Abstract
Acyl glucuronides (AGs) formed from carboxylic acid-containing drugs have been considered to be a cause of idiosyncratic drug toxicity (IDT). Chemical stability of AG is supposed to relate to the reactivity. In this study, the half-lives of 21 AGs of carboxylic drugs in the potassium phosphate buffer (KPB), human serum albumin (HSA) solution and human fresh plasma were analyzed in relation to the IDT risk derived from these drugs. The carboxylic drugs were classified into three safety categories of 'safe', 'warning' and 'withdrawn' in terms of their IDT risk. As for the results, the half-lives of AGs in KPB correlated with the IDT risk better than those in HSA solution or in human fresh plasma with regard to the separation of the 'safe' drugs from the 'warning' drugs or the 'withdrawn' drugs. In KPB, while the half-lives in the 'safe' category were 7.2 h or longer, those in the 'withdrawn' category were 1.7 h or shorter. The classification value of the half-life in KPB which separated the 'safe' drugs from the 'withdrawn' drugs was calculated to be 3.6 h by the regression analysis. In conclusion, this is the first report which clearly shows the relationship between the IDT risk and chemical stability of AG in several in vitro systems. The KPB buffer system was considered to be the best for evaluating the stability of AG, and the classification value of the half-life in KPB would serve as a useful key predictor for the IDT risk.
- glucuronidation
- half-life
- hepatotoxicity
- hypersensitivity
- idiosyncratic drug reactions
- in vitro toxicity assays
Footnotes
- Received April 27, 2010.
- Accepted July 6, 2010.
- The American Society for Pharmacology and Experimental Therapeutics