Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, Illinois; and Department of Bioengineering, University of Illinois at Chicago, Chicago, Illinois
Drug Metab Dispos. 2018 Nov;46(11):1626-1637. doi: 10.1124/dmd.118.083295. Epub 2018 Aug 22.
Metabolism in the liver often determines the overall clearance rates of many pharmaceuticals. Furthermore, induction or inhibition of the liver drug metabolism enzymes by perpetrator drugs can influence the metabolism of victim drugs (drug-drug interactions). Therefore, determining liver-drug interactions is critical during preclinical drug development. Unfortunately, studies in animals are often of limited value because of significant differences in the metabolic pathways of the liver across different species. To mitigate such limitations, the pharmaceutical industry uses a continuum of human liver models, ranging from microsomes to transfected cell lines and cultures of primary human hepatocytes (PHHs). Of these models, PHHs provide a balance of high-throughput testing capabilities together with a physiologically relevant cell type that exhibits all the characteristic enzymes, cofactors, and transporters. However, PHH monocultures display a rapid decline in metabolic capacity. Consequently, bioengineers have developed several tools, such as cellular microarrays, micropatterned cocultures, self-assembled and bioprinted spheroids, and perfusion devices, to enhance and stabilize PHH functions for ≥2 weeks. Many of these platforms have been validated for drug studies, whereas some have been adapted to include liver nonparenchymal cells that can influence hepatic drug metabolism in health and disease. Here, we focus on the design features of such platforms and their representative drug metabolism validation datasets, while discussing emerging trends. Overall, the use of engineered human liver platforms in the pharmaceutical industry has been steadily rising over the last 10 years, and we anticipate that these platforms will become an integral part of drug development with continued commercialization and validation for routine screening use.
肝脏中的代谢通常决定了许多药物的总体清除率。此外，加害药物对肝药物代谢酶的诱导或抑制会影响受害药物的代谢（药物相互作用）。因此，在临床前药物开发过程中确定肝药物相互作用至关重要。不幸的是，由于不同物种肝脏代谢途径存在显著差异，动物研究往往价值有限。为了减轻这些限制，制药行业使用了一系列人类肝脏模型，从微粒体到转染细胞系和原代人肝细胞（PHH）培养物。在这些模型中，PHH 提供了高通量测试能力的平衡，以及一种具有生理相关性的细胞类型，该细胞类型表现出所有特征酶、辅助因子和转运蛋白。然而，PHH 单核培养物的代谢能力迅速下降。因此，生物工程师已经开发了几种工具，例如细胞微阵列、微图案共培养物、自组装和生物打印球体以及灌注设备，以增强和稳定 PHH 的功能，使其至少维持 2 周。这些平台中的许多已针对药物研究进行了验证，而有些则已被改编为包括肝非实质细胞，这些细胞可以影响健康和疾病中的肝药物代谢。在这里，我们重点介绍这些平台的设计特点及其代表性的药物代谢验证数据集，同时讨论新兴趋势。总体而言，在过去 10 年中，制药行业中使用工程化人类肝脏平台的情况稳步上升，我们预计这些平台将成为药物开发不可或缺的一部分，随着商业化和常规筛选用途的不断验证而继续发展。
