Sex-dependent metabolism of ketamine and (2R,6R)-hydroxynorketamine in mice and humans

Abstract

Background: Ketamine is rapidly metabolized to norketamine and hydroxynorketamine (HNK) metabolites. In female mice, when compared to males, higher levels of ( 2R,6R;2S,6S)-HNK have been observed following ketamine treatment, and higher levels of ( 2R,6R)-HNK following the direct administration of ( 2R,6R)-HNK. Aim: The objective of this study was to evaluate the impact of sex in humans and mice, and gonadal hormones in mice on the metabolism of ketamine to form norketamine and HNKs and in the metabolism/elimination of ( 2R,6R)-HNK. Methods: In CD-1 mice, we utilized gonadectomy to evaluate the role of circulating gonadal hormones in mediating sex-dependent differences in ketamine and ( 2R,6R)-HNK metabolism. In humans (34 with treatment-resistant depression and 23 healthy controls) receiving an antidepressant dose of ketamine (0.5 mg/kg i.v. infusion over 40 min), we evaluated plasma levels of ketamine, norketamine, and HNKs. Results: In humans, plasma levels of ketamine and norketamine were higher in males than females, while ( 2R,6R;2S,6S)-HNK levels were not different. Following ketamine administration to mice (10 mg/kg i.p.), Cmax and total plasma concentrations of ketamine and norketamine were higher, and those of ( 2R,6R;2S,6S)-HNK were lower, in intact males compared to females. Direct ( 2R,6R)-HNK administration (10 mg/kg i.p.) resulted in higher levels of ( 2R,6R)-HNK in female mice. Ovariectomy did not alter ketamine metabolism in female mice, whereas orchidectomy recapitulated female pharmacokinetic differences in male mice, which was reversed with testosterone replacement. Conclusion: Sex is an important biological variable that influences the metabolism of ketamine and the HNKs, which may contribute to sex differences in therapeutic antidepressant efficacy or side effects.

Sex dependence of opioid-mediated responses to subanesthetic ketamine

“…Proper comparisons of ketamine’s therapeutic and adverse effects in male and female patients are lacking, possibly due to the limited statistical power for such subgroup analysis in current clinical trials, although sex differences have previously been reported at an anecdotal level ( 51 ). Sex-dependent ketamine and norketamine pharmacokinetics have been observed ( 52 ), and diverging correlations between treatment outcomes and depression-related inflammatory cytokines have been reported in male and female subjects ( 53 ). Moreover, preclinical investigations showed sex differences in the pharmacokinetics of ketamine and its metabolites, as well as in behavioral and physiological readouts ( 12 , 52 , 54 ).…”

“…Sex-dependent ketamine and norketamine pharmacokinetics have been observed ( 52 ), and diverging correlations between treatment outcomes and depression-related inflammatory cytokines have been reported in male and female subjects ( 53 ). Moreover, preclinical investigations showed sex differences in the pharmacokinetics of ketamine and its metabolites, as well as in behavioral and physiological readouts ( 12 , 52 , 54 ). Our results represent a critical step forward in elucidating both sex-dependent and opioid-based mechanisms underlying the action of subanesthetic ketamine.…”

“…Second, in female rats we did not control for the estrous cycle at the time of injection ( 57 ). However, the physiological effect of ketamine is not dependent on the estrous phase (diestrus or proestrus) ( 34 ), and surgical ovariectomy did not alter the plasma levels of ketamine and its metabolites in mice ( 52 ). Moreover, our randomized study design should mitigate any confounds related to the estrous phase, as female rats in each treatment group were likely imaged during different phases of the estrous cycle.…”

Estradiol enhances the mirtazapine effects on the expression of cocaine-induced locomotor sensitization in female rats

“…Various studies have documented the effect of OVX on the efficacy of various antidepressants (Estrada et al ., 2011; Ye et al ., 2016; Highland et al ., 2022). However, the results have not been conclusive.…”

Bench, bedside, and balance

“…Continuing the psychosis theme, Loureiro et al (2022) use the PCP model of schizophrenia in rats, to demonstrate effects on methylation and protein expression of NMDA receptor subunit genes in prefrontal cortex and hippocampus. In the final pre-clinical study, Highland et al (2021) examine whether metabolism of ketamine is sex-dependent, using both animal and human data. They found sex differences in mice and humans administered ketamine, with males of both species having higher levels of ketamine and one of its metabolites norketamine but higher levels of the other metabolite of ketamine, hydroxynorketamine, in female mice.…”