Metabolic Activation of Stiripentol Correlates with Cytotoxicity

Stiripentol (SRP) is an antiepileptic agent utilized in managing seizures related to Dravet syndrome. Long-term safety studies have highlighted significant adverse effects in patients including drowsiness, reduced appetite, ataxia, and elevated levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). The present study aimed at identifying the reactive metabolite of SRP and defining the potential correlation between its cytotoxicity and metabolic activation. Rat liver microsome incubation of SRP fortified with GSH as a trapping agent produced an α,β-unsaturated ketone metabolite (M1) and a related GSH conjugate (M2). Moreover, both the phase I metabolite and the GSH conjugate were detected in the bile of SRP-treated rats, indicating that both in vivo and in vitro metabolic activation of SRP took place. Notably, SRP exhibited significant cytotoxicity toward rat primary hepatocytes. Pretreatment with ketoconazole, a selective CYP3A enzyme inhibitor, mitigated the susceptibility of hepatocytes to SRP-induced cytotoxicity. These findings suggest that SRP may undergo metabolism to the α,β-unsaturated ketone metabolite, potentially contributing to the cytotoxic effects associated with SRP.