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低清除率药物的代谢稳定性预测模型研究进展
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引用本文:阮婷婷,鞠武建,熊海伟,姜利芳,许悦,王广基.低清除率药物的代谢稳定性预测模型研究进展[J].中国药科大学学报,2019,50(2):152-160.
Cite:RUAN Tingting,JU Wujian,XIONG Haiwei,JIANG Lifang,XU Yue,WANG Guangji.Advances in methodologies for predicting metabolic stability for low-clearance drugs[J].J China Pharm Univ,2019,50(2):152-160.
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作者单位
阮婷婷 中国药科大学 江苏省药物代谢动力学重点实验室上海药明康德新药开发有限公司测试事业部药性评价部 
鞠武建 上海药明康德新药开发有限公司测试事业部药性评价部 
熊海伟 上海药明康德新药开发有限公司测试事业部药性评价部 
姜利芳 上海药明康德新药开发有限公司测试事业部药性评价部 
许悦 中国药科大学 江苏省药物代谢动力学重点实验室上海药明康德新药开发有限公司测试事业部药性评价部 
王广基 中国药科大学 江苏省药物代谢动力学重点实验室 
基金项目:“重大新药创制”国家科技重大专项资助项目(No.2015ZX09501001)
中文摘要:药物代谢的稳定性测试是新药发现阶段的关键环节,实现药物的低清除率通常是药物代谢稳定性设计中的重要目标。如何准确评估低清除率药物的代谢稳定性参数,并用体外代谢数据预测人体药动学已经成为新药研发阶段的挑战。传统的肝微粒体模型和悬浮肝细胞模型的孵育时间短,低清除率药物无法产生足够的代谢转化,因此进一步模拟体内环境和延长肝细胞培养时间的新型模型逐渐发展起来。本文重点介绍了新型的低清除率药物代谢稳定性预测模型的原理和优缺点等,包括肝细胞传递式培养模型、单层贴壁肝细胞培养模型、共培养模型和微灌流模型等,同时对模型的发展趋势进行展望,以期为早期先导化合物的代谢稳定性检测提供借鉴和优化。
中文关键词:代谢稳定性  低清除率  传递式培养  共培养  微灌流  原药消除
 
Advances in methodologies for predicting metabolic stability for low-clearance drugs
Abstract:The metabolic stability test of drugs is a key step in drug discovery and achieving low clearance is frequently the goal in the design of drug. Increased drug metabolism stability can reduce drug dosage, enhance drug exposure and prolong drug half-life. Accurately assessing the metabolic stability parameters of low clearance drugs and predicting human pharmacokinetics has become a challenge. Traditional tools in vitro including microsomes and suspended primary hepatocytes are limited by incubation time, which is not long enough to make sufficient metabolic conversion. Determination of intrinsic clearance or metabolic pathways and mechanisms of drug are implicated. Novel models tend to further mimic the in vivo environment in order to prolong lifetime of hepatocytes and achieve sufficient metabolic turnover of drugs for monitoring. In vitro-in vivo correlation of intrinsic clearance of methodologies has evaluated to support the reliability in predicting human pharmacokinetics. Application of these methodologies greatly decreases the forthputting of experimental animals and the release of expensive clinical trials during the acquisition of pharmacokinetic parameters. In this review, we summarized the principles, advantages and disadvantages of the novel in vitro methodologies for metabolic stability dealing with low-turnover drugs, including hepatocyte relay method, plated human hepatocytes, coculture system and microfluidic devices. Future prospect is proposed for in vitro metabolic models and it provides reference and optimization in metabolic stability for early lead compounds.
keywords:metabolic stability  low-clearance  relay method  coculture  microfluidic  parent elimination
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