A parallel chiral-achiral liquid chromatographic method for the determination of the stereoisomers of ketamine and ketamine metabolites in the plasma and urine of patients with complex regional pain syndrome
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A parallel chiral/achiral LC-MS/MS assay has been developed and validated to measure the plasma and urine concentrations of the enantiomers of ketamine, (R)- and (S)-Ket, in complex regional pain syndrome (CRPS) patients receiving a 5-day continuous infusion of a sub-anesthetic dose of (R,S)-Ket. The method was also validated for the determination of the enantiomers of the Ket metabolites norketamine, (R)- and (S)-norKet and dehydronorketamine, (R)- and (S)-DHNK, as well as the diastereomeric metabolites hydroxynorketamine, (2S,6S)-/(2R,6R)-HNK and two hydroxyketamines, (2S,6S)-HKet and (2S,6R)-Hket. In this method, (R,S)-Ket, (R,S)-norKet and (R,S)-DHNK and the diastereomeric hydroxyl-metabolites were separated and quantified using a C(18) stationary phase and the relative enantiomeric concentrations of (R,S)-Ket, (R,S)-norKet and (R,S)-DHNK were determined using an AGP-CSP. The analysis of the results of microsomal incubations of (R)- and (S)-Ket and a plasma and urine sample from a CRPS patient indicated the presence of 10 additional compounds and glucuronides. The data from the analysis of the patient sample also demonstrated that a series of HNK metabolites were the primary metabolites in plasma and (R)- and (S)-DHNK were the major metabolites found in urine. The results suggest that norKet is the initial, but not the primary metabolite and that downstream norKet metabolites play a role in (R,S)-Ket-related pain relief in CRPS patients.
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Norketamine, DHNK, and (2R,6R;2S,6S)-HNK appear in human plasma as early as 40 minutes after an antidepressant ketamine dose, with (2R,6R;2S,6S)-HNK and (2S,6R;2R,6S)-HNK being the most abundant HNKs.
“Norketamine, DHNK, and (2R,6R;2S,6S)-HNK in particular are detected in human plasma as early as 40 minutes following an antidepressant dose of ketamine (0.5 mg/kg i.v. over 40 minutes) with the most abundant HNKs being (2R,6R;2S,6S)-HNK and (2S,6R;2R,6S)-HNK”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Moaddel et al., 2010
Results §3.4.1 reports norketamine, DHNK, and both named HNK pairs in plasma, with those HNK pairs the most abundant. But Results §3.4 and Experimental §2.7 describe sampling on day 3 of a five-day infusion for complex regional pain syndrome, not detection at 40 minutes after a 0.5 mg/kg antidepressant dose. Page numbers are unavailable in our copy. (LLM, conf=0.91)
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- Authors
- Moaddel, R., Venkata, S. L. V., Tanga, M. J., Bupp, J. E., Green, C. E., Iyer, L., Furimsky, A., Goldberg, M. E., Torjman, M. C., & Wainer, I. W.
- Affiliations
- National Institutes of Health (US)
- SRI International (US)
- Cooper University Hospital (US)
- Corresponding author
- Wainer, Irving W.
- Venue
- Talanta
- Publisher
- Elsevier BV
- Published
- 2010-10
- Volume
- 82
- Issue
- 5
- Pages
- 1892-1904
- ISSN
- 0039-9140 (ISSN-L)
- PMC
- PMC2948022
- OpenAlex
- W2037018768
- Cited by
- 108
- References
- 22
- Citations by year
- 2026: 2 · 2025: 11 · 2024: 4 · 2023: 2 · 2022: 11 · 2021: 13 · 2020: 8 · 2019: 8 · 2018: 12 · 2017: 9 · 2016: 7 · 2015: 4 · 2014: 5 · 2013: 3 · 2012: 7
- FWCI
- 1.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Talanta (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (N01AG-3-1008)
- National Institutes of Health
- Topics
- Physical Sciences › Chemistry › Spectroscopy › Analytical Chemistry and Chromatography
- Physical Sciences › Chemistry › Analytical Chemistry › Analytical Methods in Pharmaceuticals
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Forensic Toxicology and Drug Analysis
- Keywords
- ketamine, complex regional pain syndrome, stereoisomers, enantiomers, ketamine metabolites, norketamine, dehydronorketamine, hydroxynorketamine, glucuronide conjugates, microsomal metabolism, analgesia
- MeSH terms
- Analgesics, Biotransformation, Calibration, Chromatography, Liquid, Humans, Infusions, Intravenous, Ketamine, Reference Standards, Stereoisomerism, Reproducibility of Results, Glucuronides, Complex Regional Pain Syndromes, Tandem Mass Spectrometry
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