Uoti Arttu, Kurkela Mika, Niemi Mikko, Oksanen Timo, Oswald Stefan, Puustinen Lauri, Kidron Heidi, Sjöstedt Noora
Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
Drug Research Program, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
Basic Clin Pharmacol Toxicol. 2025 Jan;136(1):e14107. doi: 10.1111/bcpt.14107.
Raloxifene has low bioavailability due to extensive glucuronidation in the intestine and the liver, and its pharmacokinetics is associated with high intra- and interindividual variability. Some of this variability could be explained by the enterohepatic recycling of raloxifene, which is driven by transporter-mediated uptake and efflux and gut microbial deglucuronidation of raloxifene glucuronides. These individual processes involved in raloxifene disposition, however, have not been characterized in full detail. In this study, we evaluated the interactions of raloxifene and its three glucuronide metabolites (raloxifene 4'-glucuronide, raloxifene 6-glucuronide and raloxifene 4',6-diglucuronide) with drug transporters using Sf9 membrane vesicles and HEK293 cells. Additionally, we measured the deglucuronidation of raloxifene glucuronides in human faecal extracts. All raloxifene glucuronides were transported by MRP2 and MRP3, whereas raloxifene monoglucuronides were identified as substrates of OATP1B1, OATP1B3 and OATP2B1. All three raloxifene glucuronides were readily deglucuronidated in the presence of faecal extracts, although with high between-subject variability. The results of this study provide further understanding of the disposition of raloxifene, which can help understand the sources behind the interindividual variability in raloxifene pharmacokinetics.
雷洛昔芬在肠道和肝脏中会发生广泛的葡萄糖醛酸化，导致其生物利用度较低，并且其药代动力学存在较高的个体内和个体间变异性。这种变异性的部分原因可能是雷洛昔芬的肠肝循环，它由转运蛋白介导的摄取和外排以及雷洛昔芬葡萄糖醛酸苷的肠道微生物去葡萄糖醛酸化驱动。然而，这些参与雷洛昔芬处置的个体过程尚未得到充分详细的表征。在本研究中，我们使用Sf9膜囊泡和HEK293细胞评估了雷洛昔芬及其三种葡萄糖醛酸代谢物（雷洛昔芬4'-葡萄糖醛酸苷、雷洛昔芬6-葡萄糖醛酸苷和雷洛昔芬4',6-二葡萄糖醛酸苷）与药物转运蛋白的相互作用。此外，我们测量了人粪便提取物中雷洛昔芬葡萄糖醛酸苷的去葡萄糖醛酸化。所有雷洛昔芬葡萄糖醛酸苷均由MRP2和MRP3转运，而雷洛昔芬单葡萄糖醛酸苷被鉴定为OATP1B1、OATP1B3和OATP2B1的底物。在粪便提取物存在的情况下，所有三种雷洛昔芬葡萄糖醛酸苷都很容易发生去葡萄糖醛酸化，尽管个体间差异很大。本研究结果为雷洛昔芬的处置提供了进一步的认识，这有助于理解雷洛昔芬药代动力学个体间变异性背后的原因。
