Sex Differences in the Pharmacokinetics of Low-dose Ketamine in Plasma and Brain of Male and Female Rats.
Samantha K Saland, Mohamed Kabbaj
Journal of Pharmacology and Experimental Therapeutics December 2018 DOI: 10.1124/jpet.118.251652 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical pharmacokinetic study in rats Peer reviewed |
|---|---|
| Population | Intact male rats and female rats in diestrus or proestrus |
| Intervention | Ketamine |
| Dose | low antidepressant-like dose selectively effective in females |
| Duration | First 30 min following treatment |
| Topics | Esketamine Ketamine |
| Key points | Female rats showed higher brain and plasma concentrations of ketamine and its metabolite norketamine than males during the first 30 minutes after low-dose ketamine, largely due to slower clearance and longer half-lives. No appreciable pharmacokinetic differences appeared between proestrus and diestrus females, suggesting circulating ovarian hormone levels have negligible influence on ketamine metabolism even though they affect behavioral sensitivity. |
Abstract
Recent work from our group and others has revealed a higher sensitivity of female rodents to the antidepressant-like effects of the N-methyl d-aspartate receptor antagonist ketamine strongly influenced by circulating estrogen and progesterone levels. However, in the absence of any preclinical studies of pharmacokinetic sex differences using low-dose ketamine in rats, it is unclear whether the effects of sex and hormonal milieu on ketamine's behavioral actions are influenced by differences in ketamine metabolism between male and female rats. Therefore, this work examined whether sex and hormonal status affect ketamine metabolism and distribution in male and female rats using a low antidepressant-like dose selectively effective in females. Intact male rats and female rats in either diestrus (low estrogen, progesterone) or proestrus (high estrogen, progesterone) were administered low-dose ketamine, and their plasma and brains were collected to analyze levels of ketamine and its metabolites norketamine (NK) and dehydronorketamine. Females exhibited greater concentrations of ketamine and NK over the first 30 min following treatment in both brain and plasma, largely accounted for by slower clearance rates and longer half-lives. Interestingly, despite the impact of ovarian hormones on behavioral sensitivity to ketamine, no appreciable differences in pharmacokinetic parameters existed between proestrus and diestrus female rats. This work is the first to demonstrate sex differences in ketamine pharmacokinetics in rats, and suggests that while sex differences in metabolism may influence the amount of ketamine and NK reaching target areas in the brain, the impact of circulating hormone levels here is negligible.
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
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- Low-dose S-ketamine exerts antidepressant-like effects via enhanced hippocampal synaptic plasticity in postpartum depression rats. Neurobiology of Stress 2022
- Beyond NMDA Receptors: A Narrative Review of Ketamine's Rapid and Multifaceted Mechanisms in Depression Treatment. International Journal of Molecular Sciences December 20, 2024
- Sexually Dimorphic Behavioral Profile in a Transgenic Model Enabling Targeted Recombination in Active Neurons in Response to Ketamine and (2R,6R)-Hydroxynorketamine Administration International Journal of Molecular Sciences March 20, 2020
- A new module in the drug development process: preclinical multi-center randomized controlled trial of R-ketamine on alcohol relapse. Neuropsychopharmacology May 1, 2025
- Ketamine Reverses Chronic Stress‐Induced Behavioral Changes via the Expression of Ca 2+ ‐Permeable AMPA Receptors in Mice The FASEB Journal August 26, 2025
and 29 more in the library
Cites 3
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings) CNS Neuroscience & Therapeutics April 10, 2013
- KETAMINE'S MECHANISM OF ACTION: A PATH TO RAPID‐ACTING ANTIDEPRESSANTS Depression and Anxiety April 6, 2016