50th Anniversary Celebration Collection Special Section on New and Emerging Areas and Technologies in Drug Metabolism and Disposition, Part II—Editorial

Abstract

The special section on "New and Emerging Areas and Technologies in Drug Metabolism and Disposition, Part II" includes eight articles contributed by the current editorial advisory board (EAB) members of Drug Metabolism and Disposition (DMD) and other significant contributors to the field (Table 1). This special section is a part of the 50th Anniversary Celebration Collection. Nine other articles were published in Part I in October 2023 (Zhong et al., 2023). Together, these articles provide updates on new and emerging developments in concepts and technologies in the field of drug metabolism and disposition.Hydrolases are a group of enzymes that break chemical bonds by reactions with water. The natural functions of most hydrolases are digestive, to break down nutrients into smaller units for absorption. However, hydrolases also play a crucial role in metabolizing numerous clinically important drugs. Dr. Haojie Zhu (an EAB member) and members of his group provide a comprehensive review article (Jung and Zhu, 2024) that discusses how genetic polymorphisms and nongenetic regulators can affect hydrolases' expression and activity, consequently influencing the exposure and clinical outcomes of hydrolase substrate drugs. The information helps readers to better understand the regulation of hydrolases for refining therapeutic regimens, ultimately enhancing the efficacy and safety of drugs metabolized by the enzymes.A paper by Dr. Bhagwat Prasad (another EAB member) and his colleagues describes a quantitative proteomic approach that uses optimized sequence coverage-informed total protein to quantify the abundance and compositions of drug-metabolizing enzymes and transporters (DMETs) in pooled human liver, intestine, and kidney microsomes (Singh et al., 2024). Quantitative differences of the DMETs can be revealed in the liver, intestine, and kidney samples. Furthermore, the individual variability of some drug-metabolizing enzymes was visualized in the intestine samples. The described approach is applicable for the prediction of first-pass metabolism and tissue-specific drug clearance.Cellular and biological functions in both the nuclei and cytoplasm often occur in specific subcellular regions defined by a biophysical process called liquid-liquid phase separation (LLPS). During LLPS, biomacromolecules aggregate and condense into dense liquid condensates that coexist with a dilute phase. Pregnane X receptor (PXR) is a nuclear receptor, which plays a critical role in hepatic physiological and pathological processes and has specific subcellular localization in cytoplasm and nuclei after activation by its agonist ligands. In a research article, Dr. Huichang Bi, an EAB member, and her colleagues demonstrate that PXR does not undergo LLPS after activation by an agonist or under hyperosmotic stress in the nucleus (Zhao et al., 2024). This finding may stimulate more research focusing on the molecular events involved in the transition of PXR from cytoplasm to nuclei after activation by its agonist ligands.Therapeutic peptides are relati...