Maeda Yorinobu, Goto Yuta, Ohnishi Fumiya, Koga Syoutarou, Kawano Satoshi, Hieda Yuhzo, Goromaru Takeshi, Murakami Teruo
Laboratory of Drug Information Analytics, Faculty of Pharmacy & Pharmaceutical Sciences, Fukuyama University, Hiroshima 729-0292, Japan.
Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, 1 Sanzo, Fukuyama 729-0292, Japan.
Pharmaceutics. 2024 Dec 7;16(12):1567. doi: 10.3390/pharmaceutics16121567.
5-Aminosalicylic acid (5-ASA), the first-line therapy for ulcerative colitis, is a poorly soluble zwitterionic drug. Unformulated 5-ASA is thought to be extensively absorbed in the small intestine.
The pH-dependent solubility of 5-ASA in vitro and the intestinal membrane distribution of 5-ASA and its N-acetyl metabolite (AC-5-ASA) after the oral administration of 5-ASA were examined in fed rats. 5-ASA was administered as a suspension in water, 0.1 M HCl, or 0.1 M NaOH to untreated rats or as a solution in 5% NaHCO to lansoprazole-pretreated rats.
5-ASA solubility in vitro was higher at pH < 2 and pH > 7. In rats, the 5-ASA and AC-5-ASA were detected mostly in the small intestine at 3 h and in the colonic region at 8 h after administration. The dosing vehicle (suspension or solution) and lansoprazole pretreatment did not significantly affect the pH of the luminal fluid in rats or the 5-ASA distribution in membranes.
The 5-ASA distribution in membranes in the proximal intestine was found to be restricted by the intrinsic regional luminal pH, low solubility, and saturable membrane permeability. Unabsorbed 5-ASA in the proximal intestine was delivered to the distal intestine. The higher the oral dose of 5-ASA, the more 5-ASA may be delivered to the distal intestine due to the restricted absorption in the small intestine.
5-氨基水杨酸（5-ASA）是溃疡性结肠炎的一线治疗药物，是一种难溶性两性离子药物。未制成制剂的5-ASA被认为在小肠中会被大量吸收。
在喂食的大鼠中研究了5-ASA在体外的pH依赖性溶解度以及口服5-ASA后5-ASA及其N-乙酰代谢物（AC-5-ASA）在肠膜中的分布。将5-ASA以水、0.1 M盐酸或0.1 M氢氧化钠中的混悬液形式给予未处理的大鼠，或以5%碳酸氢钠溶液形式给予兰索拉唑预处理的大鼠。
5-ASA在体外的溶解度在pH < 2和pH > 7时较高。在大鼠中，给药后3小时5-ASA和AC-5-ASA主要在小肠中被检测到，8小时时在结肠区域被检测到。给药载体（混悬液或溶液）和兰索拉唑预处理对大鼠肠腔液的pH或5-ASA在膜中的分布没有显著影响。
发现5-ASA在近端肠道膜中的分布受到固有区域肠腔pH、低溶解度和饱和膜通透性的限制。近端肠道中未吸收的5-ASA被输送到远端肠道。5-ASA的口服剂量越高，由于在小肠中吸收受限，可能有更多的5-ASA被输送到远端肠道。
