Zhou S Y, Fleisher D, Pao L H, Li C, Winward B, Zimmermann E M
College of Pharmacy, The University of Michigan, Ann Arbor, Michigan 48109-0586, USA.
Drug Metab Dispos. 1999 Apr;27(4):479-85.
The purpose of this study was to determine the characteristics of intestinal absorption and metabolism of 5-aminosalicylic acid (5ASA). Regional perfusions of 5ASA in the anesthetized rat resulted in the appearance of N-acetyl-5-aminosalicylic acid in the intestinal lumen. Lumenal metabolite appearance was proportional to 5ASA permeability, which was 5-fold higher in the jejunum than in the ileum. Intestinal elimination significantly decreases 5ASA absorption at low lumenal drug concentrations and this process is saturated at high drug concentrations. Metabolite levels in intestinal tissue were higher than plasma levels at low perfusion drug concentrations, whereas the reverse was observed at high concentrations. Transport and metabolism of 5ASA was studied in Caco-2 monolayers. At low drug concentrations, 5ASA was preferentially transported in the basolateral (BL) to apical (AP) direction. With 5ASA incubation in either the AP or BL chamber, the N-acetyl metabolite appeared only in the AP compartment. Transport of N-acetyl-5-aminosalicylic acid was also exclusively observed in the BL to AP direction. Clinical data indicate that anti-inflammatory response to oral 5ASA correlates with the amount of 5ASA delivered to the intestinal tissue. This study shows that at lumenal levels below 200 microg/ml (concentrations that are typically achieved by controlled release dosage forms), intestinal secretion of 5ASA accounts for more than 50% of the total elimination and can significantly affect tissue levels and, therefore, may be an important factor in determining the response to 5ASA therapy.
本研究的目的是确定5-氨基水杨酸（5ASA）的肠道吸收和代谢特征。在麻醉大鼠中对5ASA进行区域灌注，导致肠腔内出现N-乙酰-5-氨基水杨酸。肠腔代谢产物的出现与5ASA的通透性成正比，空肠中的通透性比回肠高5倍。在低肠腔药物浓度时，肠道消除显著降低5ASA的吸收，且该过程在高药物浓度时达到饱和。在低灌注药物浓度时，肠组织中的代谢产物水平高于血浆水平，而在高浓度时则观察到相反情况。在Caco-2单层细胞中研究了5ASA的转运和代谢。在低药物浓度时，5ASA优先从基底外侧（BL）向顶端（AP）方向转运。在AP或BL腔室中孵育5ASA时，N-乙酰代谢产物仅出现在AP隔室中。N-乙酰-5-氨基水杨酸的转运也仅在从BL到AP的方向上观察到。临床数据表明，口服5ASA的抗炎反应与递送至肠组织的5ASA量相关。本研究表明，在肠腔水平低于200μg/ml（通常由控释剂型达到的浓度）时，5ASA的肠道分泌占总消除量的50%以上，并且可显著影响组织水平，因此可能是决定对5ASA治疗反应的一个重要因素。
