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Journal articles on the topic 'Norketamine'

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Author: Grafiati

Published: 11 March 2023

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1

Yeh, Chung-Hsin, Bo-He Chen, Xiao-Wen Tseng, Chun-Hou Liao, Wei-Kung Tsai, Han-Sun Chiang, and Yi-No Wu. "Intravesical Instillation of Norketamine, a Ketamine Metabolite, and Induced Bladder Functional Changes in Rats." Toxics 9, no. 7 (June 30, 2021): 154. http://dx.doi.org/10.3390/toxics9070154.

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This study aimed to determine the mechanism of ketamine-induced cystitis without metabolism. A total of 24 adult male Sprague-Dawley rats were separated into control, ketamine, and norketamine groups. To induce cystitis, rats in the ketamine and norketamine groups were treated with intravesical instillation of ketamine and norketamine by mini-osmotic pump, which was placed in subcutaneous space, daily for 24 h for 4 weeks. After 4 weeks, all rats were subjected to bladder functional tests. The bladders were collected for histological and pathological evaluation. Compared to control, ketamine treatment demonstrated an increase in the bladder weight, high bladder/body coefficient, contractive pressure, voiding volume, collagen deposition, reduced smooth muscle content, damaged glycosaminoglycan layer, and low bladder compliance. Compared to ketamine, norketamine treatment showed more severe collagen deposition, smooth muscle loss, damaged glycosaminoglycan layer, and increased residual urine. Intravesical administration of ketamine and norketamine induced cystitis with different urodynamic characteristics. Norketamine treatment caused more severe bladder dysfunction than ketamine treatment. Direct treatment of the bladder with norketamine induced symptoms more consistent with those of bladder outlet obstruction than ketamine cystitis. Detailed studies of cellular mechanisms are required to determine the pathogenesis of ketamine cystitis.

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Noppers, Ingeborg, Erik Olofsen, Marieke Niesters, Leon Aarts, René Mooren, Albert Dahan, Evan Kharasch, and Elise Sarton. "Effect of Rifampicin on S-ketamine and S-norketamine Plasma Concentrations in Healthy Volunteers after Intravenous S-ketamine Administration." Anesthesiology 114, no. 6 (June 1, 2011): 1435–45. http://dx.doi.org/10.1097/aln.0b013e318218a881.

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Background Low-dose ketamine is used as analgesic for acute and chronic pain. It is metabolized in the liver to norketamine via cytochrome P450 (CYP) enzymes. There are few human data on the involvement of CYP enzymes on the elimination of norketamine and its possible contribution to analgesic effect. The aim of this study was to investigate the effect of CYP enzyme induction by rifampicin on the pharmacokinetics of S-ketamine and its major metabolite, S-norketamine, in healthy volunteers. Methods Twenty healthy male subjects received 20 mg/70 kg/h (n = 10) or 40 mg/70 kg/h (n = 10) intravenous S-ketamine for 2 h after either 5 days oral rifampicin (once daily 600 mg) or placebo treatment. During and 3 h after drug infusion, arterial plasma concentrations of S-ketamine and S-norketamine were obtained at regular intervals. The data were analyzed with a compartmental pharmacokinetic model consisting of three compartments for S-ketamine, three sequential metabolism compartments, and two S-norketamine compartments using the statistical package NONMEM® 7 (ICON Development Solutions, Ellicott City, MD). Results Rifampicin caused a 10% and 50% reduction in the area-under-the-curve of the plasma concentrations of S-ketamine and S-norketamine, respectively. The compartmental analysis indicated a 13% and 200% increase in S-ketamine and S-norketamine elimination from their respective central compartments by rifampicin. Conclusions : A novel observation is the large effect of rifampicin on S-norketamine concentrations and indicates that rifampicin induces the elimination of S-ketamine's metabolite, S-norketamine, probably via induction of the CYP3A4 and/or CYP2B6 enzymes.

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Olofsen, Erik, Ingeborg Noppers, Marieke Niesters, Evan Kharasch, Leon Aarts, Elise Sarton, and Albert Dahan. "Estimation of the Contribution of Norketamine to Ketamine-induced Acute Pain Relief and Neurocognitive Impairment in Healthy Volunteers." Anesthesiology 117, no. 2 (August 1, 2012): 353–64. http://dx.doi.org/10.1097/aln.0b013e31825b6c91.

