Department of Pharmacokinetics, Dynamics & Metabolism, Pfizer Global Research & Development, Ramsgate Road, Sandwich, Kent, UK.
Drug Metab Dispos. 2010 Sep;38(9):1471-9. doi: 10.1124/dmd.109.030999. Epub 2010 Jun 1.
Bazedoxifene (BZA) acetate, a novel estrogen receptor modulator being developed for the prevention and treatment of postmenopausal osteoporosis, undergoes extensive metabolism in women after oral administration. In this study, the in vitro metabolism of [(14)C]BZA was determined in human hepatocytes and hepatic and intestinal microsomes, and the UDP glucuronosyltransferase (UGT) isozymes involved in the glucuronidation of BZA were identified. In addition, BZA was evaluated for its potential as a substrate of P-glycoprotein (P-gp) transporter in Caco-2 cell monolayers. BZA was metabolized to two monoglucuronides, BZA-4'-glucuronide and BZA-5-glucuronide, in hepatocytes and in liver and intestinal microsomes including jejunum, duodenum, and ileum. Both BZA-4'-glucuronide and BZA-5-glucuronide were major metabolites in the intestinal microsomes, whereas BZA-4'-glucuronide was the predominant metabolite in liver microsomes and hepatocytes. The kinetic parameters of BZA-4'-glucuronide formation were determined in liver, duodenum, and jejunum microsomes and with UGT1A1, 1A8, and 1A10, the most active UGT isoforms involved in the glucuronidation of BZA, whereas those of BZA-5-glucuronide were determined with all the enzyme systems except in liver microsomes and in UGT1A1 because the formation of the BZA-5-glucuronide was too low. K(m) values in liver, duodenum, and jejunum microsomes and UGT1A1, 1A8, and 1A10, were similar and ranged from 5.1 to 33.1 microM for BZA-4'-glucuronide formation and from 2.5 to 11.1 microM for BZA-5-glucuronide formation. V(max) values ranged from 0.8 to 2.9 nmol/(min . mg) protein for BZA-4'-glucuronide and from 0.1 to 1.2 nmol/(min . mg) protein for BZA-5-glucuronide. In Caco-2 cells, BZA appeared to be a P-gp substrate.
倍他索福汀（BZA）醋酸酯是一种新型的雌激素受体调节剂，用于预防和治疗绝经后骨质疏松症。在女性口服后，它会在体内广泛代谢。本研究在人肝细胞和肝微粒体及肠微粒体中测定了[14C]BZA 的体外代谢情况，并鉴定了参与 BZA 葡萄糖醛酸化的尿苷二磷酸葡萄糖醛酸转移酶（UGT）同工酶。此外，还评估了 BZA 作为 Caco-2 细胞单层中 P-糖蛋白（P-gp）转运体底物的潜力。BZA 在肝细胞中和肝及肠微粒体（包括空肠、十二指肠和回肠）中代谢为两种单葡萄糖醛酸苷，BZA-4'-葡萄糖醛酸苷和 BZA-5-葡萄糖醛酸苷。BZA-4'-葡萄糖醛酸苷和 BZA-5-葡萄糖醛酸苷都是肠微粒体中的主要代谢物，而 BZA-4'-葡萄糖醛酸苷是肝微粒体和肝细胞中的主要代谢物。BZA-4'-葡萄糖醛酸苷形成的动力学参数在肝、十二指肠和空肠微粒体中以及 UGT1A1、1A8 和 1A10 中进行了测定，这些是参与 BZA 葡萄糖醛酸化的最活跃的 UGT 同工酶，而 BZA-5-葡萄糖醛酸苷的动力学参数则在除肝微粒体和 UGT1A1 之外的所有酶系统中进行了测定，因为 BZA-5-葡萄糖醛酸苷的形成过低。肝、十二指肠和空肠微粒体以及 UGT1A1、1A8 和 1A10 中 BZA-4'-葡萄糖醛酸苷形成的 K(m)值相似，范围为 5.1 至 33.1 μM，BZA-5-葡萄糖醛酸苷形成的 K(m)值为 2.5 至 11.1 μM。BZA-4'-葡萄糖醛酸苷的 V(max)值范围为 0.8 至 2.9 nmol/(min·mg)蛋白，BZA-5-葡萄糖醛酸苷的 V(max)值范围为 0.1 至 1.2 nmol/(min·mg)蛋白。在 Caco-2 细胞中，BZA 似乎是 P-gp 底物。
