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Bioanalysis. 2012 Feb;4(3):263-9. doi: 10.4155/bio.11.316.

In vitro evaluation of the potential for drug-induced toxicity based on (35)S-labeled glutathione adduct formation and daily dose.

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  • 1Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-Ku, Tokyo 140-8710, Japan.



Drug-induced toxicity such as idiosyncratic drug toxicity is believed to be reduced when either reactive metabolite formation or exposure to a drug is minimized. The objective of the present study was therefore to clarify the relationship between the daily doses, the formation rates of reactive metabolite adduct with (35)S-glutathione (RM-GS) and the safety profiles of compounds.


The RM-GS formation rates for 113 test compounds were determined by incubation with human liver microsomes, and the test compounds were classified into three categories of safe, warning and withdrawn/black box warning. A total of 23 out of 28 withdrawn/black box warning drugs showed both a RM-GS formation rate of over 1 pmol/30 min/mg protein and a dose of over 100 mg.


These results suggest that when compounds are plotted in this region, the compounds would have a relatively high idiosyncratic drug toxicity potential.

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