Meta-Analysis of the Turnover of Intestinal Epithelia in Preclinical Animal Species and Humans
Meta-Analysis of the Turnover of Intestinal Epithelia in Preclinical Animal Species and Humans
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DOI：
10.1124/dmd.114.058404
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发表时间：
2014-12-01
影响因子：
3.9
通讯作者：
Rostami-Hodjegan, Amin
中科院分区：
文献类型：
--
作者：
Darwich, Adam S.;Aslam, Umair;Rostami-Hodjegan, Amin
由于小肠上皮细胞的快速更新，肠细胞更新的速度在决定肠壁药物代谢酶的水平方面起着重要作用。目前基于生理的药代动力学（PBPK）模型考虑酶和肠细胞恢复作为一个集中的一级速率。肠细胞更新的评估将使酶和肠细胞更新更机械地建模。通过文献回顾和统计分析，建立了人类和临床前物种的肠细胞周转。共有85项研究报告了6个物种的1602名受试者的肠细胞周转。在小鼠中，几何加权联合平均（WX）肠细胞周转率为2.81±1.14天（n = 169）。大鼠肠细胞周转率加权算术平均值为2.37天（n = 501）。人类胃肠道上皮细胞（n = 265）的WX肠细胞周转率为3.48 +/- 1.55天，与细胞色素P450酶在体外的周转率相当（0.96-4.33天）。统计分析表明，与临床前物种相比，人类的肠细胞周转时间更长。提取的数据过于稀疏，无法支持人类小肠肠细胞周转的区域差异，尽管在小鼠中有显示。利用肠细胞周转率数据，以及PBPK模型中的体外酶周转率，可以改善依赖于酶周转率的代谢药物-药物相互作用的预测（例如，基于机制的抑制和酶诱导），以及纳米颗粒递送系统的吸收和肠细胞周转率改变的特殊人群的肠道代谢。
Due to the rapid turnover of the small intestinal epithelia, the rate at which enterocyte renewal occurs plays an important role in determining the level of drug-metabolizing enzymes in the gut wall. Current physiologically based pharmacokinetic (PBPK) models consider enzyme and enterocyte recovery as a lumped first-order rate. An assessment of enterocyte turnover would enable enzyme and enterocyte renewal to be modeled more mechanistically. A literature review together with statistical analysis was employed to establish enterocyte turnover in human and preclinical species. A total of 85 studies was identified reporting enterocyte turnover in 1602 subjects in six species. In mice, the geometric weighted combined mean (WX) enterocyte turnover was 2.81 +/- 1.14 days (n = 169). In rats, the weighted arithmetic mean enterocyte turnover was determined to be 2.37 days (n = 501). Humans exhibited a geometric WX enterocyte turnover of 3.48 +/- 1.55 days for the gastrointestinal epithelia (n = 265), displaying comparable turnover to that of cytochrome P450 enzymes in vitro (0.96-4.33 days). Statistical analysis indicated humans to display longer enterocyte turnover as compared with preclinical species. Extracted data were too sparse to support regional differences in small intestinal enterocyte turnover in humans despite being indicated in mice. The utilization of enterocyte turnover data, together with in vitro enzyme turnover in PBPK modeling, may improve the predictions of metabolic drug-drug interactions dependent on enzyme turnover (e.g., mechanism-based inhibition and enzyme induction) as well as absorption of nanoparticle delivery systems and intestinal metabolism in special populations exhibiting altered enterocyte turnover.