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Background The N-methyl-D-aspartate receptor antagonist ketamine is metabolized in the liver into its active metabolite norketamine. No human data are available on the relative contribution of norketamine to ketamine-induced analgesia and side effects. One approach to assess the ketamine and norketamine contributions is by measuring the ketamine effect at varying ketamine and norketamine plasma concentrations using the CYP450 inducer rifampicin. Methods In 12 healthy male volunteers the effect of rifampicin versus placebo pretreatment on S-ketamine-induced analgesia and cognition was quantified; the S-ketamine dosage was 20 mg/h for 2 h. The relative ketamine and norketamine contribution to effect was estimated using a linear additive population pharmacokinetic-pharmacodynamic model. Results S-ketamine produced significant analgesia, psychotropic effects (drug high), and cognitive impairment (including memory impairment and reduced psychomotor speed, reaction time, and cognitive flexibility). Modeling revealed a negative contribution of S-norketamine to S-ketamine- induced analgesia and absence of contribution to cognitive impairment. At ketamine and norketamine effect concentrations of 100 ng/ml and 50 ng/ml, respectively, the ketamine contribution to analgesia is -3.8 cm (visual analog pain score) versus a contribution of norketamine of +1.5 cm, causing an overall effect of -2.3 cm. The blood-effect site equilibration half-life ranged from 0 (cognitive flexibility) to 11.8 (pain intensity) min and was 6.1 min averaged across all endpoints. Conclusions This first observation that norketamine produces effects in the opposite direction of ketamine requires additional proof. It can explain the observation of ketamine-related excitatory phenomena (such as hyperalgesia and allodynia) upon the termination of ketamine infusions.

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Goldberg, Michael E. "Pharmacodynamic Profiles of Ketamine (R)- and (S)- with 5-Day Inpatient Infusion for the Treatment of Complex Regional Pain Syndrome." Pain Physician 4;13, no. 4;7 (July 14, 2010): 379–87. http://dx.doi.org/10.36076/ppj.2010/13/379.

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Background: Ketamine might be effective in blocking central sensitization of pain transmission neurons through its effect on NMDA receptors in refractory Complex Regional Pain Syndrome (CRPS) patients. At higher doses, ketamine infusions can be associated with significant risks; outpatient therapy requires return visits for a 10-day period with variable efficacy and duration. Objective: This study determined the efficacy of a 5-day moderate dose, continuous racemic ketamine infusion. The pharmacodynamic responses to racemic ketamine and norketamine were examined. Design: Observational study Methods: In this study, ketamine was titrated from 10-40 mg/hour in 16 CRPS patients, and maintained for 5 days. Pain was assessed daily. Ketamine and norketamine concentrations were obtained on Day 1 before starting the infusion; at 60 to 90 minutes, 120 to 150 minutes, 180 to 210 minutes, and 240 to 300 minutes after the initiation of the infusion on Days 2, 3, 4, and 5; and on Day 5 at 60 minutes after the conclusion of the infusion. The plasma concentrations of (R)-ketamine, (S)-ketamine, (R)-norketamine and (S)-norketamine were determined using an enantioselective liquid chromatography – mass spectrometry method. Results: Ketamine and norketamine infusion rates stabilized 5 hours after the start of the infusion. The subjects showed no evidence of significant tachycardia, arterial oxygen desaturation, or hallucinatory responses. Subjects generally experienced minimal pain relief on day one followed by significant relief by day 3. Mean pain scores decreased from the 8-9 to 3-5 ranges; however, the analgesic response to ketamine infusion was not uniform. On day 5, there was little or no change in the pain measure assessed as the worst pain experienced over the last 24 hours in 37% of the subjects. (R)- and (S)-ketamine concentrations peaked at 240-300 min. (R)- and (S)-norketamine concentrations were lower and peaked on Day 2 of the infusion, as opposed to Day 1 for (R)- and (S)-ketamine. Significant pain relief was achieved by the second day of infusion and correlated with the maximum plasma levels of ketamine and norketamine. Pain relief continued to significantly improve over the 5 day infusion at concentrations of 200-225 ng/mL for (R)- and (S)-ketamine, and 90-120 ng/mL for(R)- and (S)-norketamine. Conclusions: A 5-day ketamine infusion for the treatment of severe CRPS provided significant (P <0.05) pain relief by Day 3 compared to baseline. The pain relief experienced on Day 2 of the infusion continued to improve over the 5-day infusion period and correlated with the maximum plasma levels of ketamine and norketamine. We speculate that downstream metabolites of ketamine and norketamine might be playing a role in its therapeutic efficacy. Key words: ketamine, norketamine, CRPS, pharmacodynamics, chronic pain, enantiomers

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Ahmad, Samir M., Mariana N. Oliveira, Nuno R. Neng, and J. M. F. Nogueira. "A Fast and Validated High Throughput Bar Adsorptive Microextraction (HT-BAµE) Method for the Determination of Ketamine and Norketamine in Urine Samples." Molecules 25, no. 6 (March 22, 2020): 1438. http://dx.doi.org/10.3390/molecules25061438.

