Time-Dependent Inhibition of CYP1A2 by Stiripentol and Structurally Related Methylenedioxyphenyl Compounds via Metabolic Intermediate Complex Formation

Stiripentol (STP), an antiepileptic agent, causes drug-drug interactions by inhibiting cytochrome P450 (P450) enzymes. STP contains a methylenedioxyphenyl (MDP) group, which could form inhibitory metabolic intermediate complexes (MICs) with P450. The present study examined the possible time-dependent inhibition of CYP1A2 via MIC formation by STP and structurally related MDP compounds such as isosafrole. Time-dependent inhibition was observed in human liver microsomes for CYP1A2, but not CYP3A4. Spectral analysis of the liver microsomes from CYP1A-induced rats incubated with STP and NADPH revealed a Soret peak at approximately 455 nm, which was largely eliminated by potassium ferricyanide. Similar spectra were obtained for all the other MDP compounds, albeit in varying amounts. Thus, the extent of time-dependent CYP1A2 inhibition and MIC formation were in good agreement. In addition, the dissociation of MIC by potassium ferricyanide partially attenuated the impairment of CYP1A2 activity, suggesting that MIC is involved in the time-dependent inhibition of CYP1A2 by STP. In conclusion, STP, like other MDP compounds, caused time-dependent CYP1A2 inhibition via MIC formation, and this may be involved in drug-drug interactions associated with the clinical use of STP. Significance Statement The present study found that stiripentol, an antiepileptic agent, caused a time-dependent inhibition of CYP1A2. Stiripentol like isosafrole has a methylenedioxyphenyl group and generated MI complexes with CYP1A2. This is a new case of the time-dependent CYP inhibition by a methylenedioxyphenyl containing drug via MI complex formation.