DMPK Research Laboratory, Mitsubishi Tanabe Corporation, 2-2-50, Kawagishi, Toda-shi, Saitama, 335-8505, Japan.
Drug Metab Dispos. 2011 Sep;39(9):1495-502. doi: 10.1124/dmd.111.040030. Epub 2011 Jun 6.
Raloxifene is extensively glucuronidated in humans, effectively reducing its oral bioavailability (2%). It was also reported to be glucuronidated in preclinical animals, but its effects on the oral bioavailability have not been fully elucidated. In the present study, raloxifene and its glucuronides in the portal and systemic blood were monitored in Gunn rats deficient in UDP-glucuronosyltransferase (UGT) 1A, Eisai hyperbilirubinemic rats (EHBRs), which hereditarily lack multidrug resistance-associated protein (MRP) 2, and wild-type rats after oral administration. The in vitro-in vivo correlation (IVIVC) of four UGT substrates (raloxifene, biochanin A, gemfibrozil, and mycophenolic acid) in rats was also evaluated. In Gunn rats, the product of fraction absorbed and intestinal availability and hepatic availability of raloxifene were 0.63 and 0.43, respectively; these values were twice those observed in wild-type Wistar rats, indicating that raloxifene was glucuronidated in both the liver and intestine. The ratio of glucuronides to unchanged drug in systemic blood was substantially higher in EHBRs (129-fold) than in the wild-type Sprague-Dawley rats (10-fold), suggesting the excretion of raloxifene glucuronides caused by MRP2. The IVIVC of the other UGT substrates in rats displayed a good relationship, but the oral clearance values of raloxifene and biochanin A, which were extensively glucuronidated by rat intestinal microsomes, were higher than the predicted clearances using rat liver microsomes, suggesting that intestinal metabolism may be a great contributor to the first-pass effect. Therefore, evaluation of intestinal and hepatic glucuronidation for new chemical entities is important to improve their pharmacokinetic profiles.
雷洛昔芬在人体内广泛发生葡萄糖醛酸化反应，使药物的口服生物利用度（2%）显著降低。有报道称，该药在临床前动物体内也发生葡萄糖醛酸化反应，但有关其对口服生物利用度的影响尚未完全阐明。在本研究中，我们在缺乏 UDP-葡糖醛酸基转移酶（UGT）1A 的 Gunn 大鼠、遗传性缺乏多药耐药相关蛋白 2（MRP2）的 Eisai 高胆红素血症大鼠（EHBR）和口服给药后的野生型大鼠中，监测了门静脉和全身血液中的雷洛昔芬及其葡萄糖醛酸结合物。我们还评估了大鼠中 4 种 UGT 底物（雷洛昔芬、大豆苷元、吉非贝齐和麦考酚酸）的体外-体内相关性（IVIVC）。在 Gunn 大鼠中，雷洛昔芬的吸收分数、肠内可用性和肝内可用性的产物分别为 0.63 和 0.43；这些值是野生型 Wistar 大鼠的两倍，表明雷洛昔芬在肝脏和肠道中均发生葡萄糖醛酸化反应。在 EHBR 中，系统血液中葡萄糖醛酸结合物与原形药物的比值（129 倍）显著高于野生型 Sprague-Dawley 大鼠（10 倍），提示雷洛昔芬葡萄糖醛酸结合物由 MRP2 排泄。大鼠中其他 UGT 底物的 IVIVC 显示出良好的相关性，但在大鼠肠微粒体中广泛发生葡萄糖醛酸化的雷洛昔芬和大豆苷元的口服清除率值高于使用大鼠肝微粒体预测的清除率值，提示肠道代谢可能是首过效应的重要贡献者。因此，评估新化学实体的肠内和肝内葡萄糖醛酸化对于改善其药代动力学特征非常重要。