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We developed, optimized and validated a fast analytical cycle using high throughput bar adsorptive microextraction and microliquid desorption (HT-BAμE-μLD) for the extraction and desorption of ketamine and norketamine in up to 100 urine samples simultaneously, resulting in an assay time of only 0.45 min/sample. The identification and quantification were carried out using large volume injection-gas chromatography-mass spectrometry operating in the selected ion monitoring mode (LVI-GC-MS(SIM)). Several parameters that could influencing HT-BAµE were assayed and optimized in order to maximize the recovery yields of ketamine and norketamine from aqueous media. These included sorbent selectivity, desorption solvent and time, as well as shaking rate, microextraction time, matrix pH, ionic strength and polarity. Under optimized experimental conditions, suitable sensitivity (1.0 μg L−1), accuracy (85.5–112.1%), precision (≤15%) and recovery yields (84.9–105.0%) were achieved. Compared to existing methods, the herein described analytical cycle is much faster, environmentally friendly and cost-effective for the quantification of ketamine and norketamine in urine samples. To our knowledge, this is the first work that employs a high throughput based microextraction approach for the simultaneous extraction and subsequent desorption of ketamine and norketamine in up to 100 urine samples simultaneously.

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Le Nedelec, Martin, Paul Glue, Helen Winter, Chelsea Goulton, and Natalie J. Medlicott. "The effect of route of administration on the enantioselective pharmacokinetics of ketamine and norketamine in rats." Journal of Psychopharmacology 32, no. 10 (June 13, 2018): 1127–32. http://dx.doi.org/10.1177/0269881118780013.

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Background: Ketamine has been shown to produce a rapid and potent antidepressant response in patients with treatment-resistant depression. Currently ketamine is most commonly administered as a 40-minute intravenous infusion, though it is unknown whether this is the optimal route of administration. Aims: To determine the plasma concentration time course of the R- and S-enantiomers of ketamine and norketamine following administration of ketamine by four different routes of administration. Methods: Plasma from conscious non-anaesthetised rats was collected following administration of ketamine by either subcutaneous (SC), intramuscular (IM), intravenous infusion (IVI) or intravenous bolus (IVB) routes of administration. Concentrations of the enantiomers of ketamine and norketamine were determined by LC/MS. Results: Administration by the SC, IM and IVI routes produced an overall similar drug exposure. In contrast, administration by the IVB route produced approximately 15-fold higher peak plasma concentrations for the enantiomers of ketamine and an approximately four-fold lower AUC for the enantiomers of norketamine. Conclusions: Route of administration can significantly influence ketamine and norketamine exposures. These differences may influence safety and tolerability, and potentially drug efficacy in humans. This knowledge adds to current research into the optimisation of the use of ketamine for the treatment of depression.

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Highland, Jaclyn N., Cristan A. Farmer, Panos Zanos, Jacqueline Lovett, Carlos A. Zarate, Ruin Moaddel, and Todd D. Gould. "Sex-dependent metabolism of ketamine and (2R,6R)-hydroxynorketamine in mice and humans." Journal of Psychopharmacology 36, no. 2 (December 31, 2021): 170–82. http://dx.doi.org/10.1177/02698811211064922.

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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.

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Sigtermans, Marnix, Albert Dahan, René Mooren, Martin Bauer, Benjamin Kest, Elise Sarton, and Erik Olofsen. "S(+)-ketamine Effect on Experimental Pain and Cardiac Output." Anesthesiology 111, no. 4 (October 1, 2009): 892–903. http://dx.doi.org/10.1097/aln.0b013e3181b437b1.

