Lemmens Glenn, Van Camp Arno, Kourula Stephanie, Vanuytsel Tim, Augustijns Patrick
Drug Delivery and Disposition, KU Leuven, Gasthuisberg O&N II, Herestraat 49-Box 921, 3000 Leuven, Belgium.
Drug Metabolism and Pharmacokinetics, Janssen R&D, Turnhoutseweg 30, 2340 Beerse, Belgium.
Pharmaceutics. 2021 Jan 26;13(2):161. doi: 10.3390/pharmaceutics13020161.
The increasing prevalence of colonic diseases calls for a better understanding of the various colonic drug absorption barriers of colon-targeted formulations, and for reliable in vitro tools that accurately predict local drug disposition. In vivo relevant incubation conditions have been shown to better capture the composition of the limited colonic fluid and have resulted in relevant degradation and dissolution kinetics of drugs and formulations. Furthermore, drug hurdles such as efflux transporters and metabolising enzymes, and the presence of mucus and microbiome are slowly integrated into drug stability- and permeation assays. Traditionally, the well characterized Caco-2 cell line and the Ussing chamber technique are used to assess the absorption characteristics of small drug molecules. Recently, various stem cell-derived intestinal systems have emerged, closely mimicking epithelial physiology. Models that can assess microbiome-mediated drug metabolism or enable coculturing of gut microbiome with epithelial cells are also increasingly explored. Here we provide a comprehensive overview of the colonic physiology in relation to drug absorption, and review colon-targeting formulation strategies and in vitro tools to characterize colonic drug disposition.
结肠疾病患病率的不断上升，要求我们更好地了解结肠靶向制剂的各种结肠药物吸收屏障，并需要可靠的体外工具来准确预测局部药物处置情况。已证明体内相关孵育条件能更好地反映有限结肠液的成分，并能得出药物和制剂相关的降解及溶解动力学。此外，诸如外排转运体和代谢酶等药物屏障，以及黏液和微生物群的存在，正逐渐被纳入药物稳定性和渗透试验中。传统上，特征明确的Caco-2细胞系和尤斯灌流室技术用于评估小分子药物的吸收特性。最近，出现了各种源自干细胞的肠道系统，能紧密模拟上皮生理学。能够评估微生物群介导的药物代谢或实现肠道微生物群与上皮细胞共培养的模型也在越来越多地被探索。在此，我们全面概述了与药物吸收相关的结肠生理学，并综述了结肠靶向制剂策略以及用于表征结肠药物处置的体外工具。
