CYP3A4 activity variations can lead to stratified metabolism of abemaciclib

The interindividual variability of CYP3A4 activity complicates precision pharmacotherapy, particularly for drugs with narrow therapeutic windows. To explore the relationship between CYP3A4 polymorphisms and metabolic phenotypes, this study used abemaciclib as a probe substrate within a translational framework. The in vitro platform combined a reconstituted enzyme catalysis system for high-throughput inhibitor screening with UPLC-MS/MS metabolic profiling. In vivo pharmacokinetic studies were performed in female SD rats, with optimized sampling during the elimination phase. Human CYP3A4 baculosomes were engineered using baculovirus-mediated expression in Sf21 cells to investigate genetic influences on metabolic variability. Molecular docking and dynamics simulations were also performed to investigate structural differences in inhibitory activity. Results showed that letrozole significantly inhibited CYP3A4-mediated abemaciclib metabolism, reduced its clearance and increased its area under the blood concentration-time curve (AUC) and maximum blood concentration (C max ) through mixed inhibition. Moreover, CYP3A4 polymorphisms substantially impacted abemaciclib pharmacokinetics. Kinetic simulations revealed that the CYP3A4.28 variant formed a stable complex with letrozole, enhancing inhibition, while the CYP3A4.30 variant lost catalytic activity. These findings underscored the critical role of CYP3A4 activity and genetic polymorphisms in drug metabolism and highlighted the necessity for personalized treatment approaches.