Abstract：
The biliary excretion of pharmaceutical and food-related compounds is an important factor for assessing pharmacokinetics and toxicities in humans, and a highly predictive in vitro method for human biliary excretion is required. We have developed a simple in vitro culture method for generating extended and functional bile canaliculi using cryopreserved human hepatocytes. We evaluated the uptake of compounds by hepatocytes and bile canaliculi, and the biliary excretion index (BEI) was calculated. After 21 days of culture, the presence of extended and functional bile canaliculi was confirmed by the uptake of two fluorescent substrates. Positive BEIs were observed for taurocholic acid-d4, rosuvastatin, pitavastatin, pravastatin, valsartan, olmesartan, and topotecan (reported biliary-excreted compounds in humans), but no difference in BEI was observed for salicylic acid (a nonbiliary-excreted compound). Furthermore, 8 of 21 food-related compounds with specific structures and reported biliary transporter involvement exhibited positive BEIs. The developed in vitro system was characterized by functional bile canaliculus-like structures, and it could be applied to the prediction of the biliary excretion of pharmaceutical and food-related compounds.
摘要：
药物和食品相关化合物的胆汁排泄是评估人体药代动力学和毒性的重要因素，并且需要一种高度预测性的体外方法来进行人胆汁排泄。我们已经开发了一种简单的体外培养方法，用于使用冷冻保存的人肝细胞产生延长的功能性胆小管。我们评估了肝细胞和胆小管对化合物的摄取，并计算胆汁排泄指数(BEI)。培养21天后，两种荧光底物的摄取证实了延伸和功能性胆小管的存在。观察到牛磺胆酸-d4、瑞舒伐他汀的BEIs阳性，匹伐他汀,普伐他汀,缬沙坦,奥美沙坦,和托泊替康（报道的人类胆汁排泄的化合物），但水杨酸(一种非胆汁排泄化合物)的BEI没有差异.此外，具有特定结构和报告的胆道转运蛋白受累的21种食物相关化合物中的8种表现出阳性BEIs。开发的体外系统的特征是功能性胆小管样结构，它可以应用于药物和食品相关化合物的胆汁排泄预测。
