Institute of Pharmaceutical Technology, Johann Wolfgang Goethe University, 60438 Frankfurt am Main, Germany.
J Pharm Sci. 2010 Jun;99(6):2899-904. doi: 10.1002/jps.22026.
Delayed absorption of nifedipine when administered as a 20 mg immediate release soft gelatin capsule to fasted volunteers has been reported. Physiologically based pharmacokinetic (PBPK) modeling and in vitro dissolution data were used to explore our hypothesis that at high doses of nifedipine it precipitates in the stomach. Plasma concentration-time profiles following different doses of nifedipine were simulated using commercial PBPK software and compared to in vivo data. In vitro dissolution tests were performed with Adalat 10 mg capsules in different volumes of fasted state simulated gastric fluid (FaSSGF). The discrepancy in plasma concentration-time profiles between the different nifedipine doses could be well simulated, assuming protracted dissolution for the 20 mg dose. Nifedipine release from one Adalat 10 capsule in 250 or 500 mL FaSSGF was completed within 15 min whereas when release from two capsules, corresponding to 20 mg nifedipine, was studied in 250 mL FaSSGF, a maximum of about 75% drug dissolved was observed after 15 min followed by a decline in the % dissolved to a final value of approximately 40%. Based on the in silico and in vitro results it can be concluded that the observed prolongation in nifedipine absorption following the 20 mg dose was likely caused by nifedipine precipitation in human stomach.
据报道，将硝苯地平作为 20mg 速释软胶囊给空腹志愿者服用时，其吸收会延迟。采用基于生理的药代动力学（PBPK）模型和体外溶出数据来探讨我们的假设，即在高剂量硝苯地平时，它会在胃中沉淀。使用商业 PBPK 软件模拟了不同剂量硝苯地平的血浆浓度-时间曲线，并将其与体内数据进行了比较。在不同体积的空腹模拟胃液（FaSSGF）中对 Adalat 10mg 胶囊进行了体外溶出试验。假设 20mg 剂量的溶出时间延长，可以很好地模拟不同硝苯地平剂量的血浆浓度-时间曲线之间的差异。一个 Adalat 10 胶囊在 250 或 500mL FaSSGF 中的硝苯地平释放在 15 分钟内完成，而当在 250mL FaSSGF 中研究两个胶囊（相当于 20mg 硝苯地平）的释放时，在 15 分钟后观察到最大约 75%的药物溶解，随后溶解的%下降到最终值约为 40%。基于体内和体外结果，可以得出结论，观察到的 20mg 剂量后硝苯地平吸收延长可能是由于硝苯地平在人胃中的沉淀所致。