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Background Low-dose ketamine behaves as an analgesic in the treatment of acute and chronic pain. To further understand ketamine's therapeutic profile, the authors performed a population pharmacokinetic-pharmacodynamic analysis of the S(+)-ketamine analgesic and nonanalgesic effects in healthy volunteers. Methods Ten men and ten women received a 2-h S(+)-ketamine infusion. The infusion was increased at 40 ng/ml per 15 min to reach a maximum of 320 ng/ml. The following measurements were made: arterial plasma S(+)-ketamine and S(+)-norketamine concentrations, heat pain intensity, electrical pain tolerance, drug high, and cardiac output. The data were modeled by using sigmoid Emax models of S(+)-ketamine concentration versus effect and S(+)-ketamine + S(+)-norketamine concentrations versus effect. Results Sex differences observed were restricted to pharmacokinetic model parameters, with a 20% greater elimination clearance of S(+)-ketamine and S(+)-norketamine in women resulting in higher drug plasma concentrations in men. S(+)-ketamine produced profound drug high and analgesia with six times greater potency in the heat pain than the electrical pain test. After ketamine-infusion, analgesia rapidly dissipated; in the heat pain test but not the electrical pain test, analgesia was followed by a period of hyperalgesia. Over the dose range tested, ketamine produced a 40-50% increase in cardiac output. A significant consistent contribution of S(+)-norketamine to overall effect was detected for none of the outcome parameters. Conclusions S(+)-ketamine displays clinically relevant sex differences in its pharmacokinetics. It is a potent analgesic at already low plasma concentrations, but it is associated with intense side effects.

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Swartjes, Maarten, Aurora Morariu, Marieke Niesters, Leon Aarts, and Albert Dahan. "Nonselective and NR2B-selective N -methyl-d-aspartic Acid Receptor Antagonists Produce Antinociception and Long-term Relief of Allodynia in Acute and Neuropathic Pain." Anesthesiology 115, no. 1 (July 1, 2011): 165–74. http://dx.doi.org/10.1097/aln.0b013e31821bdb9b.

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Background At low dose, the nonselective N-methyl-D-aspartate receptor antagonist ketamine produces potent analgesia. In humans, psychedelic side effects limit its use. To assess whether other N-methyl-D-aspartate receptor antagonist have an improved therapeutic utility index, we compared antinociceptive, side effect, and locomotor activity of three N-methyl-D-aspartate receptor antagonists. Methods Ketamine, its active metabolite norketamine, and the NR2B-selective antagonist traxoprodil (CP-101,606) were tested in rat models of acute antinociception (paw-withdrawal response to heat) and chronic neuropathic pain (spared nerve injury). Side effects (stereotypical behavior, activity level) were scored and locomotor function of the nerve-injured paw was assessed using computerized gait analysis. In the chronic pain model, treatment was given 7 days after surgery, for 3 h on 5 consecutive days. Results All three N-methyl-D-aspartate receptor antagonists caused dose-dependent antinociception in the acute pain model and relief of mechanical and cold allodynia for 3-6 weeks after treatment in the chronic pain model (P < 0.05 vs. saline). In both tests, ketamine was most potent. Norketamine was as much as two times less potent and traxoprodil was up to 8 times less potent than ketamine (based on area under the curve measures). Nerve injury caused an inability to use the affected paw that either did not improve after treatment (ketamine, traxoprodil) or showed only a limited effect (norketamine). Traxoprodil, but not ketamine or norketamine, showed clear separation between effect and side effect. Conclusions The observation that traxoprodil causes relief of chronic pain outlasting the treatment period with no side effects makes it an attractive alternative to ketamine in the treatment of chronic neuropathic pain.

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Paul, Rajib K., Nagendra S. Singh, Mohammed Khadeer, Ruin Moaddel, Mitesh Sanghvi, Carol E. Green, Kathleen O’Loughlin, Marc C. Torjman, Michel Bernier, and Irving W. Wainer. "(R,S)-Ketamine Metabolites (R,S)-norketamine and (2S,6S)-hydroxynorketamine Increase the Mammalian Target of Rapamycin Function." Anesthesiology 121, no. 1 (July 1, 2014): 149–59. http://dx.doi.org/10.1097/aln.0000000000000285.

