人类长期肝脏模型的比较,用于缓慢代谢化合物的清除预测
Lena C Preiss1, Katrin Georgi1, Volker M Lauschke1
1Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (L.C.P., V.M.L.); Department of Drug Metabolism and Pharmacokinetics (DMPK), The Healthcare Business of Merck KGaA, Darmstadt, Germany (L.C.P., K.G., C.P.); Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany (V.M.L.); and University of Tuebingen, Tuebingen, Germany (V.M.L.).
概括
准确预测人类清除对于药物开发至关重要. 微阵列球形培养和微模式共培养 (MPCC) 为预测低清除化合物提供了强大的体外工具.
科学领域:
- 药物发现和开发 药物发现和开发
- 肝病学 肝病学是一种肝病学.
- 毒理学 毒理学 毒理学
背景情况:
- 准确预测人类清除在药物开发中至关重要.
- 低清除化合物越来越普遍,这给现有的体外模型带来了挑战.
- 在体外系统需要验证,以可靠地推断清除数据.
研究的目的:
- 为了比较来自各种体外肝脏模型的清除预测的准确性.
- 评估不同模型对低清除化合物评估的适用性.
- 为了确定最佳的体外系统,用于人体清除外推.
主要方法:
- 悬浮培养与四种长期稳定的体外肝脏模型进行比较:HepaRG三明治,Hμrel静态共培养,Hepatopac微模式共培养 (MPCC) 和微阵列球形培养.
- 在长时间的潜伏期内评估肝细胞活力和代谢活性.
- 评估清除预测的准确性和一致性跨模型低周转率化合物.
主要成果:
- 悬浮和HepaRG培养对低清除化合物的确定具有有限的效用.
- 微粒的随机共同培养偶尔无法检测低和中等清除化合物的显著周转.
- 微阵列球形培养提供了最强大的测量,而MPCC在回归校正后提供了最准确的预测.
结论:
- 微阵列球形培养物和MPCC是适合在体外工具的人类推断低代谢周转率化合物.
- 所有测试的体外法都倾向于预测清除不足,需要回归校正.
- 该研究强调了为特定药物化合物特性选择适当的体外模型的重要性.
相关概念视频
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01:25Clearance Models: Compartment Models
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