Lai Yurong, Chu Xiaoyan, Di Li, Gao Wei, Guo Yingying, Liu Xingrong, Lu Chuang, Mao Jialin, Shen Hong, Tang Huaping, Xia Cindy Q, Zhang Lei, Ding Xinxin
Drug Metabolism, Gilead Sciences Inc., Foster City, CA 94404, USA.
Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Kenilworth, NJ 07033, USA.
Acta Pharm Sin B. 2022 Jun;12(6):2751-2777. doi: 10.1016/j.apsb.2022.03.009. Epub 2022 Mar 17.
Drug metabolism and pharmacokinetics (DMPK) is an important branch of pharmaceutical sciences. The nature of ADME (absorption, distribution, metabolism, excretion) and PK (pharmacokinetics) inquiries during drug discovery and development has evolved in recent years from being largely descriptive to seeking a more quantitative and mechanistic understanding of the fate of drug candidates in biological systems. Tremendous progress has been made in the past decade, not only in the characterization of physiochemical properties of drugs that influence their ADME, target organ exposure, and toxicity, but also in the identification of design principles that can minimize drug-drug interaction (DDI) potentials and reduce the attritions. The importance of membrane transporters in drug disposition, efficacy, and safety, as well as the interplay with metabolic processes, has been increasingly recognized. Dramatic increases in investments on new modalities beyond traditional small and large molecule drugs, such as peptides, oligonucleotides, and antibody-drug conjugates, necessitated further innovations in bioanalytical and experimental tools for the characterization of their ADME properties. In this review, we highlight some of the most notable advances in the last decade, and provide future perspectives on potential major breakthroughs and innovations in the translation of DMPK science in various stages of drug discovery and development.
药物代谢与药代动力学（DMPK）是药学领域的一个重要分支。近年来，在药物发现和开发过程中，对药物吸收、分布、代谢、排泄（ADME）和药代动力学（PK）的研究性质已从主要是描述性的，发展到寻求对生物系统中候选药物命运进行更定量和更具机制性的理解。在过去十年中取得了巨大进展，不仅在表征影响药物ADME、靶器官暴露和毒性的物理化学性质方面，而且在确定可将药物相互作用（DDI）潜力降至最低并减少损耗的设计原则方面。膜转运蛋白在药物处置、疗效和安全性中的重要性，以及与代谢过程的相互作用，已得到越来越多的认可。对超越传统小分子和大分子药物的新剂型（如肽、寡核苷酸和抗体药物偶联物）的投资大幅增加，这就需要在生物分析和实验工具方面进一步创新，以表征它们的ADME性质。在本综述中，我们重点介绍过去十年中一些最显著的进展，并对DMPK科学在药物发现和开发各个阶段的转化中潜在的重大突破和创新提供未来展望。
