Pfizer Worldwide Research & Development, Clinical Pharmacology, 1 Portland Street, Cambridge, MA 02139 (A.S.-B.); Pfizer Worldwide Research & Development, PDM, Eastern Point Road, Groton, 06340 (A.D.R.); Pfizer Worldwide Research & Development, Inflammation and Immunology, 1 Portland Street, Cambridge, MA 02139 (M.L., M.K.); Pfizer Worldwide Research & Development, Discovery Sciences, Eastern Point Road, Groton, 06340 (R.D.); Assistant Professor, Department of Pharmaceutics, UWRAPT H268, Health Science Building, Seattle (B.P.); Pfizer Worldwide Research & Development, Early Clinical Development, Clinical Pharmacology, 1 Portland Street, Cambridge, MA 02139 (N.T.).
Drug Metab Dispos. 2018 Nov;46(11):1581-1587. doi: 10.1124/dmd.118.082784. Epub 2018 Aug 20.
Intestinal disposition of small molecules involves interplay of drug metabolizing enzymes (DMEs), transporters, and host-microbiome interactions, which has spurred the development of in vitro intestinal models derived from primary tissue sources. Such models have been bioengineered from intestinal crypts, mucosal extracts, induced pluripotent stem cell (iPSC)-derived organoids, and human intestinal tissue. This minireview discusses the utility and limitations of these human-derived models in support of small molecule drug metabolism and disposition. Enteroids from human intestinal crypts, organoids derived from iPSCs using growth factors or small molecule compounds, and enterocytes extracted from mucosal scrapings show key absorptive cell morphology while are limited in quantitative applications due to the lack of accessibility to the apical compartment, the lack of monolayers, or low expression of key DMEs, transporters, and nuclear hormone receptors. Despite morphogenesis to epithelial cells, similar challenges have been reported by more advanced technologies that have explored the impact of flow and mechanical stretch on proliferation and differentiation of Caco-2 cells. Most recently, bioengineered human intestinal epithelial or ileal cells have overcome many of the challenges, as the DME and transporter expression pattern resembles that of native intestinal tissue. Engineering advances may improve such models to support longer-term applications and meet end-user needs. Biochemical characterization and transcriptomic, proteomic, and functional endpoints of emerging novel intestinal models, when referenced to native human tissue, can provide greater confidence and increased utility in drug discovery and development.
小分子的肠道处置涉及药物代谢酶（DMEs）、转运体和宿主-微生物组相互作用的相互作用，这促使人们开发了源自原代组织来源的体外肠道模型。这些模型是从肠隐窝、黏膜提取物、诱导多能干细胞（iPSC）衍生的类器官和人类肠道组织生物工程化而来的。这篇综述讨论了这些源自人类的模型在支持小分子药物代谢和处置方面的用途和局限性。源自人类肠隐窝的类肠器官、使用生长因子或小分子化合物的 iPSC 衍生的类器官，以及从黏膜刮片中提取的肠细胞，显示出关键的吸收细胞形态，但由于缺乏对顶腔的可及性、缺乏单层或关键 DMEs、转运体和核激素受体的低表达，在定量应用中受到限制。尽管形成了肠上皮细胞，但更先进的技术也报告了类似的挑战，这些技术探索了流动和机械拉伸对 Caco-2 细胞增殖和分化的影响。最近，生物工程化的人类肠道上皮或回肠细胞克服了许多挑战，因为 DME 和转运体的表达模式类似于天然肠道组织。工程学的进步可能会改善这些模型，以支持更长期的应用并满足最终用户的需求。新兴的新型肠道模型的生化特征以及转录组、蛋白质组和功能终点，当与天然人类组织参考时，可以为药物发现和开发提供更大的信心和更高的实用性。