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Abstract Background: Subanesthetic doses of (R,S)-ketamine are used in the treatment of neuropathic pain and depression. In the rat, the antidepressant effects of (R,S)-ketamine are associated with increased activity and function of mammalian target of rapamycin (mTOR); however, (R,S)-ketamine is extensively metabolized and the contribution of its metabolites to increased mTOR signaling is unknown. Methods: Rats (n = 3 per time point) were given (R,S)-ketamine, (R,S)-norketamine, and (2S,6S)-hydroxynorketamine and their effect on the mTOR pathway determined after 20, 30, and 60 min. PC-12 pheochromocytoma cells (n = 3 per experiment) were treated with escalating concentrations of each compound and the impact on the mTOR pathway was determined. Results: The phosphorylation of mTOR and its downstream targets was significantly increased in rat prefrontal cortex tissue by more than ~2.5-, ~25-, and ~2-fold, respectively, in response to a 60-min postadministration of (R,S)-ketamine, (R,S)-norketamine, and (2S,6S)-hydroxynorketamine (P < 0.05, ANOVA analysis). In PC-12 pheochromocytoma cells, the test compounds activated the mTOR pathway in a concentration-dependent manner, which resulted in a significantly higher expression of serine racemase with ~2-fold increases at 0.05 nM (2S,6S)-hydroxynorketamine, 10 nM (R,S)-norketamine, and 1,000 nM (R,S)-ketamine. The potency of the effect reflected antagonistic activity of the test compounds at the α7-nicotinic acetylcholine receptor. Conclusions: The data demonstrate that (R,S)-norketamine and (2S,6S)-hydroxynorketamine have potent pharmacological activity both in vitro and in vivo and contribute to the molecular effects produced by subanesthetic doses of (R,S)-ketamine. The results suggest that the determination of the mechanisms underlying the antidepressant and analgesic effects of (R,S)-ketamine requires a full study of the parent compound and its metabolites.

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Hernando, Marcos Veguillas, Jonathan C. Moore, Rowena A. Howie, Richard A. Castledine, Samuel L. Bourne, Gareth N. Jenkins, Peter Licence, Martyn Poliakoff, and Michael W. George. "High Yielding Continuous-Flow Synthesis of Norketamine." Organic Process Research & Development 26, no. 4 (March 26, 2022): 1145–51. http://dx.doi.org/10.1021/acs.oprd.1c00407.

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Desta, Zeruesenay, Ruin Moaddel, Evan T. Ogburn, Cong Xu, Anuradha Ramamoorthy, Swarajya Lakshmi Vattem Venkata, Mitesh Sanghvi, Michael E. Goldberg, Marc C. Torjman, and Irving W. Wainer. "Stereoselective and regiospecific hydroxylation of ketamine and norketamine." Xenobiotica 42, no. 11 (May 21, 2012): 1076–87. http://dx.doi.org/10.3109/00498254.2012.685777.

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Swartjes, M., M. Hollmann, L. Aarts, A. Dahan, and A. Morariu. "Norketamine versus ketamine - Analgesic potential and side effects." European Journal of Anaesthesiology 27 (June 2010): 202–3. http://dx.doi.org/10.1097/00003643-201006121-00650.

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Chen, Cheng-yi, and Xiaowei Lu. "Enantioselective Syntheses of (S)-Ketamine and (S)-Norketamine." Organic Letters 21, no. 16 (August 8, 2019): 6575–78. http://dx.doi.org/10.1021/acs.orglett.9b02575.

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Chen, Lu, Yong Gong, and Rhys Salter. "Synthesis of carbon-14 labeled ketamine and norketamine." Journal of Labelled Compounds and Radiopharmaceuticals 61, no. 11 (July 29, 2018): 864–68. http://dx.doi.org/10.1002/jlcr.3669.

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Hashimoto, Kenji, and Chun Yang. "Is (S)-norketamine an alternative antidepressant for esketamine?" European Archives of Psychiatry and Clinical Neuroscience 269, no. 7 (July 14, 2018): 867–68. http://dx.doi.org/10.1007/s00406-018-0922-2.

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Olofsen, Erik, Jasper Kamp, Thomas K. Henthorn, Monique van Velzen, Marieke Niesters, Elise Sarton, and Albert Dahan. "Ketamine Psychedelic and Antinociceptive Effects Are Connected." Anesthesiology 136, no. 5 (February 21, 2022): 792–801. http://dx.doi.org/10.1097/aln.0000000000004176.

