Liu Xin, Li Miaomiao, Woo Sukyung
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY 14214-8033, USA.
Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, OH 43210-1267, USA.
Pharmaceutics. 2024 Sep 4;16(9):1167. doi: 10.3390/pharmaceutics16091167.
The efficacy and potential toxicity of drug treatments depends on the drug concentration at its site of action, intricately linked to its distribution within diverse organelles of mammalian cells. These organelles, including the nucleus, endosome, lysosome, mitochondria, endoplasmic reticulum, Golgi apparatus, lipid droplets, exosomes, and membrane-less structures, create distinct sub-compartments within the cell, each with unique biological features. Certain structures within these sub-compartments possess the ability to selectively accumulate or exclude drugs based on their physicochemical attributes, directly impacting drug efficacy. Under pathological conditions, such as cancer, many cells undergo dynamic alterations in subcellular organelles, leading to changes in the active concentration of drugs. A mechanistic and quantitative understanding of how organelle characteristics and abundance alter drug partition coefficients is crucial. This review explores biological factors and physicochemical properties influencing subcellular drug distribution, alongside strategies for modulation to enhance efficacy. Additionally, we discuss physiologically based computational models for subcellular drug distribution, providing a quantifiable means to simulate and predict drug distribution at the subcellular level, with the potential to optimize drug development strategies.
药物治疗的疗效和潜在毒性取决于其作用部位的药物浓度，而这又与药物在哺乳动物细胞不同细胞器内的分布密切相关。这些细胞器包括细胞核、内体、溶酶体、线粒体、内质网、高尔基体、脂滴、外泌体和无膜结构，它们在细胞内形成了不同的亚区室，每个亚区室都具有独特的生物学特性。这些亚区室内的某些结构能够根据药物的物理化学属性选择性地积累或排除药物，直接影响药物疗效。在癌症等病理条件下，许多细胞的亚细胞器会发生动态变化，导致药物活性浓度改变。对细胞器特征和丰度如何改变药物分配系数进行机制性和定量性的理解至关重要。本综述探讨了影响亚细胞药物分布的生物学因素和物理化学性质，以及调节这些因素以提高疗效的策略。此外，我们还讨论了基于生理学的亚细胞药物分布计算模型，该模型提供了一种可量化的方法来模拟和预测亚细胞水平的药物分布，具有优化药物开发策略的潜力。
