Interaction with Mixed Micelles in the Intestine Attenuates the Permeation Enhancing Potential of Alkyl-Maltosides

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• 作者：Kerstin Gradauer ; Ayano Nishiumi ; Kota Unrinin ; Haruki Higashino ; Makoto Kataoka ; Betty L. Pedersen ; Stephen T. Buckley ; Shinji Yamashita
• 刊名：Molecular Pharmaceutics
• 出版年：2015
• 出版时间：July 6, 2015
• 年：2015
• 卷：12
• 期：7
• 页码：2245-2253
• 全文大小：354K
• ISSN：1543-8392

文摘

The purpose of the present study was to investigate the interaction of intestinal permeation enhancers with lipid and surfactant components present in the milieu of the small intestine. Maltosides of different chain lengths (decyl-, dodecyl-, and tetradecyl-maltoside; DM, DDM, TDM, respectively) were used as examples of nonionic, surfactant-like permeation enhancers, and their effect on the permeation of FD₄ across Caco-2 monolayers was monitored. To mimic the environment of the small intestine, modified versions of fasted and fed state simulated intestinal fluid (FaSSIF_mod, FeSSIF_mod6.5, respectively) were used in addition to standard transport media (TM). Compared to the buffer control, 0.5 mM DDM led to a 200-fold permeation enhancement of FD₄ in TM. However, this was dramatically decreased in FaSSIF_mod, where a concentration of 5 mM DDM was necessary in order to elicit a moderate, 4-fold, permeation enhancement. Its capacity to promote permeation was diminished further when FeSSIF_mod6.5 was employed. Even when cells were exposed to a concentration of 5 mM, no significant permeation enhancement of FD₄ was observed. Analogous effects were observed in the case of DM and TDM, with slight deviations on account of differences in their critical micelle concentration (CMC). This observation was corroborated by calculating the amount of maltoside monomer versus micellar bound maltoside in FaSSIF_mod and FeSSIF_mod6.5, which demonstrated a reduced amount of free monomer in these fluids. To evaluate the in vivo significance of our findings, DDM solutions in TM, FaSSIF_mod, and FeSSIF_mod6.5 were used for closed intestinal loop studies in rats. Consistent with the results found in in vitro permeation studies, these investigations illustrated the overwhelming impact of sodium taurocholate/lecithin micelles on the permeation enhancing effect of DDM. While DDM led to a 20-fold increase in FD₄ bioavailability when it was applied in TM, no significant permeation enhancement was seen in FaSSIF_mod/FeSSIF_mod6.5. Collectively, these investigations highlight the importance of using biorelevant media when evaluating the potency of permeation enhancers. In doing so, this ensures improved correlations between in vitro and in vivo studies and thus enables an early and more accurate assessment of promising permeation enhancers.