Pharmacokinetic interaction between ketamine and ethanol: evaluation and forensic implications

Ketamine (KET) is a psychoactive compound used medically but often misused in ethanol (EtOH)-facilitated sexual assault (EFSA), posing serious forensic challenges. Because EtOH may alter KET absorption and metabolism, understanding their pharmacokinetic interaction is critical for accurate toxicological interpretation in EFSA cases. This study aimed to evaluate the potential pharmacokinetic interactions between KET and EtOH through in vitro metabolism studies and in vivo rat experiments.

Prior to evaluating the PK interaction, in vitro metabolism studies were conducted using human and rat liver microsomes to identify the major circulating metabolites of KET. To assess the effects of EtOH on KET metabolism and disposition, KET (30 mg/kg) and EtOH (2 g/kg, 30%) were orally co-administered to rats, and blood and urine samples were collected over time. The plasma concentrations and urinary excretion of KET and its metabolites were analyzed using liquid chromatography-tandem mass spectrometry.

Metabolism profiling study confirmed that KET undergoes sequential oxidative and conjugative metabolism, primarily forming norketamine (NK) and hydroxynorketamine (HNK) as major metabolites, along with dehydronorketamine (DHNK) and HNK-glucuronide (HNK-GLU) as minor ones. Pharmacokinetic studies showed that ethanol did not significantly alter plasma or urinary levels of KET, NK, or HNK. Accordingly, EtOH was not considered to have a significant impact on the KET PK and metabolism.

This study provides experimental evidence that, under acute ethanol co-exposure conditions, no significant PK interaction between KET and EtOH was observed. These findings may help inform the interpretation of toxicological findings related to KET use in EFSA cases.