Comparative pharmacology in the rat of ketamine and its two principal metabolites, norketamine and (Z)-6-hydroxynorketamine

Leung, Louis; Baillie, Thomas A.

doi:10.1021/jm00161a043

Cited by 121 publications

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“…Separate incubations with the two 6-hydroxyketamine diastereomers with liver microsomes only revealed the formation of the corresponding demethylated analogs, suggesting that 6-hydroxynorketamine is not a precursor of 5,6-dehydronorketamine [20]. Administration of (Z)-6-hydroxynorketamine to rats produced neither general anesthesia nor central nervous system excitation despite the fact that this compound was found to readily enter brain tissue from systemic circulation [22]. Furthermore, using GC-MS with and without analyte derivatization, Savchuk et al, monitored various ketamine metabolites in alkaline hexane extracts of unhydrolyzed whole blood and urine of surgical patients [23].…”

Section: Introductionmentioning

confidence: 95%

CE provides evidence of the stereoselective hydroxylation of norketamine in equines

et al. 2009

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CE provides evidence of the stereoselective hydroxylation of norketamine in equinesCE with multiple isomer sulfated-CD as selector was used for the simultaneous analysis of the stereoisomers of ketamine, norketamine, 5,6-dehydronorketamine and hydroxylated metabolites of norketamine in liquid/liquid extracts of (i) in vitro incubations with ketamine or norketamine and equine liver microsomes and (ii) plasma and urine of ponies receiving a target-controlled infusion of ketamine under isoflurane anesthesia. Hydroxynorketamine metabolites with the hydroxy group at the cyclohexanone ring could be shown to be formed stereoselectively both in vitro and in vivo. Due to the lack of standard compounds, urinary extracts were fractionated by HPLC followed by characterization of the collected fractions with CE and LC-MS n with 0.7 mmu mass discrimination. Comparison of LC-MS n data obtained with the fractions, an in vitro microsomal sample, and both pony urine and hydrolyzed pony urine led to the identification of four hydroxylated norketamine metabolites with hydroxylation at the cyclohexanone ring, two with hydroxylation at the aromatic ring and four hydroxylated metabolites of ketamine. Due to the lower detection sensitivity, only the four hydroxynorketamine metabolites with hydroxylation at the cyclohexanone ring were observed by CE. The data suggest that demethylation of ketamine followed by hydroxylation of norketamine at the cyclohexanone ring is the major metabolic pathway in equine species and that the ketamine metabolism is highly stereoselective.

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Section: Introductionmentioning

confidence: 95%

CE provides evidence of the stereoselective hydroxylation of norketamine in equines

et al. 2009

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“…KET is rapidly metabolized with the principal metabolites being an active metabolite, norketamine (NKET), and an inactive metabolite, 6-hydroxynorketamine (5). KET is demethylated to NKET by the liver microsomal cytochrome P450 system.…”

Section: Introductionmentioning

confidence: 99%

Detection of Ketamine and Norketamine in Urine of Nonhuman Primates after a Single Dose of Ketamine using Microplate Enzyme-Linked Immunosorbent Assay (ELISA) and NCI-GC-MS

Negrusz

Adamowicz

Saini

et al. 2005

Journal of Analytical Toxicology

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The general anesthetic ketamine (Ketalar | Ketaject, Vetalar) (KET) is used in human and veterinary medicine for induction of anesthesia for short surgical procedures and routine veterinary examination. Its illicit use by teenagers in rave parties has been reported, and it has recently been identified as a substance associated with sexual assault. One aim of this paper was to study the elimination of KET and its major metabolite norketamine (NKET) in urine collected from five nonhuman primates that received a single dose (5 mg/kg, I.M.) of KET and to study elimination patterns to determine how long after drug administration KET and NKET can be detected. Another aim of this study was to develop and validate a highly sensitive negative ion chemical ionization-gas chromatography-mass spectrometry (NCI-GC-MS) method for the simultaneous quantitation of KET and its major metabolite NKET in urine and to analyze urine samples collected from the animals. The last aim of this study was to apply and evaluate a newly developed ELISA screening methodology for detection of KET and its metabolites in the same urine samples collected from primates which received a single dose of KET. In two monkeys, KET was detected in urine up to 3 days after drug administration (32-7070 ng/mL); in one monkey, it was detected up to 4 days (65-13,500 ng/mL); in one monkey, it was detected only on days 1 and 2 (4000 and 70 ng/mL, respectively); and in one monkey, it was detected 10 days after KET injection (22-35,000 ng/mL). NKET concentrations ranged from 63 pg/mL to 1.75 pg/mL, and it remained in the urine throughout the entire 35-day study period in 4 out of 5 animals. In one monkey, NKET was detected up to 31 days after KET administration. Urine analysis using ELISA revealed that KET and NKET can be easily detectable at 25 ng/mL. In one monkey, KET and its metabolites were detected in urine up to 4 days after drug administration, up to 7 days in two monkeys, up to 11 days in one monkey, and 16 days after KET injection in one monkey. Urine extraction followed by screening using ELISA methodology allowed for significant extension of the detection period in all animals from the study. It is believed that the KET elimination in urine of nonhuman primates is slightly faster than in humans. We propose that NCI-GC-MS be employed to detect NKET as a target compound in urine in toxicological investigations of drug-facilitated sexual assault when KET use by the perpetrator is suspected.

