PDF(Pubmed)
Abstract：
The development of safe and effective medications requires a profound understanding of their pharmacokinetic (PK) and pharmacodynamic properties. PK studies have been built through investigation of enzymes and transporters that drive drug absorption, distribution, metabolism, and excretion (ADME). Like many other disciplines, the study of ADME gene products and their functions has been revolutionized through the invention and widespread adoption of recombinant DNA technologies. Recombinant DNA technologies use expression vectors such as plasmids to achieve heterologous expression of a desired transgene in a specified host organism. This has enabled the purification of recombinant ADME gene products for functional and structural characterization, allowing investigators to elucidate their roles in drug metabolism and disposition. This strategy has also been used to offer recombinant or bioengineered RNA (BioRNA) agents to investigate the posttranscriptional regulation of ADME genes. Conventional research with small noncoding RNAs such as microRNAs (miRNAs) and small interfering RNAs has been dependent on synthetic RNA analogs that are known to carry a range of chemical modifications expected to improve stability and PK properties. Indeed, a novel transfer RNA fused pre-miRNA carrier-based bioengineering platform technology has been established to offer consistent and high-yield production of unparalleled BioRNA molecules from Escherichia coli fermentation. These BioRNAs are produced and processed inside living cells to better recapitulate the properties of natural RNAs, representing superior research tools to investigate regulatory mechanisms behind ADME. SIGNIFICANCE STATEMENT: This review article summarizes recombinant DNA technologies that have been an incredible boon in the study of drug metabolism and PK, providing investigators with powerful tools to express nearly any ADME gene products for functional and structural studies. It further overviews novel recombinant RNA technologies and discusses the utilities of bioengineered RNA agents for the investigation of ADME gene regulation and general biomedical research.
摘要：
开发安全有效的药物需要对其药代动力学（PK）和药效学特性有深刻的了解。PK研究是通过研究驱动药物吸收的酶和转运蛋白而建立的，分布，新陈代谢，和排泄（ADME）。像许多其他学科一样，通过重组DNA技术的发明和广泛采用,ADME基因产物及其功能的研究已经发生了革命性的变化。重组DNA技术使用表达载体如质粒来实现所需转基因在特定宿主生物体中的异源表达。这使得用于功能和结构表征的重组ADME基因产物的纯化成为可能。允许研究人员阐明他们在药物代谢和处置中的作用。该策略也已用于提供重组或生物工程RNA（BioRNA）试剂，以研究ADME基因的转录后调节。对诸如微小RNA(miRNA)和小干扰RNA的小的非编码RNA的常规研究已经依赖于合成的RNA类似物,所述合成的RNA类似物已知携带预期改善稳定性和PK性质的一系列化学修饰。的确,已经建立了一种新的转移RNA融合的基于pre-miRNA载体的生物工程平台技术，以提供来自大肠杆菌发酵的无与伦比的BioRNA分子的一致和高产量生产。这些BioRNA在活细胞内产生和加工，以更好地概括天然RNA的特性，代表优越的研究工具，以调查ADME背后的调节机制。重要声明：这篇综述文章总结了重组DNA技术，这些技术在药物代谢和PK研究中具有令人难以置信的优势，为研究人员提供强大的工具来表达几乎任何ADME基因产物，用于功能和结构研究。它进一步概述了新型重组RNA技术，并讨论了生物工程RNA试剂在ADME基因调控研究和一般生物医学研究中的应用。
