Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium.
J Pharm Sci. 2013 Oct;102(10):3800-7. doi: 10.1002/jps.23698. Epub 2013 Aug 12.
The present study pursued to profile the intestinal solubility of nine HIV protease inhibitors (PIs) in fasted- and fed-state human intestinal fluids (FaHIF, FeHIF) aspirated from four volunteers. In addition, the ability of fasted- and fed-state simulated intestinal fluids (FaSSIF, FeSSIF) to predict the intestinal solubility was evaluated. All PIs were poorly soluble in FaHIF (from 7 μM for ritonavir to 327 μM for darunavir) and FeHIF (from 15 μM for atazanavir to 409μM for darunavir). For four of nine PIs, food intake significantly enhanced the solubilizing capacity of intestinal fluids (up to 18.4-fold increase for ritonavir). The intersubject variability (average coefficient of variance CVfed = 60.6%, CVfasted = 40.4%) was higher as compared with the intrasubject variability (CVfed = 41.3%, CVfasted = 20.5%). PI solubilities correlated reasonably well between FaSSIF and FaHIF (R = 0.817), but not between FeSSIF and FeHIF (R = 0.617). To conclude, postprandial conditions increased the inter- and intrasubject variability of the PIs. The inability of FeSSIF to accurately predict the FeHIF solubility emphasizes the need for a multivariate approach to determine solubility profiles, taking into account solid-state characteristics, pH, mixed bile acid/phospholipid micelles, and digestive products.
本研究旨在描述九种 HIV 蛋白酶抑制剂（PI）在空腹和进食状态下人肠液（FaHIF、FeHIF）中的肠溶性。此外，还评估了空腹和进食状态模拟肠液（FaSSIF、FeSSIF）预测肠溶性的能力。所有 PI 在 FaHIF 中的溶解度均较差（从利托那韦的 7 μM 到达芦那韦的 327 μM）和 FeHIF（从阿扎那韦的 15 μM 到达芦那韦的 409μM）。对于九种 PI 中的四种，进食显著增强了肠液的增溶能力（利托那韦的增溶能力增加了 18.4 倍）。与个体内变异性（CVfed = 41.3%，CVfasted = 20.5%）相比，个体间变异性（CVfed = 60.6%，CVfasted = 40.4%）更高。FaSSIF 和 FaHIF 之间的 PI 溶解度相关性较好（R = 0.817），但 FeSSIF 和 FeHIF 之间的相关性较差（R = 0.617）。总之，餐后条件增加了 PI 的个体间和个体内变异性。FeSSIF 无法准确预测 FeHIF 溶解度，这强调需要采用多变量方法来确定溶解度谱，同时考虑到固体状态特性、pH 值、混合胆汁酸/磷脂胶束和消化产物。
