Mechanistic Toxicology Lab, Department of Pharmaceutical Sciences, University of Connecticut School of Pharmacy, 69 North Eagleville Road Unit 3092, Storrs, CT 06269-3092, USA.
Curr Drug Metab. 2011 Mar;12(3):245-52. doi: 10.2174/138920011795101877.
Many nonsteroidal anti-inflammatory drugs (NSAIDs) are carboxylic acid-containing compounds that are conjugated in the liver to acyl glucuronides and excreted across the hepatocanalicular membrane into bile. Chronic and acute NSAID use has not only been associated with gastric injury but also increasingly recognized to cause small intestinal injury (enteropathy). The mechanisms of NSAID enteropathy are still unknown, but a combination of topical effects (including mitochondrial injury) combined with inhibition of COX1/2, followed by an inflammatory response triggered by LPS-mediated activation of LTR4 on macrophages, have been implicated in the pathogenesis. Some of the nucleophilic proteins that are targeted by the electrophilic NSAID acyl glucuronides or their iso-glucuronides have been identified both in bile canaliculi and on the apical membrane domain of enterocytes (e.g., aminopeptidase N); however, the mechanistic role of covalent adducts has remained enigmatic. In contrast, it has become increasingly clear that acyl glucuronide formation is a major toxicokinetic determinant, in that the drug conjugates are a transport form delivering the drug to the more distal parts of the jejunum/ileum, where the glucuronic acid moiety is cleaved off the aglycone due to higher local pH and the presence of bacterial β-glucuronidase. Through this mechanism, high local concentrations of the parent NSAID can be attained, potentially leading to local tissue injury. Thus, even if one considers the formation of acyl glucuronides not as a potentially dangerous toxophore by virtue of their protein-reactivity, acyl glucuronides could still be a red flag in drug development if excreted at high rates into bile and delivered to more distal areas of the small intestine where high amounts of parent drug is released.
许多非甾体抗炎药（NSAIDs）是含有羧酸的化合物，在肝脏中与酰基葡萄糖醛酸轭合，并通过肝细胞管腔膜分泌到胆汁中。慢性和急性 NSAID 使用不仅与胃损伤有关，而且越来越被认为会引起小肠损伤（肠病）。NSAID 肠病的机制尚不清楚，但局部效应（包括线粒体损伤）与 COX1/2 抑制的结合，随后由 LPS 介导的巨噬细胞上 LTR4 的激活触发炎症反应，被认为与发病机制有关。已经在胆小管和肠上皮细胞的顶膜域（例如氨基肽酶 N）中鉴定出一些亲核蛋白，这些蛋白被亲电 NSAID 酰基葡萄糖醛酸或其同型葡萄糖醛酸轭合物靶向；然而，共价加合物的机械作用仍然是神秘的。相比之下，酰基葡萄糖醛酸形成是主要的毒代动力学决定因素，这一点变得越来越清楚，即药物缀合物是一种输送形式，将药物输送到空肠/回肠的更远部位，由于局部 pH 值较高和存在细菌β-葡萄糖醛酸酶，葡萄糖醛酸部分从糖苷配基上脱落。通过这种机制，可以达到局部高浓度的母体 NSAID，可能导致局部组织损伤。因此，即使人们认为酰基葡萄糖醛酸由于其与蛋白质的反应性而不是潜在的危险毒性基团，但如果酰基葡萄糖醛酸以高速率排泄到胆汁中并输送到含有大量母体药物的小肠的更远部位，它们仍然可能是药物开发中的一个危险信号。
