The major therapeutic strategy for acid-related gastrointestinal diseases in clinic is to reduce the excretion of gastric acid by oral administration of proton-pump inhibitors (PPIs). However, it is quite a challenge to study the oral absorption behaviors of PPIs considering their extreme instability under gastrointestinal environment. As a result, little information has been reported on PPI oral absorption so far, hindering the further development of PPI-contained oral preparations. Here, we first investigated the degradation rate of three representative PPIs, including ilaprazole, ilaprazole sodium and rabeprazole sodium. Then a modified in situ intestine absorption method in rat was established:through the temperature control by the heat exchangers, the perfusate was kept at physiological temperature only when passing through the intestine while it was maintained at 4 °C outside the intestine. Therefore PPIs could maintained sufficiently high stability under proper temperature control. Our data demonstrated that both ilaprazole and ilaprazole sodium exhibited significantly higher absorption efficiency than rabeprazole sodium did through the comparison of their apparent permeability coefficients and steady-state plasma concentrations after perfusion in the duodenum, jejunum, ileum and colon, mainly attributing to their more suitable oil-water partition coefficient. The duodenum could be the best site for the oral absorption of PPIs. Ilaprazole outperformed its sodium salt form with its stable absorption behavior in tested four intestinal segments. Furthermore, after intravenous or oral administration, ilaprazole exhibited a longer residence time and a higher accumulation in the stomach than in most of other tissues/organs. However, it was also found that the accumulation was heterogeneous and mainly located in mucosa cells of the stomach. Our further study indicated that there was no significant difference on the oral absorption efficiency of ilaprazole between female and male rats but ilaprazole underwent a faster metabolism in male rats after oral absorption. Our study provided a valuable guidance for the design of oral formulation and the optimization of PPI-contained formulations.

中文翻译：

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质子泵抑制剂体内肠道吸收和生物分布的研究。

临床上与酸有关的胃肠道疾病的主要治疗策略是通过口服质子泵抑制剂（PPI）来减少胃酸的排泄。然而，考虑到PPI在胃肠环境下的极度不稳定，研究PPI的口服吸收行为是一个挑战。结果，到目前为止，关于PPI口服吸收的信息很少，阻碍了含PPI的口服制剂的进一步开发。在这里，我们首先研究了三种代表性PPI的降解率，包括ilaprazole，ilaprazole钠和rabeprazole钠。然后建立了改良的大鼠原位肠吸收方法：通过换热器控制温度，灌注液仅在通过肠道时才保持在生理温度，而在肠道外则保持在4°C。因此，PPI在适当的温度控制下可以保持足够高的稳定性。我们的数据表明，通过比较十二指肠，空肠，回肠和结肠的灌注后的表观渗透系数和稳态血药浓度，艾拉唑和艾拉唑钠的吸收效率均明显高于拉贝拉唑钠，主要归因于它们更合适油水分配系数。十二指肠可能是口服吸收PPI的最佳部位。在测试的四个肠段中，依拉拉唑的钠盐形式具有稳定的吸收性能，其表现优于钠盐形式。此外，静脉或口服给药后，与大多数其他组织/器官相比，艾拉拉唑在胃中的显示时间更长，并且积累更高。然而，还发现积累是异质的，并且主要位于胃的粘膜细胞中。我们的进一步研究表明，雌性和雄性大鼠对艾拉普拉唑的口服吸收效率没有显着差异，但口服吸收后，艾拉拉唑在雄性大鼠中的代谢更快。我们的研究为口服制剂的设计和优化含PPI的制剂提供了有价值的指导。还发现积累是异质的，并且主要位于胃的粘膜细胞中。我们的进一步研究表明，雌性和雄性大鼠对艾拉普拉唑的口服吸收效率没有显着差异，但口服吸收后，艾拉拉唑在雄性大鼠中的代谢更快。我们的研究为口服制剂的设计和优化含PPI的制剂提供了有价值的指导。还发现积累是异质的，并且主要位于胃的粘膜细胞中。我们的进一步研究表明，雌性和雄性大鼠对艾拉普拉唑的口服吸收效率没有显着差异，但口服吸收后，艾拉拉唑在雄性大鼠中的代谢更快。我们的研究为口服制剂的设计和优化含PPI的制剂提供了有价值的指导。