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“…The best characterized metabolite is the main metabolite norketamine, a three to five times weaker NMDA receptor antagonist than ketamine [11][12][13][14]. In pre-clinical models, it caused anaesthesia [12], and at lower doses, augmented the effects of morphine in models of thermal, peripheral neuropathic and tonic inflammatory pain [15].…”

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confidence: 99%

Interactions of (2S,6S;2R,6R)‐Hydroxynorketamine, a Secondary Metabolite of (R,S)‐Ketamine, with Morphine

Lilius

Viisanen

Jokinen

et al. 2017

Basic Clin Pharma Tox

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Ketamine and its primary metabolite norketamine attenuate morphine tolerance by antagonising N-methyl-D-aspartate (NMDA) receptors. Ketamine is extensively metabolized to several other metabolites. The major secondary metabolite (2S,6S;2R,6R)-hydroxynorketamine (6-hydroxynorketamine) is not an NMDA antagonist. However, it may modulate nociception through negative allosteric modulation of a7 nicotinic acetylcholine receptors. We studied whether 6-hydroxynorketamine could affect nociception or the effects of morphine in acute or chronic administration settings. Male Sprague Dawley rats received subcutaneous 6-hydroxynorketamine or ketamine alone or in combination with morphine, as a cotreatment during induction of morphine tolerance, and after the development of tolerance induced by subcutaneous minipumps administering 9.6 mg morphine daily. Tail flick, hot plate, paw pressure and rotarod tests were used. Brain and serum drug concentrations were quantified with high-performance liquid chromatography-tandem mass spectrometry. Ketamine (10 mg/kg), but not 6-hydroxynorketamine (10 and 30 mg/kg), enhanced antinociception and decreased rotarod performance following acute administration either alone or combined with morphine. Ketamine efficiently attenuated morphine tolerance. Acutely administered 6-hydroxynorketamine increased the brain concentration of morphine (by 60%), and brain and serum concentrations of 6-hydroxynorketamine were doubled by morphine pre-treatment. This pharmacokinetic interaction did not, however, lead to altered morphine tolerance. Co-administration of 6-hydroxynorketamine 20 mg/kg twice daily did not influence development of morphine tolerance. Even though morphine and 6-hydroxynorketamine brain concentrations were increased after co-administration, the pharmacokinetic interaction had no effect on acute morphine nociception or tolerance. These results indicate that 6-hydroxynorketamine does not have antinociceptive properties or attenuate opioid tolerance in a similar way as ketamine.Opioids are widely used to manage severe acute and cancer pain. However, prolonged opioid use in chronic non-cancer pain may have severe drawbacks, including the development of tolerance and dependence. In the United States, eighty per cent of new heroin users have previously misused prescription opioids, and the opioid epidemic has been declared a national emergency [1]. Long-term opioid use may even lead to opioid-induced hyperalgesia that can compromise opioid analgesia and lead to further increases in opioid doses [2]. New approaches are needed to provide safer opioid analgesia with lower doses.Several N-methyl-D-aspartate (NMDA) receptor antagonists have been shown to attenuate opioid tolerance [3-5] mainly via pharmacodynamic interactions. Ketamine, a clinically used NMDA antagonist, produces anaesthesia and also analgesia at lower doses. Clinical evidence supports the perioperative use of low-dose ketamine with morphine to decrease the need for morphine [6], whereas there is lack of evidence to supp...

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Comparative pharmacology in the rat of ketamine and its two principal metabolites, norketamine and (Z)-6-hydroxynorketamine

Cited by 121 publications

References 0 publications

CE provides evidence of the stereoselective hydroxylation of norketamine in equines

CE provides evidence of the stereoselective hydroxylation of norketamine in equines

Detection of Ketamine and Norketamine in Urine of Nonhuman Primates after a Single Dose of Ketamine using Microplate Enzyme-Linked Immunosorbent Assay (ELISA) and NCI-GC-MS

Interactions of (2S,6S;2R,6R)‐Hydroxynorketamine, a Secondary Metabolite of (R,S)‐Ketamine, with Morphine

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