Purpose

Raloxifene undergoes extensive glucuronidation in the gastrointestinal (GI) tract and the liver. However, the impact of age on raloxifene disposition has never been studied. The purpose of this paper is to determine glucuronidation and Pharmacokinetics (PK) profiles of raloxifene in rats at different ages.

Methods

Raloxifene glucuronidation was characterized using S9 fractions prepared from different intestinal segments and the liver of F344 rats at 4-, 11-, and 28-week. PK studies were conducted to determine raloxifene oral bioavailability at different ages. Raloxifene and its glucuronides were quantified using LC-MS/MS.

Results

Raloxifene-6-glucuronide and raloxifene-4′-glucuronide were detected as the major metabolites and the ratio of these two glucuronides were different ranging from 2.1 to 4.9 folds in the ileum, jejunum, liver, and duodenum, and from 14.5 to 50 folds in the colon. The clearances in the duodenum at 4-week for both two glucuronides were significantly lower than those at the other two ages. PK studies showed that the oral bioavailability of raloxifene is age dependent. The absolute oral bioavailability of raloxifene was 3.5-folds higher at 4-week compared to that at 11-weeks. When raloxifene was administered through IV bolus, its half-life was 5.9 ± 1.16 h and 3.7 ± 0.68 h at 11-and 4-week, respectively.

Conclusion

These findings suggested that raloxifene metabolism in the duodenum was significantly slower at young age in rats, which increased the oral bioavailability of raloxifene. At 11-week, enterohepatic recycling efficiency was higher than that of 4-week. Raloxifene’s dose at different ages should be carefully considered.

中文翻译：

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雷洛昔芬在大鼠中的年龄和区域依赖性分布

目的

雷洛昔芬在胃肠道（GI）和肝脏中经历广泛的葡萄糖醛酸化。然而，从未研究过年龄对雷洛昔芬处置的影响。本文的目的是确定不同年龄大鼠中雷洛昔芬的葡萄糖醛酸化和药代动力学 (PK) 曲线。

方法

在 4、11 和 28 周时，使用从不同肠段和 F344 大鼠肝脏制备的 S9 组分表征雷洛昔芬葡萄糖醛酸化。进行 PK 研究以确定不同年龄的雷洛昔芬口服生物利用度。使用 LC-MS/MS 对雷洛昔芬及其葡糖苷酸进行定量。

结果

雷洛昔芬-6-葡萄糖苷酸和雷洛昔芬-4'-葡萄糖苷酸被检测为主要代谢物，这两种葡萄糖苷酸的比例在回肠、空肠、肝脏和十二指肠中的比例为2.1至4.9倍，在14.5至50倍之间在结肠。两种葡萄糖苷酸在 4 周时十二指肠的清除率均显着低于其他两个年龄组的清除率。PK 研究表明，雷洛昔芬的口服生物利用度与年龄有关。与 11 周相比，雷洛昔芬的绝对口服生物利用度在 4 周时高 3.5 倍。当通过静脉推注给予雷洛昔芬时，其半衰期在第 11 周和第 4 周时分别​​为 5.9 ± 1.16 小时和 3.7 ± 0.68 小时。

结论

这些发现表明，在大鼠年轻时，雷洛昔芬在十二指肠中的代谢明显减慢，这增加了雷洛昔芬的口服生物利用度。11周时，肠肝循环效率高于4周。应仔细考虑不同年龄的雷洛昔芬剂量。