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Background Ketamine produces potent analgesia combined with psychedelic effects. It has been suggested that these two effects are associated and possibly that analgesia is generated by ketamine-induced dissociation. The authors performed a post hoc analysis of previously published data to quantify the pharmacodynamic properties of ketamine-induced antinociception and psychedelic symptoms. The hypothesis was that ketamine pharmacodynamics (i.e., concentration–effect relationship as well as effect onset and offset times) are not different for these two endpoints. Methods Seventeen healthy male volunteers received escalating doses of S- and racemic ketamine on separate occasions. Before, during, and after ketamine infusion, changes in external perception were measured together with pain pressure threshold. A population pharmacokinetic–pharmacodynamic analysis was performed that took S- and R-ketamine and S- and R-norketamine plasma concentrations into account. Results The pharmacodynamics of S-ketamine did not differ for antinociception and external perception with potency parameter (median [95% CI]) C50, 0.51 (0.38 to 0.66) nmol/ml; blood-effect site equilibration half-life, 8.3 [5.1 to 13.0] min), irrespective of administration form (racemic ketamine or S-ketamine). R-ketamine did not contribute to either endpoint. For both endpoints, S-norketamine had a small antagonistic effect. Conclusions The authors conclude that their data support an association or connectivity between ketamine analgesia and dissociation. Given the intricacies of the study related to the pain model, measurement of dissociation, and complex modeling of the combination of ketamine and norketamine, it is the opinion of the authors that further studies are needed to detect functional connectivity between brain areas that produce the different ketamine effects. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

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Nakamura, K., T. Watanabe, K. Itaya, K. Sakata, M. Sakata, Y. Kamata, T. Kawamata, K. Omote, and A. Namiki. "KETAMINE AND NORKETAMINE PLASMA LEVEL AFTER ORAL KETAMINE THERAPY." Therapeutic Drug Monitoring 21, no. 4 (August 1999): 431. http://dx.doi.org/10.1097/00007691-199908000-00020.

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Moore, K. A., J. Sklerov, B. Levine, and A. J. Jacobs. "Urine Concentrations of Ketamine and Norketamine Following Illegal Consumption." Journal of Analytical Toxicology 25, no. 7 (October 1, 2001): 583–88. http://dx.doi.org/10.1093/jat/25.7.583.

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HOLTMANJR, J., P. CROOKS, J. JOHNSONHARDY, M. HOJOMAT, M. KLEVEN, and E. WALA. "Effects of norketamine enantiomers in rodent models of persistent pain." Pharmacology Biochemistry and Behavior 90, no. 4 (October 2008): 676–85. http://dx.doi.org/10.1016/j.pbb.2008.05.011.

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HERD, DAVID W., BRIAN J. ANDERSON, and NICHOLAS H. G. HOLFORD. "Modeling the norketamine metabolite in children and the implications for analgesia." Pediatric Anesthesia 17, no. 9 (September 2007): 831–40. http://dx.doi.org/10.1111/j.1460-9592.2007.02257.x.

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de Jong, Lutea A. A., Rouhollah Qurishi, Marieke P. J. Stams, Michael Böttcher, and Cornelis A. J. de Jong. "Prolonged Ketamine and Norketamine Excretion Profiles in Urine After Chronic Use." Journal of Clinical Psychopharmacology 40, no. 3 (2020): 300–304. http://dx.doi.org/10.1097/jcp.0000000000001191.

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HOLTMANJR, J., P. CROOKS, J. JOHNSONHARDY, and E. WALA. "Interaction between morphine and norketamine enantiomers in rodent models of nociception." Pharmacology Biochemistry and Behavior 90, no. 4 (October 2008): 769–77. http://dx.doi.org/10.1016/j.pbb.2008.05.019.

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Holtman, J., P. Crooks, M. Kleven, M. Hojahmat, J. Johnson, K. Etscheidt, and E. Wala. "(142) Oral efficacy of S-norketamine in preclinical rodent pain models." Journal of Pain 9, no. 4 (April 2008): 11. http://dx.doi.org/10.1016/j.jpain.2008.01.061.

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Xiang, Ping, Qiran Sun, Baohua Shen, and Min Shen. "Disposition of ketamine and norketamine in hair after a single dose." International Journal of Legal Medicine 125, no. 6 (December 9, 2010): 831–40. http://dx.doi.org/10.1007/s00414-010-0534-5.

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Lee, Vicky W. M., Jack Y. K. Cheng, Samuel T. C. Cheung, Yiu-chung Wong, and Della W. M. Sin. "The first international proficiency test on ketamine and norketamine in hair." Forensic Science International 219, no. 1-3 (June 2012): 272–77. http://dx.doi.org/10.1016/j.forsciint.2012.01.017.

