人体熊去氧胆酸代谢及其生物等效性研究的技术挑战

熊去氧胆酸（UDCA）是一种用于胆汁淤积性肝病治疗的重要药物。UDCA作为内源性药物的代表，在人体内具有胆汁酸特有的宿主-肠道菌群共代谢和肝-胆-肠循环处置特征，这为其仿制药研发带来了高度的技术挑战。这些技术挑战不仅有来源于分子两亲性质的生物药剂学问题和来源于大规格的药剂学问题，更有来源于内源性、长半衰期、高变异、准确测定多个代谢物的药代动力学问题。基于此，本文系统整理了人体UDCA药代动力学和内源性UDCA代谢相关的文献资料和技术指南，剖析了UDCA生物等效性（BE）研究的现状和关键技术挑战，并提出了相应的解决思路，期望为UDCA仿制药研发及BE试验的技术攻关提供有价值的参考。

Ursodeoxycholic acid (UDCA) is an essential drug for the treatment of cholestatic liver diseases. As the most important representative of endogenous drugs, the metabolism and disposition of UDCA in human is characterized by both host-gut microbial co-metabolism and hepato-billilary-intestinal circulation. These distinct metabolic and pharmacokinetic features have brought great challenges into the bioequivalence (BE) evaluation of UDCA generic formulations. These challenges include not only biopharmaceutical problems derived from the unique physiochemical properties of amphiphilic molecules and the large single dose, but also the drug metabolism and pharmacokinetic problems associated with endogenous metabolism, long terminal half-life, high inter-and intra-individual variations, as well as accurate determination of UDCA and its metabolites. This review summarized academic and industrial literatures about the clinical pharmacokinetics and endogenous metabolism of UDCA. Current guidelines and technical challenges of UDCA BE studies were extensively discussed. Knowledge summarized in this review is expected to provide valuable reference for the development of UDCA generic formulations.