Kataoka Makoto, Fukahori Miho, Ikemura Atsumi, Kubota Ayaka, Higashino Haruki, Sakuma Shinji, Yamashita Shinji
Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan.
Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan.
Eur J Pharm Biopharm. 2016 Apr;101:103-11. doi: 10.1016/j.ejpb.2016.02.002. Epub 2016 Feb 9.
The aim of the present study was to evaluate the effects of gastric pH on the oral absorption of poorly water-soluble drugs using an in vitro system. A dissolution/permeation system (D/P system) equipped with a Caco-2 cell monolayer was used as the in vitro system to evaluate oral drug absorption, while a small vessel filled with simulated gastric fluid (SGF) was used to reflect the gastric dissolution phase. After applying drugs in their solid forms to SGF, SGF solution containing a 1/100 clinical dose of each drug was mixed with the apical solution of the D/P system, which was changed to fasted state-simulated intestinal fluid. Dissolved and permeated amounts on applied amount of drugs were then monitored for 2h. Similar experiments were performed using the same drugs, but without the gastric phase. Oral absorption with or without the gastric phase was predicted in humans based on the amount of the drug that permeated in the D/P system, assuming that the system without the gastric phase reflected human absorption with an elevated gastric pH. The dissolved amounts of basic drugs with poor water solubility, namely albendazole, dipyridamole, and ketoconazole, in the apical solution and their permeation across a Caco-2 cell monolayer were significantly enhanced when the gastric dissolution process was reflected due to the physicochemical properties of basic drugs. These amounts resulted in the prediction of higher oral absorption with normal gastric pH than with high gastric pH. On the other hand, when diclofenac sodium, the salt form of an acidic drug, was applied to the D/P system with the gastric phase, its dissolved and permeated amounts were significantly lower than those without the gastric phase. However, the oral absorption of diclofenac was predicted to be complete (96-98%) irrespective of gastric pH because the permeated amounts of diclofenac under both conditions were sufficiently high to achieve complete absorption. These estimations of the effects of gastric pH on the oral absorption of poorly water-soluble drugs were consistent with observations in humans. In conclusion, the D/P system with the gastric phase may be a useful tool for better predicting the oral absorption of poorly water-soluble basic drugs. In addition, the effects of gastric pH on the oral absorption of poorly water-soluble drugs may be evaluated by the D/P system with and without the gastric phase.
本研究的目的是使用体外系统评估胃内pH值对难溶性药物口服吸收的影响。配备Caco-2细胞单层的溶出/渗透系统（D/P系统）用作评估口服药物吸收的体外系统，而装有模拟胃液（SGF）的小容器用于反映胃溶出阶段。将药物的固体形式加入SGF后，将含有每种药物1/100临床剂量的SGF溶液与D/P系统的顶端溶液混合，该顶端溶液已更换为禁食状态模拟肠液。然后监测2小时内药物溶解和渗透量与给药量的关系。使用相同药物进行了类似实验，但未设置胃阶段。根据D/P系统中药物渗透量，预测人类在有或无胃阶段情况下的口服吸收情况，假设无胃阶段的系统反映了胃内pH值升高时人类的吸收情况。由于碱性药物的物理化学性质，当反映胃溶出过程时，顶端溶液中难溶性碱性药物（即阿苯达唑、双嘧达莫和酮康唑）的溶解量及其跨Caco-2细胞单层的渗透量显著增加。这些量导致预测正常胃pH值时的口服吸收高于高胃pH值时的口服吸收。另一方面，当将酸性药物双氯芬酸钠的盐形式应用于有胃阶段的D/P系统时，其溶解和渗透量显著低于无胃阶段的情况。然而，无论胃pH值如何，双氯芬酸的口服吸收预计是完全的（96-98%），因为在两种情况下双氯芬酸的渗透量都足够高以实现完全吸收。这些关于胃pH值对难溶性药物口服吸收影响的估计与人体观察结果一致。总之，有胃阶段的D/P系统可能是更好预测难溶性碱性药物口服吸收的有用工具。此外，可通过有或无胃阶段的D/P系统评估胃pH值对难溶性药物口服吸收的影响。
