Enzymatic hydrolysis of acyl glucuronide metabolites in human liver microsomes correlates to the risk of idiosyncratic drug toxicity.

Acyl glucuronide (AG) is a reactive metabolite that causes idiosyncratic drug toxicity (IDT). Although the instability of AG is used to predict the IDT risk of novel drug candidates, it sometimes overestimates the IDT risk. We investigated whether the rate of enzymatic AG hydrolysis in human liver microsomes (HLM) can predict the risk of IDT. We used 16 drugs classified into three categories in terms of IDT risk: drugs withdrawn from the market owing to severe IDT (withdrawn, WDN) and drugs still being on the market, regardless of IDT risk (warning, WA) or not (safe, SA). AG was incubated with HLM, and the resulting parent drugs for AG hydrolysis were quantified using HPLC. The rate of enzymatic AG hydrolysis in the HLM of WDN was higher than that in WA and SA, and no difference was observed between WA and SA. We categorized WA and SA as commercially available (CA) drugs and performed a logistic regression analysis. The rate of enzymatic AG hydrolysis in HLM significantly distinguished WDN drugs from CA drugs, with an estimated classification value of 0.189 nmol/min/mg protein. In conclusion, the rate of enzymatic AG hydrolysis in HLM may be useful for predicting the risk in drug development.