PDF(Pubmed)
Abstract：
Biliary excretion is a major drug elimination pathway that affects their efficacy and safety. The currently available in vitro sandwich-cultured hepatocyte method is cumbersome because drugs accumulate in the closed bile canalicular lumen formed between hepatocytes and their amounts cannot be mealsured directly. This study proposes a hepatocyte culture model for the rapid evaluation of drug biliary excretion using permeation assays. When hepatocytes are cultured on a permeable support coated with the cell adhesion protein claudins, an open-form bile canalicular lumen is formed at the surface of the permeable support. Upon application to the basolateral (blood) side, drugs appear on the bile canalicular side. The biliary excretion clearance of several drugs, as estimated from the obtained permeabilities, correlates well with the reported in vivo biliary excretion clearance in humans. Thus, the established model is useful for applications in the efficient evaluation of biliary excretion during drug discovery and development.
摘要：
胆汁排泄是影响其疗效和平安性的主要药物消除通路。目前可用的体外夹心培养的肝细胞方法很麻烦，因为药物会积聚在肝细胞之间形成的封闭的胆管腔中，并且无法直接测量其数量。这项研究提出了一种肝细胞培养模型，用于使用渗透测定法快速评估药物胆汁排泄。当肝细胞在涂有细胞粘附蛋白claudins的可渗透支持物上培养时，在可渗透支撑体的表面形成开放形式的胆小管腔。应用于基底外侧（血液）侧后，药物出现在胆管一侧。几种药物的胆汁排泄清除率，根据获得的渗透率估计，与人类体内报道的胆汁排泄清除率密切相关。因此，所建立的模型可用于药物发现和开发过程中胆汁排泄的有效评估。
