Pfizer Global Research and Development, St. Louis Laboratories, Chesterfield, Missouri 63017, USA.
J Pharm Sci. 2011 Nov;100(11):4722-33. doi: 10.1002/jps.22664. Epub 2011 Jun 9.
The farnesoid X receptor (FXR) belongs to one of the human nuclear receptor superfamilies that regulate gene transcription. FXR is widely expressed in liver, gall bladder, intestine, kidney, and adrenal glands. It serves as a key controller of bile acid homeostasis through its regulation of bile acid synthesis, conjugation, secretion, and absorption. FXR is also known to play a role in lipid regulation, triglyceride synthesis, and lipoprotein metabolism and clearance. We used a commercially available FXR agonist, GW4064, as a model compound to assess preclinical efficacy in two species (hamster and cynomolgus monkey). The crystalline GW4064, however, was found to have limited solubility, which resulted in poor oral bioavailability. This made it difficult to assess in vivo efficacy at the exposure levels desired. The physiochemical properties of GW4064 were assessed and both salt and self-emulsifying drug delivery system (SEDDS) formulation were developed and tested. The SEDDS formulation was found to greatly improve the oral bioavailability of GW4064, and permitted the evaluation of FXR agonist target efficacy.
法尼醇 X 受体（FXR）属于核受体超家族之一，可调节基因转录。FXR 在肝脏、胆囊、肠道、肾脏和肾上腺中广泛表达。它通过调节胆汁酸的合成、结合、分泌和吸收，充当胆汁酸动态平衡的关键控制器。FXR 还在脂质调节、甘油三酯合成以及脂蛋白代谢和清除中发挥作用。我们使用市售的 FXR 激动剂 GW4064 作为模型化合物，在两种物种（仓鼠和食蟹猴）中评估临床前疗效。然而，结晶的 GW4064 溶解度有限，导致口服生物利用度差。这使得难以在所需的暴露水平下评估体内疗效。评估了 GW4064 的物理化学性质，并开发和测试了盐和自乳化药物递送系统（SEDDS）制剂。SEDDS 制剂大大提高了 GW4064 的口服生物利用度，并允许评估 FXR 激动剂的靶标疗效。
