Organotypic systems in drug metabolism and toxicity: challenges and opportunities

被引:16
|
作者
Dash, Ajit [1 ,2 ]
Blackman, Brett R. [3 ,4 ]
Wamhoff, Brian R. [2 ,3 ]
机构
[1] HemoShear LLC, Liver Surrogate Syst, Charlottesville, VA 22903 USA
[2] Univ Virginia, Dept Surg, Charlottesville, VA USA
[3] Univ Virginia, Dept Med, Charlottesville, VA USA
[4] Univ Virginia, Dept Biomed Engn, Charlottesville, VA USA
关键词
3-D models; co-culture; flow-based systems; hemodynamics; hepatocyte; heterotypic; in vitro; liver; metabolism; organotypic; toxicity; SINUSOIDAL ENDOTHELIAL-CELLS; ADULT-RAT HEPATOCYTES; LONG-TERM CULTURE; EXTRACELLULAR-MATRIX; GENE-EXPRESSION; IN-VITRO; LIVER-INJURY; CYTOCHROME-P450; EXPRESSION; HEPATOBILIARY DISPOSITION; 3-DIMENSIONAL COCULTURE;
D O I
10.1517/17425255.2012.693161
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Introduction: The frequent failure of high-throughput screening cell-based tools to accurately predict in vivo responses, coupled with limitations of animal models in predicting human safety or drug efficacy, impairs the de-risking process for biotechnology/pharmaceutical companies as they make important decisions to enter human clinical trials. Organotypic systems strive to fill the gap between these screening and in vivo studies and provide a solution. Areas covered: The authors examine the various approaches to recreate physiological response on the bench and trace the evolution of organotypic systems, while discussing intrinsic challenges and opportunities that lie ahead. Furthermore, they cite literature that is the foundation of several biotechnology research companies addressing this issue and discuss major government-funded initiatives to aid the development of these systems in an effort to fill this existing gap. Expert opinion: Decisions from translational systems that bridge basic drug efficacy and toxicity with clinical outcome must be benchmarked against human-relevant endpoints and clinical data for early meaningful pre-clinical decisions. The use of human primary cells coupled with emerging technologies that allow precise control of the culture environment and analysis of meaningful endpoints paves the way for human organotypic systems as a major initiative in de-risking the drug discovery and development process.
引用
收藏
页码:999 / 1014
页数:16
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