Zhi J, Melia A T, Funk C, Viger-Chougnet A, Hopfgartner G, Lausecker B, Wang K, Fulton J S, Gabriel L, Mulligan T E
Hoffmann-La Roche, Inc. Nutley, New Jersey 07110-1199, USA.
J Clin Pharmacol. 1996 Nov;36(11):1006-11. doi: 10.1177/009127009603601104.
To determine the metabolic profile of minimally absorbed orlistat in obese/overweight patients, an open-label, single-dose study was performed in eight obese/overweight volunteers between 23 and 68 years of age. Each subject received a single oral dose of 360 mg orlistat containing approximately 400 muCi of 14C-labeled orlistat. Serial blood samples were collected at specified times over 10 hours after administration of orlistat for determination of total radioactivity, unchanged orlistat, and major metabolites in the plasma. Urine samples were collected over 24 hours and analyzed to evaluate the urinary recovery of total radioactivity and the profile of orlistat metabolites in the urine. In addition, all fecal samples were collected and analyzed for total radioactivity. Urinary and fecal recovery of the administered dose of total radioactivity were 1.13 +/- 0.50% (24-hour data only) and 96.4 +/- 18.1% (n = 7), respectively. Maximum observed concentration (Cmax) and time to Cmax (tmax) values of plasma total radioactivity were 150 +/- 51 ng.eq/mL and 6.8 +/- 1.5 hrs, respectively. All these parameters obtained in obese/ overweight subjects were similar to those reported previously in healthy subjects. On the basis of the area under the concentration-time curve from 0 to 10 hours (AUC0-10), two major metabolites comprise a total of approximately 42% of the total radioactivity in plasma. The primary metabolite (M1) has a short half-life (approximately 2 hours), whereas the secondary metabolite (M3) disappeared at a slower rate. No strikingly apparent difference in the urinary metabolic profile was observed between two gender groups. It is concluded that the disposition of orlistat appears to be similar between normal and obese/overweight subjects. Of the minimal fraction of the dose that was absorbed systemically, the presence of two major metabolites accounts for approximately 42%.
为了确定肥胖/超重患者中最小吸收量的奥利司他的代谢情况，对8名年龄在23至68岁之间的肥胖/超重志愿者进行了一项开放标签、单剂量研究。每位受试者口服单剂量360 mg奥利司他，其中含有约400 μCi的14C标记奥利司他。在服用奥利司他后的10小时内，在特定时间采集系列血样，以测定血浆中的总放射性、未变化的奥利司他和主要代谢物。收集24小时内的尿样并进行分析，以评估尿中总放射性的回收率以及尿中奥利司他代谢物的情况。此外，收集所有粪便样本并分析其总放射性。给药剂量的总放射性在尿中的回收率和粪便中的回收率分别为1.13±0.50%（仅24小时数据）和96.4±18.1%（n = 7）。血浆总放射性的最大观察浓度（Cmax）和达峰时间（tmax）值分别为150±51 ng.eq/mL和6.8±1.5小时。在肥胖/超重受试者中获得的所有这些参数与先前在健康受试者中报告的参数相似。根据0至10小时的浓度-时间曲线下面积（AUC0-10），两种主要代谢物总共约占血浆中总放射性的42%。主要代谢物（M1）半衰期较短（约2小时），而次要代谢物（M3）消失速度较慢。在两个性别组之间未观察到尿代谢情况有明显差异。结论是，正常受试者和肥胖/超重受试者中奥利司他的处置情况似乎相似。在全身吸收的最小剂量部分中，两种主要代谢物约占42%。
