Abstract
The risk of idiosyncratic drug toxicity (IDT) is of great concern to the pharmaceutical industry. Current hypotheses based on retrospective studies suggest that the occurrence of IDT is related to covalent binding and daily dose. We determined the covalent binding of 42 radiolabeled drugs in three test systems (human liver microsomes and hepatocytes in vitro and rat liver in vivo) to assess the risk of IDT. On the basis of safety profiles given in official documentation, tested drugs were classified into the safety categories of safe, warning, black box warning, and withdrawn. The covalent binding in each of the three test systems did not distinguish the safety categories clearly. However, when the log-normalized covalent binding was plotted against the log-normalized daily dose, the distribution of the plot in the safety categories became clear. An ordinal logistic regression analysis indicated that both covalent binding and daily dose were significantly correlated with safety category and that covalent binding in hepatocytes was the best predictor among the three systems. When two separation lines were drawn on the correlation graph between covalent binding in human hepatocytes and daily dose by a regression analysis to create three zones, 30 of 37 tested drugs were located in zones corresponding to their respective classified safety categories. In conclusion, we established a zone classification system using covalent binding in human hepatocytes and daily dose for the risk assessment of IDTs.
Footnotes
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.109.027797.
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ABBREVIATIONS: IDT, idiosyncratic drug toxicity; SJS, Stevens-Johnson syndrome; HLM, human liver microsome; WDN, drugs withdrawn from the market; BBW, drugs with a black box warning for IDT in the PDR; WNG, drugs without a black box warning but with a warning for IDT (severe hepatotoxicity, neutropenia, agranulocytosis, or SJS) in either the PDR or Japanese labeling; SAFE, drugs without any warning in either the PDR or Japanese labeling.
- Accepted May 27, 2009.
- Received March 31, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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