Properties of the optical isomers and metabolites of ketamine on the high affinity transport and catabolism of monoamines

Abstract

Racemic ketamine HCl, its optical isomers and the metabolites of the parent drug were incubated with synaptosomal-rich fractions obtained from rat cerebral cortex to evaluate the effect of these agents on the high affinity transport processes of the monoamine neurotransmitters. Each of the agents caused a concentration-dependent inhibition of the transport processes. The (+) isomer of ketamine HCl was about four times more potent than the (−) isomer on catecholamine transport while the (−) isomer appeared slightly more effective against serotonin transport. Both metabolite I and II of ketamine were weaker inhibitors than the parent drug. Metabolite I was shown to be a competitive inhibitor as had previously been demonstrated for ketamine, and was also found to inhibit the oxidative deamination of the monoamines more effectively than ketamine. The possible significance of the effects of the optical isomers and the metabolites of ketamine on monoamine metabolism is discussed in relation to quantitative differences observed in the pharmacological activity of the agents.