可预测性
共价键
化学
共价结合
生物化学
组合化学
药理学
医学
有机化学
数学
统计
作者
Leslie Z. Benet,H Spahn-Langguth,Seigo Iwakawa,C Volland,Takeshi Mizuma,Sascha Mayer,E Mutschler,Emil T. Lin
出处
期刊:Life Sciences
[Elsevier BV]
日期:1993-01-01
卷期号:53 (8): PL141-PL146
被引量:159
标识
DOI:10.1016/0024-3205(93)90279-c
摘要
Although metabolism via glucuronide conjugation has generally been considered a detoxification route for carboxylic acids, the newly discovered chemical reactivity of these conjugates, leading to covalent binding with proteins, is consistent with the toxicity observed for drugs containing the carboxylic acid moiety. Here we report that degradation rates (intramolecular rearrangement and hydrolysis) for 9 drug glucuronide metabolites show an excellent correlation (r2=0.995) with the extents of drug covalent binding to albumin in vitro. Furthermore, this binding capacity is predictable based on chemical structure of the acid and depends on the degree of substitution at the carbon alpha to the carboxylic acid. The in vivo covalent binding in humans for these drugs is also predictable (r2=0.873) when the extent of adduct formation is corrected for the measured plasma glucuronide concentrations. These results suggest that the structure of a carboxylic acid drug may predict the degree to which the corresponding acyl glucuronides will form covalent adducts that probably/possibly lead to toxicity. This information could be a useful adjunct in drug design.
科研通智能强力驱动
Strongly Powered by AbleSci AI