The Inhibitory Effect of Anastrozole on the Metabolism of Abemaciclib <i>In Vitro</i> and <i>In Vivo</i>

Anastrozole and abemaciclib are clinically recommended in combination for the treatment of advanced breast cancer. However, the potential drug–drug interaction between them remains poorly characterized, posing a potential risk for altered drug exposure and toxicity. This study aimed to systematically investigate the effect of anastrozole on the metabolism and pharmacokinetics of abemaciclib. Using a combined in vitro and in vivo approach, we characterized this interaction via UPLC-MS/MS analysis of abemaciclib and its major metabolites (M2 and M20). In vitro enzymatic assays demonstrated that anastrozole significantly inhibits the metabolism of abemaciclib. Consistent with these findings, in vivo studies in female Sprague–Dawley rats showed that 7-day pretreatment with anastrozole prior to abemaciclib administration substantially decreased abemaciclib clearance, resulting in markedly increased systemic exposure (AUC0–t, AUC0–∞, and Cmax). Given that abemaciclib is predominantly metabolized by CYP3A4, we further examined whether genetic polymorphisms in this enzyme influence the observed interaction. Our results revealed that CYP3A4 genetic polymorphisms significantly modulate the inhibitory potency of anastrozole. These findings indicate that anastrozole acts as a CYP3A4 inhibitor, altering abemaciclib disposition in a genotype-dependent manner. This study highlights a clinically significant drug interaction with potential toxicological implications and provides a mechanistic basis for genotype-guided therapy in patients receiving this combination regimen.