Enantioselective CE analysis of hepatic ketamine metabolism in different species in vitro.

This research article speaks to the varying metabolic responses to ketamine—an anesthetic commonly used in both human and veterinary medicine—in different species (human, horses and dogs). The study employs an enantioselective CE assay to evaluate these responses and elucidates distinct ketamine metabolizing patterns across the species considered.

Study Methodology

• The researchers used a technique called enantioselective CE assay to study how ketamine and its derivatives are metabolised in the liver in humans, horses, and dogs. Ketamine is a mixture of two mirror-image molecules (enantiomers) known as S-ketamine and R-ketamine.
• The team used ‘racemic’ ketamine—which is a 50-50 mix of these two enantiomers—and measured how it was metabolised into different byproducts in microsomal preparations, which are essentially liver cell extracts.
• The ketamine was left to incubate with these microsomes for three hours, during which samples were frequently collected for analysis.

Findings

• The study found that ketamine was transformed or ‘metabolised’ into a molecule called norketamine (NK), dehyrdonorketamine and three hydroxylated NK metabolites. This was true for all three species, indicating a level of metabolic consistency between human, horse, and canine subjects.
• However, the researchers noticed variations between different species with regards to the rate of production of these metabolites and the ‘stereoselectivity’ i.e. preference for converting one enantiomer over another, of the hydroxylated NK metabolites.
• Clearance rate—the speed at which a drug is processed and removed from the body—also differed across species. Strikingly, the S-enantiomer was processed more slowly in humans when it was part of the racemic mixture than when it was administered alone. This was not the case in equine microsomes.
• On the contrary, greater efficiency in metabolizing the racemic mixture over the single S-enantiomer was observed in the canine subjects.

Implications

• The research has valuable clinical implications for the application of single S-ketamine versus racemic ketamine. Differences across species could influence decisions about what form of ketamine to use, depending on the species being treated. This could potentially promote more efficient and effective anaesthesia in both human and animal medicine.