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Yang, Chun, Shizuka Kobayashi, Kazuhito Nakao, Chao Dong, Mei Han, Youge Qu, Qian Ren, et al. "AMPA Receptor Activation–Independent Antidepressant Actions of Ketamine Metabolite (S)-Norketamine." Biological Psychiatry 84, no. 8 (October 2018): 591–600. http://dx.doi.org/10.1016/j.biopsych.2018.05.007.

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Schmitz, Andrea, Regula Theurillat, Paul-Gerhard Lassahn, Meike Mevissen, and Wolfgang Thormann. "CE provides evidence of the stereoselective hydroxylation of norketamine in equines." ELECTROPHORESIS 30, no. 16 (August 2009): 2912–21. http://dx.doi.org/10.1002/elps.200900221.

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Otto, M. E., K. R. Bergmann, G. Jacobs, and Michiel J. van Esdonk. "Predictive performance of parent-metabolite population pharmacokinetic models of (S)-ketamine in healthy volunteers." European Journal of Clinical Pharmacology 77, no. 8 (February 11, 2021): 1181–92. http://dx.doi.org/10.1007/s00228-021-03104-1.

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Abstract Purpose The recent repurposing of ketamine as treatment for pain and depression has increased the need for accurate population pharmacokinetic (PK) models to inform the design of new clinical trials. Therefore, the objectives of this study were to externally validate available PK models on (S)-(nor)ketamine concentrations with in-house data and to improve the best performing model when necessary. Methods Based on predefined criteria, five models were selected from literature. Data of two previously performed clinical trials on (S)-ketamine administration in healthy volunteers were available for validation. The predictive performances of the selected models were compared through visual predictive checks (VPCs) and calculation of the (root) mean (square) prediction errors (ME and RMSE). The available data was used to adapt the best performing model through alterations to the model structure and re-estimation of inter-individual variability (IIV). Results The model developed by Fanta et al. (Eur J Clin Pharmacol 71:441–447, 2015) performed best at predicting the (S)-ketamine concentration over time, but failed to capture the (S)-norketamine Cmax correctly. Other models with similar population demographics and study designs had estimated relatively small distribution volumes of (S)-ketamine and thus overpredicted concentrations after start of infusion, most likely due to the influence of circulatory dynamics and sampling methodology. Model predictions were improved through a reduction in complexity of the (S)-(nor)ketamine model and re-estimation of IIV. Conclusion The modified model resulted in accurate predictions of both (S)-ketamine and (S)-norketamine and thereby provides a solid foundation for future simulation studies of (S)-(nor)ketamine PK in healthy volunteers after (S)-ketamine infusion.

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Gálvez, Verònica, Adrienne Li, Christina Huggins, Paul Glue, Donel Martin, Andrew A. Somogyi, Angelo Alonzo, Anthony Rodgers, Philip B. Mitchell, and Colleen K. Loo. "Repeated intranasal ketamine for treatment-resistant depression – the way to go? Results from a pilot randomised controlled trial." Journal of Psychopharmacology 32, no. 4 (March 15, 2018): 397–407. http://dx.doi.org/10.1177/0269881118760660.

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Background: Ketamine research in depression has mostly used intravenous, weight-based approaches, which are difficult to translate clinically. Intranasal (IN) ketamine is a promising alternative but no controlled data has been published on the feasibility, safety and potential efficacy of repeated IN ketamine treatments. Methods: This randomised, double-blind, placebo-controlled pilot study compared a 4-week course of eight treatments of 100 mg ketamine or 4.5 mg midazolam. Each treatment was given as 10 separate IN sprays, self-administered 5 min apart. The study was stopped early due to poor tolerability after five treatment-resistant depressed participants were included. Feasibility, safety (acute and cumulative), cognitive and efficacy outcomes were assessed. Plasma ketamine and norketamine concentrations were assayed after the first treatment. Results: Significant acute cardiovascular, psychotomimetic and neurological side effects occurred at doses < 100 mg ketamine. No participants were able to self-administer all 10 ketamine sprays due to incoordination; treatment time occasionally had to be extended (>45 min) due to acute side effects. No hepatic, cognitive or urinary changes were observed after the treatment course in either group. There was an approximately two-fold variation in ketamine and norketamine plasma concentrations between ketamine participants. At course end, one participant had remitted in each of the ketamine and midazolam groups. Conclusions: IN ketamine, with the drug formulation and delivery device used, was not a useful treatment approach in this study. Absorption was variable between individuals and acute tolerability was poor, requiring prolonged treatment administration time in some individuals. The drug formulation, the delivery device, the insufflation technique and individual patient factors play an important role in tolerability and efficacy when using IN ketamine for TRD.

