In vivo analysis of supersaturation/precipitation/absorption behavior after oral administration of pioglitazone hydrochloride salt; determinant site of oral absorption.
In vivo analysis of supersaturation/precipitation/absorption behavior after oral administration of pioglitazone hydrochloride salt; determinant site of oral absorption.
复制标题
口服盐酸吡格列酮后过饱和/沉淀/吸收行为的体内分析；
DOI：
10.1016/j.ejps.2017.06.011
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Yoshikawa H.
中科院分区：
文献类型：
--
作者：
Tanaka Y;Sugihara M;Kawakami A;Imai S;Itou T;Murase H;Saiki K;Kasaoka S;Yoshikawa H.
本研究的目的是评价大鼠口服高渗透亲脂基质吡格列酮(PG)及其盐酸盐(PG-HCl)后在胃肠道(GI)的体内过饱和/沉淀/吸收行为。在经典封闭体系中的体外沉淀实验中，在模拟胃条件下过饱和度稳定的情况下，在模拟肠道条件下PG大量沉淀，尤其是在较高的初始过饱和度时。尽管如此，在低剂量和高剂量PG-HCl的活体中，分别观察到了吸收的显著和适度的改善。根据口服低剂量PG-HCl后PG的管腔浓度分析表明，大部分从胃中排出的溶解PG在十二指肠中沉淀之前被迅速吸收。在高剂量PG-HCl作用下，PG在十二指肠内部分沉淀，但被一定程度吸收。因此，吸收的程度主要取决于十二指肠的沉淀行为。此外，口服来自体外沉淀研究的PG-HCl后的吸收高于预期，可能是由于小肠的吸收过程，这抑制了药物的析出。这项研究成功地阐明了吸收过程对高渗透亲油碱盐配方的过饱和/沉淀/吸收行为的影响和关键吸收部位，这是基于对液体浓度的直接观察。我们的发现可能有助于开发理想的基于生理的药代动力学模型和体外预测溶出度工具，和/或将硅胶和试管数据转化为活体结果。
The purpose of this study was to evaluatein vivosupersaturation/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 thein vitroprecipitation 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 observedin vivoat 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 fromin vitroprecipitation 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 ofin vivoluminal concentration. Our findings may be beneficial in developing an ideal physiologically based pharmacokinetic model andin vitropredictive dissolution tools and/or translating thein silicoandin vitrodata to thein vivooutcome.