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The effect of route of administration on the enantioselective pharmacokinetics of ketamine and norketamine in rats.

Martin Le Nedelec, Paul Glue, Helen Winter, Chelsea Goulton, Natalie J. Medlicott

Journal of Psychopharmacology October 2018 DOI: 10.1177/0269881118780013 (opens in new tab)

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AI-extracted from the abstract
Characteristics Preclinical pharmacokinetic study in rats Peer reviewed
Population Conscious, non-anaesthetised rats
Intervention Ketamine
Measures LC/MS
Topics Depression Ketamine Esketamine
Keywords Lcms Norketamine Pharmacokinetics
Key points Subcutaneous, intramuscular, and intravenous infusion routes gave similar overall ketamine exposure in rats, whereas intravenous bolus produced about 15-fold higher peak plasma concentrations of ketamine enantiomers and about four-fold lower norketamine AUC. The authors argue that route of administration significantly influences ketamine and norketamine exposure, with possible implications for safety, tolerability, and efficacy in humans.

Abstract

Ketamine has been shown to produce a rapid and potent antidepressant response in patients with treatment-resistant depression. Currently ketamine is most commonly administered as a 40-minute intravenous infusion, though it is unknown whether this is the optimal route of administration. To determine the plasma concentration time course of the R- and S-enantiomers of ketamine and norketamine following administration of ketamine by four different routes of administration. Plasma from conscious non-anaesthetised rats was collected following administration of ketamine by either subcutaneous (SC), intramuscular (IM), intravenous infusion (IVI) or intravenous bolus (IVB) routes of administration. Concentrations of the enantiomers of ketamine and norketamine were determined by LC/MS. Administration by the SC, IM and IVI routes produced an overall similar drug exposure. In contrast, administration by the IVB route produced approximately 15-fold higher peak plasma concentrations for the enantiomers of ketamine and an approximately four-fold lower AUC for the enantiomers of norketamine. Route of administration can significantly influence ketamine and norketamine exposures. These differences may influence safety and tolerability, and potentially drug efficacy in humans. This knowledge adds to current research into the optimisation of the use of ketamine for the treatment of depression.

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Other preclinical and animal studies on ketamine for depression, most cited first.

Study Year Design Participants
Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression Rats 2020 Preclinical study
A Single Subanesthetic Dose of Ketamine Relieves Depression-like Behaviors Induced by Neuropathic Pain in Rats Rats with spared nerve injury (neuropathic pain model), sham-operated rats, and control... 2011 Animal experimental study
Comparison of (R)-ketamine and lanicemine on depression-like phenotype and abnormal composition of gut microbiota in a social defeat stress model Susceptible mice after chronic social defeat stress 2017 Preclinical animal study
Comparison of R-ketamine and rapastinel antidepressant effects in the social defeat stress model of depression Susceptible mice in the social defeat stress model 2016 Animal experimental study
Ketamine and its metabolite, (2R,6R)-HNK, restore hippocampal LTP and long-term spatial memory in the Wistar-Kyoto rat model of depression Wistar-Kyoto (WKY) rats and Wistar control rats 2020 Preclinical study

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