Inhibition Mechanism of Ketamine-Apatinib by CYP2C9 and 3A4: A Prediction of Possible Drug-Drug Interaction.
Xiang Zheng, Haiyan Chen, Dan Lin, Guo-Xin Hu, Hongyu Zhou
Biopharmaceutics & drug disposition May 21, 2025 DOI: 10.1002/bdd.70008 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro study Peer reviewed |
|---|---|
| Interventions | Apatinib Ketamine |
| Topics | Ketamine Esketamine |
| Keywords | Apatinib Competitive inhibition Cytochrome p450 proteins Drug-interactions Cancer-treatment Pharmacokinetics Enzyme-inhibition Pain-management |
| Citations | 2 |
| Key points | Apatinib inhibits ketamine metabolism through noncompetitive, competitive, and mixed-model inhibition of CYP2C9 and CYP3A4 isoforms. |
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.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cites 9
- Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation American Journal of Psychiatry March 17, 2021
- Taming the Ketamine Tiger Anesthesiology August 6, 2010
- Harm related to recreational ketamine use and its relevance for the clinical use of ketamine. A systematic review and comparison study Expert Opinion on Drug Safety June 26, 2021
- Ketamine as Potential Treatment for Postpartum Depression: A Narrative Review Annals of Clinical Psychiatry November 1, 2022
- Ketamine for mood disorders, anxiety, and suicidality in children and adolescents: a systematic review. European Child & Adolescent Psychiatry 2025
and 4 more in the library