glutathione adduct formation and daily dose

Background: 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. Results: 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with human liver microsomes, and the test compounds were classified into three categories of safe, warning and withdrawn/black box warning. A total of 23 out of 28 withdrawn/black box warning drugs showed both a RM–GS formation rate of over 1 pmol/30 min/mg protein and a dose of over 100 mg. Conclusion: These results suggest that when compounds are plotted in this region, the compounds would have a relatively high idiosyncratic drug toxicity potential.