Drug testing and analysis
June 1, 2021
Islam Amine Larabi, Fanny Zerizer, Alice Ameline et al.
23 citations
A new ketamine analogue, deschloro-N-ethyl-ketamine (O-PCE), involved in severe intoxications and deaths, was metabolically profiled for the first time. After incubating O-PCE with human liver microsomes and analyzing urine and hair from a 43-year-old male user using high-resolution mass spectrometry, 15 metabolites were identified. Nine metabolites detected in urine extended the detection window after O-PCE itself was no longer present. The five most abundant urinary markers were 2-en-PCA-N-Glu (34%), M3 (16%), O-PCA-N-Glu (15.4%), OH-O-PCE (15%), and OH-PCE (11.9%). In hair, nine metabolites appeared; OH-PCA dominated (78%) with a metabolite-to-parent-drug ratio of 6, making it the best marker for long-term monitoring of O-PCE exposure.
Neuropharmacology
November 1, 2024
Thi Mai Loan Nguyen, Jean-Philippe Guilloux, Céline Defaix et al.
3 citations
Ketamine produces rapid and lasting antidepressant effects in depressed patients. A metabolite called (2R,6R)-hydroxynorketamine (HNK) may contribute to these effects. In anxious male mice, blocking the liver enzyme cytochrome P450 with fluconazole before ketamine or HNK altered drug metabolism: it raised ketamine and norketamine levels in blood and brain but sharply reduced HNK levels. Fluconazole also prevented ketamine's sustained antidepressant-like actions in behavioral tests and its enhancement of cortical GABA levels 24 hours after injection. Giving (2R,6R)-HNK alone reversed fluconazole's blockade of ketamine's antidepressant-like activity. The findings suggest that HNK is essential for ketamine's sustained antidepressant effects and that drug interactions with cytochrome P450 inhibitors may affect ketamine treatment in patients.
bioRxiv Preprint Server
April 3, 2024
Thi Mai Loan Nguyen, Jean-Philippe Guilloux, Céline Defaix et al.
preprint
Ketamine's rapid antidepressant effects in depressed patients may depend on a specific metabolite, (2R,6R)-hydroxynorketamine ((6)-HNK). In male BALB/cJ mice with high anxiety, blocking liver enzymes that break down ketamine (using fluconazole) raised ketamine and norketamine levels in blood and brain but sharply reduced (6)-HNK levels. This blockade prevented ketamine's sustained antidepressant-like effects 24 hours later in behavioral tests and stopped the increase in cortical GABA levels. Giving a single dose of (2R,6R)-HNK alone restored the antidepressant-like activity. The findings indicate that (6)-HNK is essential for ketamine's lasting antidepressant effects and suggest that drug interactions affecting ketamine metabolism could matter in patients.