因素。本项目拟建立基于生理条件下CYP2C8/9基因多态性为导向的群体PK-PD-PG模型，降低IBP毒性提升疗效。课题拟完成①筛查900名PDA患儿CYP2C8/9多态性，体外诱导脐带血干细胞生成肝细胞并分析其与酶活性相关性②利用PPK定量分析（R/S）IBP在CYP2C8/9变异条件下的药代动力学特征及其手性转化机制③将PK/PD应用于IBP个体化治疗，减少不良反应及并发症。本研究将揭示早产儿中IBP代谢机制，建立基因导向型个体化治疗策略，提高PDA治疗水平。

动脉导管开放（PDA）是早产儿最常见的先心病之一，严重时甚至危及生命。口服布洛芬（IBP）关闭PDA 使用方便，疗效佳，但早产儿中个体差异大。目前已建立口服布洛芬的高效液相-串联质谱（HPLC-MS/MS）法。新生儿采样方法学获得了国家实用新型专利一项（专利号：中国201220359037.X.）。本项目已完成对120例患儿血液样本的CYP2C9*3 和C-65 （rs9332127）功能变异位点的基因测序工作。目前已收入符合纳入排除条件的新生儿4例。

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