Influence of Semaglutide on CYP450 Enzymes and Potential Drug–Drug Interactions

Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is increasingly used for the treatment of type 2 diabetes and obesity. Despite its widespread and growing use, its effects on hepatic drug-metabolizing enzymes remain poorly understood. The cytochrome P450 (CYP) enzyme system is critical for the metabolism of many commonly prescribed medications, and alterations in CYP activity can significantly impact drug efficacy and safety.

Our preliminary analysis of a publicly available gene expression dataset comparing saline- and semaglutide-treated mice revealed significant changes in the expression of multiple CYP enzymes. These findings suggest that semaglutide may modulate hepatic drug metabolism; however, the translational relevance of these changes to humans remains unclear.

To validate these observations, we will use CYP-responsive HepaRG human liver cells to compare semaglutide-treated and untreated conditions. Rifampicin will be included as a positive control to confirm induction of canonical CYP genes and ensure system responsiveness. Gene expression changes will be quantified using qPCR, followed by RNA sequencing to enable comprehensive transcriptional profiling.

This study will determine whether semaglutide alters CYP expression in human liver cells and helps determine its potential to influence drug metabolism, thereby providing critical insight into possible drug-drug interactions in patients receiving semaglutide alongside other medications.