Central Research Laboratories, ZERIA Pharmaceutical Co., Ltd., Saitama, Japan.
Mol Pharm. 2011 Aug 1;8(4):1083-9. doi: 10.1021/mp200088z. Epub 2011 May 19.
Asacol, a medication that delivers delayed release 5-aminosalicylic acid (5-ASA), is a useful therapeutic agent for inflammatory bowel disease (IBD), but the relationship between its pharmacological actions and intestinal concentrations has not been studied in detail. Therefore, our aim was to assess 5-ASA's pharmacological actions as a function of its concentration at its target site. We first evaluated 5-ASA's release profiles in vitro by the paddle method and found that Asacol starts to release 5-ASA at pH ≥ 7. Orally administered Asacol pharmacokinetic parameters were evaluated in dogs. Asacol's T(max) was much longer than that of the time-dependent release 5-ASA formulation. We also determined 5-ASA's distribution in the intestinal mucosa and found that it is effectively delivered there by Asacol. These results indicated that Asacol released 5-ASA in a pH-dependent manner, resulting in efficient delivery to the large intestine. We also compared the mucosal 5-ASA concentrations with the IC(50) values for scavenging free radicals or suppressing LTB(4) production. The 5-ASA concentration in the large intestine was higher than IC(50) values necessary to suppress inflammatory processes. We also report the release characteristics of Asacol and the targeted delivery of 5-ASA to affected sites in IBD patients.
艾塞可，一种能够提供 5-氨基水杨酸（5-ASA）的延迟释放药物，是一种治疗炎症性肠病（IBD）的有效治疗药物，但它的药理作用与其在肠道中的浓度之间的关系尚未得到详细研究。因此，我们的目的是评估 5-ASA 的药理作用与其在靶部位的浓度之间的关系。我们首先通过桨法评估了 5-ASA 的体外释放曲线，并发现艾塞可在 pH 值≥7 时开始释放 5-ASA。我们还在狗体内评估了口服艾塞可的药代动力学参数。艾塞可的 T(max)明显长于时间依赖性释放 5-ASA 制剂。我们还测定了 5-ASA 在肠黏膜中的分布，发现艾塞可能有效地将其递送至大肠。这些结果表明，艾塞可以 pH 依赖性的方式释放 5-ASA，从而有效地将其递送至大肠。我们还比较了黏膜 5-ASA 浓度与清除自由基或抑制 LTB4 产生的 IC50 值。大肠中的 5-ASA 浓度高于抑制炎症过程所需的 IC50 值。我们还报告了艾塞可的释放特性以及在 IBD 患者中对受影响部位的 5-ASA 靶向递送。
