The ontogeny and inter-individual variability of drug- metabolizing enzymes and transporters in human liver.

Drug dosing for children is frequently suboptimal when relying on the traditional approach of normalizing doses based on body weight or surface area. Thus, the ontogeny profiling of drug-metabolizing enzymes (DMEs) is important to help develop physiologically-based pharmacokinetic (PBPK) models for predicting safer pediatric dosing. In particular interest are hydrolases are one of the most diverse classes of DMEs and catalyze reactions containing esters, amides, phosphates, etc. in both drugs and prodrugs. Hydrolases such as carboxyl esterases, cathepsins, and arylacetamide deacetylase have been studied for their involvement in drug metabolism. However, a significant number of hydrolases have not yet been appropriately characterized, and as such their influence on drug metabolism remains unknown. Moreover, there is a lack of comprehensive data on the ontogeny and inter-individual variability in expression of these enzymes. Here a characterization of the age-dependent protein abundance of hydrolases in viable primary human hepatocytes isolated from pediatric (n=50) and adult (n=8) donors (Female=28; Male=30) using quantitative global proteomics-based total protein approach was performed.

传统上基于体重或体表面积标准化给药剂量的方案，常难以实现儿童患者的最优给药。因此，药物代谢酶（drug-metabolizing enzymes, DMEs）的发育谱分析，有助于构建基于生理学的药代动力学（physiologically-based pharmacokinetic, PBPK）模型，以预测更安全的儿童给药方案。水解酶是药物代谢酶中种类最为多样的类别之一，可催化药物与前体药物中含酯键、酰胺键、磷酸酯键等的反应。羧基酯酶、组织蛋白酶、芳基乙酰胺脱乙酰酶等水解酶已被证实参与药物代谢过程。然而，仍有大量水解酶尚未得到充分表征，其对药物代谢的影响尚不明确。此外，目前仍缺乏关于这些酶表达的发育谱及个体间差异的全面数据。本研究采用基于定量全局蛋白质组学的总蛋白分析法，对50名儿科供者与8名成人供者（女性28名，男性30名）分离得到的活性原代人肝细胞中水解酶的年龄依赖性蛋白丰度进行了表征。