Effect of honokiol on abemaciclib metabolism both in vitro and in vivo

Co-administration of multiple drugs typically induces drug-drug interactions (DDIs). DDIs have the potential to exert significant effects on the pharmacokinetics and therapeutic efficacy of the drugs employed. The treatment for estrogen receptor-positive (ER+) breast cancer is advancing with the incorporation of third-generation selective CDK4/6 inhibitors, such as abemaciclib. Honokiol, a bioactive phytochemical derived from Magnolia species, possesses broad anti-cancer actions. The study aimed to, in vitro and in vivo, investigate the impact of honokiol on the pharmacokinetics of abemaciclib.

To measure the IC50 values of honokiol on abemaciclib in vitro, rat liver microsomes (RLMs) were used. Eighteen Sprague-Dawley rats were randomly assigned to three groups: honokiol multiple-dose, honokiol single dose and control. All rats received a 10 mg/kg (high energy diet: 1.6 mg/kg) dose of abemaciclib. The plasma concentration of abemaciclib was measured utilizing ultra-performance liquid chromatography-tandem mass spectrometry (UPLC/MS-MS) technique. Molecular docking was performed with AutoDock software to analyse the binding energies of honokiol and abemaciclib to CYP3A4.

IC50 values for abemaciclib were determined in vitro in RLMs at 27.6 μM. The results showed that the values of area under the plasma concentration and mean residence time of abemaciclib were significantly increased and the values of Cmax and Tmax were significantly extended when rats were pretreated with honokiol. In contrast, our results revealed that CLz/F values were markedly decreased (P < .05). Honokiol and abemaciclib possess the amino acid residue ALA370 as their binding site, which may explain why they compete for metabolism via the CYP3A4 enzyme.

Honokiol and abemaciclib show significant DDIs in vitro and in vivo and more attention is required when administered synchronously.