Inhibition Mechanism of Ketamine-Apatinib by CYP2C9 and 3A4: A Prediction of Possible Drug-Drug Interaction.
Biopharmaceutics & drug disposition – May 21, 2025
Source: PubMed
Summary
When cancer pain meets cancer treatment, interesting drug interactions emerge. Scientists discovered that apatinib, a cancer-fighting drug, affects how the body processes ketamine, a powerful pain medication. The interaction occurs through cytochrome P450 proteins in the liver, with apatinib showing competitive inhibition of key enzymes. This means patients receiving both drugs may need adjusted dosing to prevent side effects.
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.