Drug Metabolism and Pharmacokinetics, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Drug Metabolism and Pharmacokinetics, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Drug Discov Today. 2021 Oct;26(10):2244-2258. doi: 10.1016/j.drudis.2021.04.002. Epub 2021 Apr 20.
Drug properties of antisense oligonucleotides (ASOs) differ significantly from those of traditional small-molecule therapeutics. In this review, we focus on ASO disposition, mainly as characterized by distribution and biotransformation, of nonconjugated and conjugated ASOs. We introduce ASO chemistry to allow the following in-depth discussion on bioanalytical methods and determination of distribution and elimination kinetics at low concentrations over extended periods of time. The resulting quantitative data on the parent oligonucleotide, and the identification and quantification of formed metabolites define the disposition. Proper quantitative understanding of disposition is pivotal for nonclinical to clinical predictions, supports communication with health agencies, and increases the probability of delivering optimal ASO therapy to patients.
反义寡核苷酸（ASO）的药物特性与传统小分子治疗药物有很大的不同。在这篇综述中，我们主要关注非缀合和缀合 ASO 的分布和生物转化特性，即 ASO 的处置。我们介绍了 ASO 化学，以便能够深入讨论生物分析方法以及在较长时间内以低浓度测定分布和消除动力学。关于母体寡核苷酸的定量数据，以及形成的代谢物的鉴定和定量定义了处置。对处置进行适当的定量理解对于从非临床到临床的预测至关重要，支持与卫生机构的沟通，并增加向患者提供最佳 ASO 治疗的可能性。
