The effect of repeated administration of lumateperone on cytochrome P450 expression and activity in rat liver

Antipsychotic drugs are used for long-term treatment of schizophrenia and other psychotic-related symptoms. Our present work aimed at investigating the effects of chronic administration of the third-generation antipsychotic drug lumateperone on the expression of cytochrome P450 (CYP) enzymes involved in drug metabolism and transcription factors in rat liver. Male Wistar rats received lumateperone (1 mg/kg) once daily for 14 days. 24 h after the last dose, their livers were excised, and CYP enzyme expression and activity were measured. In addition, the expression of transcription factors and serum hormone concentrations were evaluated. Lumateperone significantly increased the CYP expression and/or activity of CYP2A, CYP2B, and CYP3A enzymes, but decreased that of CYP2D enzymes. The observed changes in CYP enzymes were in line with alterations in transcription factors: lumateperone elevated the mRNA level of PXR and reduced that of FXR in the liver. Simultaneously, increased corticosterone levels and decreased T 4 levels in serum were observed. Repeated lumateperone administration modulated the expression and activity of selected hepatic CYP enzymes in rats. These findings indicate biological effects on hepatic drug-metabolizing pathways in a rat model. Relevance to human drug–drug interactions remains to be established in in vitro pharmacokinetic studies.