Tanaka Yusuke, Sugihara Masahisa, Kawakami Ayaka, Imai So, Itou Takafumi, Murase Hirokazu, Saiki Kazunori, Kasaoka Satoshi, Yoshikawa Hiroshi
Laboratory of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hiro-koshingai, Kure, Hiroshima 737-0112, Japan.
Sawai Pharmaceutical Co., Ltd., 5-2-30 Miyahara, Yodogawa-ku, Osaka, Osaka 532-0003, Japan.
Eur J Pharm Sci. 2017 Aug 30;106:431-438. doi: 10.1016/j.ejps.2017.06.011. Epub 2017 Jun 9.
The purpose of this study was to evaluate in vivo supersaturation/precipitation/absorption behavior in the gastrointestinal (GI) tract based on the luminal concentration-time profiles after oral administration of pioglitazone (PG, a highly permeable lipophilic base) and its hydrochloride salt (PG-HCl) to rats. In the in vitro precipitation experiment in the classic closed system, while the supersaturation was stable in the simulated gastric condition, PG drastically precipitated in the simulated intestinal condition, particularly at a higher initial degree of supersaturation. Nonetheless, a drastic and moderate improvement in absorption was observed in vivo at a low and high dose of PG-HCl, respectively. Analysis based on the luminal concentration of PG after oral administration of PG-HCl at a low dose revealed that most of the dissolved PG emptied from the stomach was rapidly absorbed before its precipitation in the duodenum. At a high dose of PG-HCl, PG partly precipitated in the duodenum but was absorbed to some extent. Therefore, the extent of the absorption was mainly dependent on the duodenal precipitation behavior. Furthermore, a higher-than expected absorption after oral administration of PG-HCl from in vitro precipitation study may be due to the absorption process in the small intestine, which suppresses the precipitation by removal of the drug. This study successfully clarify the impact of the absorption process on the supersaturation/precipitation/absorption behavior and key absorption site for a salt formulation of a highly permeable lipophilic base based on the direct observation of in vivo luminal concentration. Our findings may be beneficial in developing an ideal physiologically based pharmacokinetic model and in vitro predictive dissolution tools and/or translating the in silico and in vitro data to the in vivo outcome.
本研究的目的是基于对大鼠口服吡格列酮（PG，一种高渗透性亲脂性碱）及其盐酸盐（PG-HCl）后胃肠道（GI）管腔内浓度-时间曲线，评估其在胃肠道中的体内过饱和/沉淀/吸收行为。在经典封闭系统的体外沉淀实验中，虽然在模拟胃液条件下过饱和状态稳定，但PG在模拟肠液条件下会急剧沉淀，尤其是在较高的初始过饱和度时。尽管如此，分别在低剂量和高剂量的PG-HCl给药后，在体内观察到吸收有显著和适度的改善。基于低剂量PG-HCl口服给药后PG的管腔内浓度分析表明，从胃中排空的大部分溶解PG在十二指肠沉淀之前就被迅速吸收了。在高剂量的PG-HCl给药时，PG在十二指肠部分沉淀，但仍有一定程度的吸收。因此，吸收程度主要取决于十二指肠的沉淀行为。此外，从体外沉淀研究来看，PG-HCl口服给药后高于预期的吸收可能是由于小肠中的吸收过程，该过程通过药物的消除抑制了沉淀。本研究基于对体内管腔内浓度的直接观察，成功阐明了吸收过程对高渗透性亲脂性碱盐制剂的过饱和/沉淀/吸收行为的影响以及关键吸收部位。我们的研究结果可能有助于建立理想的生理药代动力学模型和体外预测溶出工具，和/或将计算机模拟和体外数据转化为体内结果。
