Inhibition Mechanism of Ketamine-Apatinib by CYP2C9 and 3A4: A Prediction of Possible Drug-Drug Interaction.

Apatinib, a VEGFR2 inhibitor used for gastric cancer, inhibits the metabolism of the pain-relief drug ketamine by interacting with cytochrome P450 enzymes. In laboratory assays, apatinib acted as a noncompetitive inhibitor of CYP2C9*1, CYP2C9*16, and rat liver microsomes; a competitive inhibitor of CYP2C9*3 and CYP2C9*13; and a mixed-model inhibitor of four CYP3A4 alleles. Molecular docking showed apatinib binds more strongly to CYP3A4*1 than ketamine does. Co-administration may increase adverse effects in poor metabolizers, and in vivo studies are needed to confirm this interaction.

Study at a glance

Abstract

Most cancer patients experience severe pain, and apatinib, a vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor, demonstrates therapeutic efficacy against gastric cancer. Ketamine, a psychotropic drug used for cancer pain relief, exhibits potential in inhibiting gastric cancer progression but is associated with dose-dependent adverse effects including neurological toxicity and dependency. Thus, clarifying whether apatinib influences ketamine therapy when co-administered is critical. In this study, we investigated apatinib's inhibitory effects on ketamine metabolism using CYP2C9 and CYP3A4 isoform assays. Results showed that apatinib exerted inhibition of ketamine metabolism, acted as a noncompetitive inhibitor of CYP2C9*1, CYP2C9*16, and rat liver microsomes (RLM), a competitive inhibitor of CYP2C9*3 and CYP2C9*13, and a mixed-model inhibitor of four CYP3A4 alleles (*1, *4, *18, and *23). Molecular docking revealed apatinib's stronger binding affinity (-10.4 kcal/mol) to CYP3A4*1 than ketamine (-6.9 kcal/mol). Consequently, co-administration may increase adverse risk in poor metabolizers (PMs), warranting in vivo validation of their therapeutic interaction.