BMAL1-mediated transcriptional regulation of CYP3A13 drives circadian rhythms in intestinal first-pass metabolism

Intestinal first-pass metabolism serves as the primary metabolic barrier during the absorption of orally administered drugs, in which cytochrome P450 (CYP) enzymes (particularly the CYP3A subfamily) play a critical role. This study demonstrates that the CYP3A family is highly expressed in the jejunum, with CYP3A13 as the predominant isoform. Its expression and metabolic activity exhibit a robust circadian rhythm with significantly higher expression during the night than during the day, which directly influences the exposure rhythm of the orally administered drug verapamil. Furthermore, through in-vivo and in-vitro experiments, we demonstrate that the core circadian clock gene Bmal1 positively regulates the expression and function of CYP3A13. Using luciferase reporter assays and chromatin immunoprecipitation (ChIP), we further elucidate the underlying transcriptional regulatory mechanism, showing that Bmal1 directly transactivates CYP3A13 by binding to an E-box element. This study enhances the understanding of the circadian regulatory mechanisms of intestinal drug metabolism and provides a theoretical foundation for individualized chronotherapy in clinical practice.