Chandrasekaran Appavu, McKeand William E, Sullivan Pamela, DeMaio William, Stoltz Randall, Scatina JoAnn
Wyeth Research, Collegeville, PA 19426, USA.
Drug Metab Dispos. 2009 Jun;37(6):1219-25. doi: 10.1124/dmd.108.023861. Epub 2009 Mar 9.
Bazedoxifene is a selective estrogen receptor modulator under development for the prevention and treatment of osteoporosis. The disposition of [(14)C]bazedoxifene was determined in six healthy postmenopausal women after administration of a single oral dose of 20 mg (200 microCi). After dosing, blood was collected at frequent intervals, and urine and fecal samples were collected for up to 10 days. Aliquots of plasma, blood, urine, and fecal homogenates were analyzed for concentrations of radioactivity. Bazedoxifene metabolite profiles in plasma and feces were determined by high-performance liquid chromatography with radioactivity flow detection; metabolite structures were confirmed by liquid chromatography-mass spectrometry. Bazedoxifene was rapidly absorbed, exhibiting a mean peak plasma concentration of 3.43 ng/ml at 1.2 h postdose. The total mean recovery of the radioactive dose in excreta was 85.6%, with the majority recovered in feces (84.7%) and only a small fraction (0.81%) in urine. Radiochromatograms of plasma revealed that glucuronidation was the major metabolic pathway; little or no cytochrome P450-mediated metabolism was evident. The majority of circulating radioactivity was constituted by metabolites, with bazedoxifene-5-glucuronide being the predominant metabolite (up to 95%). Bazedoxifene-4'-glucuronide was a minor metabolite (up to 20%), and unchanged bazedoxifene represented 0 to 13% of the radioactivity in most plasma samples. Unchanged bazedoxifene was the major radioactive component in feces, however, reflecting unabsorbed drug and/or glucuronides that were hydrolyzed by intestinal bacterial enzymes. [(14)C]Bazedoxifene was generally well tolerated. These findings demonstrated that, after oral administration in healthy postmenopausal women, bazedoxifene was rapidly absorbed, metabolized via glucuronidation, and excreted predominantly in feces.
巴多昔芬是一种正在研发用于预防和治疗骨质疏松症的选择性雌激素受体调节剂。在6名健康绝经后女性单次口服20mg（200μCi）剂量后，测定了[¹⁴C]巴多昔芬的处置情况。给药后，频繁采集血液样本，并收集尿液和粪便样本长达10天。分析血浆、血液、尿液和粪便匀浆的等分试样中的放射性浓度。通过放射性流动检测的高效液相色谱法测定血浆和粪便中巴多昔芬的代谢物谱；通过液相色谱 - 质谱法确认代谢物结构。巴多昔芬吸收迅速，给药后1.2小时血浆平均峰值浓度为3.43ng/ml。排泄物中放射性剂量的总平均回收率为85.6%，大部分在粪便中回收（84.7%），仅一小部分（0.81%）在尿液中回收。血浆放射性色谱图显示葡萄糖醛酸化是主要代谢途径；几乎没有细胞色素P450介导的代谢明显可见。循环中的大部分放射性由代谢物组成，其中巴多昔芬 - 5 - 葡萄糖醛酸苷是主要代谢物（高达95%）。巴多昔芬 - 4'-葡萄糖醛酸苷是次要代谢物（高达20%），在大多数血浆样本中，未改变的巴多昔芬占放射性的0至13%。然而，未改变的巴多昔芬是粪便中的主要放射性成分，这反映了未吸收的药物和/或被肠道细菌酶水解的葡萄糖醛酸苷。[¹⁴C]巴多昔芬一般耐受性良好。这些发现表明，在健康绝经后女性口服给药后，巴多昔芬迅速吸收，通过葡萄糖醛酸化代谢，并主要通过粪便排泄。
