Brouwers Joachim, Tack Jan, Augustijns Patrick
Laboratory for Pharmacotechnology and Biopharmacy, Katholieke Universiteit Leuven, Gasthuisberg O&N 2-Herestraat 49, box 921, Leuven, Belgium.
Pharm Res. 2007 Oct;24(10):1862-9. doi: 10.1007/s11095-007-9307-3. Epub 2007 Apr 19.
The purpose of this study was to explore the feasibility of linking the pharmacokinetic profile of a drug with its gastrointestinal behavior by simultaneously monitoring plasma and intraluminal drug concentrations. Fosamprenavir, a phosphate ester prodrug of the poorly water-soluble HIV-inhibitor amprenavir, was selected as model compound.
A single tablet of fosamprenavir (Telzir) was administered to 5 volunteers in the fasted and fed state (simulated by intake of a nutritional drink). Gastric and duodenal fluids were aspirated in function of time and characterized with respect to the concentration of (fos)amprenavir, inorganic phosphate and pH. In parallel, blood samples were collected and analyzed for amprenavir.
The observed plasma concentration-time profiles suggested a food-induced delay in the absorption of amprenavir: in the fed state, mean tmax increased by more than 150 min compared to the fasted state. A similar delay was seen in the duodenal appearance of fosamprenavir (concentrations in mM-range) and, after dephosphorylation, amprenavir (concentrations below 160 microM). This observation could be related to the behavior of fosamprenavir in the stomach. In the fasted state, gastric dissolution of fosamprenavir started immediately, resulting in a Cmax of 4 +/- 2 mM after 43 +/- 15 min; however, in the fed state, the fosamprenavir concentration remained below 20 microM for the first 90 min after drug intake. The postponed gastric dissolution may be attributed to a food-induced delay in tablet disintegration.
For the first time, the pharmacokinetic profile of a drug was monitored in parallel with its gastrointestinal concentrations. The observed food effect in the plasma concentration-time profile of amprenavir after intake of its phosphate ester prodrug could be related to a food-induced delay in gastric dissolution of fosamprenavir.
本研究的目的是通过同时监测血浆和肠腔内药物浓度，探索将药物的药代动力学特征与其胃肠道行为联系起来的可行性。选用水溶性差的HIV抑制剂安普那韦的磷酸酯前体药物福沙普那韦作为模型化合物。
向5名志愿者在禁食和进食状态下（通过摄入营养饮料模拟）服用一片福沙普那韦（泰尔齐）。根据时间抽取胃液和十二指肠液，并对（福）沙普那韦、无机磷酸盐浓度和pH值进行表征。同时，采集血样并分析安普那韦。
观察到的血浆浓度-时间曲线表明食物会导致安普那韦吸收延迟：在进食状态下，与禁食状态相比，平均达峰时间增加超过150分钟。福沙普那韦在十二指肠出现（浓度在毫摩尔范围内）以及去磷酸化后的安普那韦（浓度低于160微摩尔）也出现了类似的延迟。这一观察结果可能与福沙普那韦在胃中的行为有关。在禁食状态下，福沙普那韦的胃内溶解立即开始，43±15分钟后Cmax为4±2毫摩尔；然而，在进食状态下，服药后最初90分钟内福沙普那韦浓度仍低于20微摩尔。胃内溶解延迟可能归因于食物导致的片剂崩解延迟。
首次同时监测了药物的药代动力学特征及其胃肠道浓度。摄入其磷酸酯前体药物后，观察到的安普那韦血浆浓度-时间曲线中的食物效应可能与食物导致的福沙普那韦胃内溶解延迟有关。
