DataSheet1_The Role of Uptake and Efflux Transporters in the Disposition of Glucuronide and Sulfate Conjugates.xlsx

Glucuronidation and sulfation are the most typical phase II metabolic reactions of drugs. The resulting glucuronide and sulfate conjugates are generally considered inactive and safe. They may, however, be the most prominent drug-related material in the circulation and excreta of humans. The glucuronide and sulfate metabolites of drugs typically have limited cell membrane permeability and subsequently, their distribution and excretion from the human body requires transport proteins. Uptake transporters, such as organic anion transporters (OATs and OATPs), mediate the uptake of conjugates into the liver and kidney, while efflux transporters, such as multidrug resistance proteins (MRPs) and breast cancer resistance protein (BCRP), mediate expulsion of conjugates into bile, urine and the intestinal lumen. Understanding the active transport of conjugated drug metabolites is important for predicting the fate of a drug in the body and its safety and efficacy. The aim of this review is to compile the understanding of transporter-mediated disposition of phase II conjugates. We review the literature on hepatic, intestinal and renal uptake transporters participating in the transport of glucuronide and sulfate metabolites of drugs, other xenobiotics and endobiotics. In addition, we provide an update on the involvement of efflux transporters in the disposition of glucuronide and sulfate metabolites. Finally, we discuss the interplay between uptake and efflux transport in the intestine, liver and kidneys as well as the role of transporters in glucuronide and sulfate conjugate toxicity, drug interactions, pharmacogenetics and species differences.

葡萄糖醛酸化（glucuronidation）与硫酸化（sulfation）是药物最为典型的II相代谢反应。所生成的葡萄糖醛酸苷与硫酸酯结合物通常被认为无活性且安全性良好。然而，它们可能是人体循环与排泄物中最主要的药物相关物质。药物的葡萄糖醛酸苷与硫酸酯代谢物通常细胞膜通透性有限，因此其在人体内的分布与排泄需要转运蛋白介导。摄取型转运体，如有机阴离子转运体（OATs和OATPs），可介导结合物被摄取进入肝脏与肾脏；而外排型转运体，如多药耐药蛋白（MRPs）与乳腺癌耐药蛋白（BCRP），则可介导结合物被排泄至胆汁、尿液与肠腔中。阐明结合型药物代谢物的主动转运机制，对于预测药物在体内的处置过程及其安全性与有效性具有重要意义。本综述旨在梳理当前对于转运体介导的II相结合物处置过程的认知。我们综述了参与转运药物、其他外源性物质及内源性物质的葡萄糖醛酸苷与硫酸酯代谢物的肝脏、肠道与肾脏摄取型转运体相关研究文献。此外，我们还更新了外排型转运体在葡萄糖醛酸苷与硫酸酯代谢物处置过程中的作用相关进展。最后，我们讨论了肠道、肝脏与肾脏中摄取与外排转运过程之间的相互作用，以及转运体在葡萄糖醛酸苷与硫酸酯结合物毒性、药物相互作用、药物基因组学及种属差异中的作用。