A novel colon-specific steroid prodrug enhances sodium chloride absorption in rat colitis.
A novel colon-specific steroid prodrug enhances sodium chloride absorption in rat colitis.
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一种新型结肠特异性类固醇前药可增强大鼠结肠炎中氯化钠的吸收。
DOI：
10.1152/ajpgi.1995.269.2.g210
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发表时间：
1995
期刊：
影响因子：
--
通讯作者：
Empey,LR
中科院分区：
文献类型：
--
作者：
Fedorak,RN;Cui,N;Friend,DR;Madsen,KL;Empey,LR
最近合成的一种新的结肠特异性地塞米松前药-地塞米松-β-D-葡萄糖醛酸脂，可将有效剂量的地塞米松输送到结肠，但对肾上腺的抑制作用有限。在实验性大鼠结肠炎模型中，地塞米松前药在改善结肠液和电解质吸收损伤方面明显优于游离地塞米松。目前的研究检查了前药对结肠吸收的改善是否是由于钠和氯上皮转运的改变所致。在醋酸诱导的大鼠结肠炎模型上测试了地塞米松前药和游离地塞米松的疗效。通过测量结肠液净吸收率和表面积溃疡来评估诱导性结肠炎的愈合情况。在Ussing小室中测量了22Na和36Cl在结肠黏膜片上的单向跨壁通量。使用前药治疗结肠炎时，结肠中的地塞米松浓度是使用游离药物治疗时的6倍。前药通过使体内结肠液吸收恢复到正常并几乎消除结肠肉眼溃疡来加速结肠炎的愈合，而游离药物则没有。体外跨壁通量表明，除了修复粘膜完整性外，前药还能促进电中性氯化钠的吸收，超过对照动物或用游离药物治疗后的结果。前体药物和游离药物都限制了茶碱介导的净氯和钠的分泌，这一效果与这些药物在体内诱导的止泻作用一致。
A recently synthesized novel colon-specific dexamethasone prodrug, dexamethasone-beta-D-glucuronide, delivers efficacious amounts of dexamethasone to the colon with limited adrenal suppressive effects. During experimentally induced colitis in rats, the dexamethasone prodrug is significantly more potent than free dexamethasone in improving colonic fluid and electrolyte absorptive injury. The present studies examined whether the improvement in colonic absorption seen with the prodrug occurred as a consequence of alterations in sodium and chloride epithelial transport. The efficacy of the dexamethasone prodrug and free dexamethasone were tested in an acetic acid-induced rat model of colitis. Healing of the induced colitis was assessed by measuring net colonic fluid absorption and surface area ulceration. Transmural unidirectional fluxes of 22Na and 36Cl across sheets of colonic mucosa were measured in Ussing chambers. Treatment of colitis with the prodrug delivered a sixfold higher concentration of dexamethasone to the colon than did treatment with the free drug. The prodrug accelerated healing of colitis by returning in vivo colonic fluid absorption to normal and virtually eliminated colonic macroscopic ulceration, whereas the free drug did not. In vitro transmural fluxes demonstrated that, in addition to repair of mucosal integrity, the prodrug enhanced electroneutral sodium chloride absorption over and above that seen in control animals or after treatment with the free drug. Both the prodrug and the free drug limited theophylline-mediated net chloride and sodium secretion, an effect that would be consistent with the antidiarrheal effect induced by these drugs in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)