Marathe P H, Sandefer E P, Kollia G E, Greene D S, Barbhaiya R H, Lipper R A, Page R C, Doll W J, Ryo U Y, Digenis G A
Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, USA.
J Pharmacokinet Biopharm. 1998 Feb;26(1):1-20. doi: 10.1023/a:1023236823320.
The study was conducted to assess the bioavailability of avitriptan after a standard high fat meal, in relation to gastrointestinal transit. Six healthy male subjects were enrolled in a four-period study with a partial replicate design where each was administered 150-mg avitriptan capsule (i) after an overnight fast, (ii) 5 min after a standard high-fat breakfast, and (iii) 4 hr after a standard high fat breakfast. The treatment administered in Period 3 was repeated in Period 4 to assess intrasubject variations in pharmacokinetics and gastrointestinal (GI) transit. Avitriptan capsules were specially formulated with nonradioactive samarium chloride hexahydrate which was neutron-activated to gamma-emitting samarium before dosing. Serial blood samples were collected for analysis of avitriptan up to 24-hr postdose, and serial scintigraphic images were obtained to assess the plasma concentration-time profile in relation to the GI transit of the avitriptan capsule contents. Bioavailability of avitriptan was reduced when administered in the fed condition but only the decrease in AUC(INF) was statistically significant. Tmax was significantly delayed between the fed conditions and the fasted condition. Qualitative appearance of plasma concentration-time profiles for avitriptan could be related to the manner in which the drug emptied from the stomach. It was also apparent that avitriptan exerted a secondary pharmacologic effect that temporarily suspended gastric emptying in the fasted treatment. Thus, when gastric emptying was interrupted and then resumed, the net result was a double peak in some of the individual plasma concentration profiles. Scintigraphic analysis also demonstrated that upon emptying from the stomach, avitriptan was rapidly absorbed from the upper small intestine. In the fed state, gastric emptying was slow and continuous resulting in extended absorption and a lower occurrence of double peaks. Qualitatively, the intrasubject variability in Cmax and AUC could be explained by the intrasubject variability in gastric emptying in both fasted and fed conditions.
本研究旨在评估标准高脂餐后阿伐曲坦的生物利用度及其与胃肠道转运的关系。六名健康男性受试者参与了一项为期四个阶段的部分重复设计研究，每位受试者分别在以下情况下服用150毫克阿伐曲坦胶囊：(i) 过夜禁食后；(ii) 标准高脂早餐后5分钟；(iii) 标准高脂早餐后4小时。在第4阶段重复第3阶段的治疗，以评估受试者体内药代动力学和胃肠道（GI）转运的个体差异。阿伐曲坦胶囊特别配制有非放射性六水合氯化钐，给药前经中子活化成为发射γ射线的钐。在给药后长达24小时内采集系列血样用于分析阿伐曲坦，并获取系列闪烁图像以评估与阿伐曲坦胶囊内容物胃肠道转运相关的血浆浓度-时间曲线。在进食状态下给药时，阿伐曲坦的生物利用度降低，但只有AUC(INF)的降低具有统计学意义。进食状态和禁食状态之间Tmax显著延迟。阿伐曲坦血浆浓度-时间曲线的定性表现可能与药物从胃中排空的方式有关。同样明显的是，阿伐曲坦具有次要药理作用，可在禁食治疗中暂时中止胃排空。因此，当胃排空中断然后恢复时，最终结果是一些个体血浆浓度曲线出现双峰。闪烁扫描分析还表明，从胃中排空后，阿伐曲坦迅速从小肠上段吸收。在进食状态下，胃排空缓慢且持续，导致吸收延长且双峰出现的发生率较低。定性地说，禁食和进食状态下Cmax和AUC的个体内变异性可以通过胃排空的个体内变异性来解释。
