使用蛋白质学信息相对表达因子方法成功预测人类肝脏中运输药物的度
Mengyue Yin1, Ankit Balhara1, Solène Marie2
1Department of Pharmaceutics, University of Washington, Seattle, Washington, USA.
Clinical pharmacology and therapeutics
|December 1, 2023
概括
预测组织中的药物度对于疗效和安全至关重要. 使用运输体表达细胞的新型相对表达因子 (REF) 方法准确预测药物清除和组织水平,帮助药物开发.
科学领域:
- 药理动力学和药物新陈代谢
- 传送器生物学 传送器生物学
- 药物开发 药物开发
背景情况:
- 精确预测组织药物度对于确定药物的有效性和毒性至关重要.
- 血液-组织屏障中的载体蛋白质使得从血水平对组织药物度的预测变得复杂.
- 现有的方法面临挑战,因为在体外研究中无法获得原始组织细胞.
研究的目的:
- 评估相对表达因子 (REF) 方法在预测载体介导药物清除和组织度方面的有效性.
- 为了验证使用糖和皮塔瓦斯塔丁作为模型化合物的REF方法.
- 评估REF与体内数据相对应的体外衍生清除值的准确性.
主要方法:
- 在各种运输体表达细胞和囊泡中,确定了基布里德和皮塔瓦斯塔丁的基于运输体的内在清除 (CL).
- 利用相对表达因子 (REF) 将体外CLs扩展到体内预测.
- 将预测的肝胆清除和肝脏度 (AUC,Cmax) 与来自正子发射断层扫描成像的体内数据进行了比较.
主要成果:
- 在体内预测的甘胺和皮塔瓦斯塔丁的肝胆清除值在成像衍生值的两倍范围内.
- 两种药物的预测肝脏度 (AUC和Cmax) 都在观察到的数据的两倍范围内.
- 通过REF方法,在体外成功地扩大了基于载体的CLs,以准确预测体内药物处置.
结论:
- 相对表达因子 (REF) 方法是预测载体介导药物清除的可靠方法.
- 这种方法可以准确预测组织中药物度,从而提高药物开发的速度.
- REF方法提供了一种有价值的工具,用于克服在血组织障碍处预测药物行为的挑战.
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