The novel third-generation antipsychotic drug brexpiprazole affects hepatic transcription factors, serum hormone levels, and cytochrome P450 enzymes after prolonged treatment: pharmacological significance.

Background: Brexpiprazole is a third-generation antipsychotic used for the treatment of schizophrenia or as an adjunctive drug for the treatment of affective and neurological disorders. The combined treatments with brexpiprazole and other drugs that are also cytochrome P450 (CYP) substrates may lead to pharmacokinetic drug-drug interactions. Our present work aimed to investigate the effects of prolonged administration of brexpiprazole on the expression of hepatic transcription factors and CYP drug-metabolizing enzymes.

Methods: Male Wistar rats received brexpiprazole (1 mg/kg ip.) for two weeks. Their livers were excised 24 h after the last dose, and the activities (HPLC), protein levels (Western blotting), and mRNAs (qRT-PCR) of CYP enzymes were measured. In parallel, the expression of hepatic transcription factors (Western blotting, qRT-PCR) and the concentration of serum hormones (ELISA) were assessed.

Results: Brexpiprazole produced a broad-spectrum effect on CYP expression and activity. It enhanced the expression and activity of CYP1A, CYP2A, CYP3A1/2, and the activity of CYP2B, but decreased the expression/activity of CYP2Ds and CYP2E1. The observed changes in CYP enzymes corresponded to alterations in transcription factors: the increased expression of PXR and AhR, and decreased expression of PPARγ, LXR, and FXR. The above modifications in CYP enzymes' expression were accompanied by enhanced corticosterone and reduced T₄ serum levels.

Conclusions: Brexpiprazole affects the expression of hepatic transcription factors and CYP, which may impact its own biotransformation and the metabolism of endogenous substances and concomitantly administered drugs, and lead to drug-drug interactions of pharmacological/clinical importance.