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Rao, Lesley K., Alicia M. Flaker, Christina C. Friedel, and Evan D. Kharasch. "Role of Cytochrome P4502B6 Polymorphisms in Ketamine Metabolism and Clearance." Anesthesiology 125, no. 6 (December 1, 2016): 1103–12. http://dx.doi.org/10.1097/aln.0000000000001392.

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Abstract Background At therapeutic concentrations, cytochrome P4502B6 (CYP2B6) is the major P450 isoform catalyzing hepatic ketamine N-demethylation to norketamine in vitro. The CYP2B6 gene is highly polymorphic. The most common variant allele, CYP2B6*6, is associated with diminished hepatic CYP2B6 expression and catalytic activity compared with wild-type CYP2B6*1/*1. CYP2B6.6, the protein encoded by the CYP2B6*6 allele, and liver microsomes from CYP2B6*6 carriers had diminished ketamine metabolism in vitro. This investigation tested whether humans with the CYP2B6*6 allele would have decreased clinical ketamine metabolism and clearance. Methods Thirty volunteers with CYP2B6*1/*1, *1/*6, or *6/*6 genotypes (n = 10 each) received a subsedating dose of oral ketamine. Plasma and urine concentrations of ketamine and the major CYP2B6-dependent metabolites were determined by mass spectrometry. Subjects’ self-assessment of ketamine effects were also recorded. The primary outcome was ketamine N-demethylation, measured as the plasma norketamine/ketamine area under the curve ratio. Secondary outcomes included plasma ketamine enantiomer and metabolite area under the plasma concentration–time curve, maximum concentrations, apparent oral clearance, and metabolite formation clearances. Results There was no significant difference between CYP2B6 genotypes in ketamine metabolism or any of the secondary outcome measures. Subjective self-assessment did reveal some differences in energy and level of awareness among subjects. Conclusions These results show that while the CYP2B6*6 polymorphism results in diminished ketamine metabolism in vitro, this allelic variant did not affect single, low-dose ketamine metabolism, clearance, and pharmacokinetics in vivo. While in vitro drug metabolism studies may be informative, clinical investigations in general are needed to validate in vitro observations.

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Gao, Shenghua, Xuezhi Gao, Zenong Wu, Houyong Li, Zhezhou Yang, and Fuli Zhang. "Process for (S)-Ketamine and (S)-Norketamine via Resolution Combined with Racemization." Journal of Organic Chemistry 85, no. 13 (June 8, 2020): 8656–64. http://dx.doi.org/10.1021/acs.joc.0c01090.

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Bushnell, T. G., and J. Craig. "Response of chronic neuropathic pain syndromes to ketamine: a role for norketamine?" Pain 60, no. 1 (January 1995): 115. http://dx.doi.org/10.1016/0304-3959(94)00123-v.

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Wang, Pan-Fen, Alicia Neiner, and Evan D. Kharasch. "Stereoselective Ketamine Metabolism by Genetic Variants of Cytochrome P450 CYP2B6 and Cytochrome P450 Oxidoreductase." Anesthesiology 129, no. 4 (October 1, 2018): 756–68. http://dx.doi.org/10.1097/aln.0000000000002371.

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Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Human ketamine N-demethylation to norketamine in vitro at therapeutic concentrations is catalyzed predominantly by the cytochrome P4502B6 isoform (CYP2B6). The CYP2B6 gene is highly polymorphic. CYP2B6.6, the protein encoded by the common variant allele CYP2B6*6, exhibits diminished ketamine metabolism in vitro compared with wild-type CYP2B6.1. The gene for cytochrome P450 oxidoreductase (POR), an obligatory P450 coenzyme, is also polymorphic. This investigation evaluated ketamine metabolism by genetic variants of human CYP2B6 and POR. Methods CYP2B6 (and variants), POR (and variants), and cytochrome b5 (wild-type) were coexpressed in a cell system. All CYP2B6 variants were expressed with wild-type POR and b5. All POR variants were expressed with wild-type CYP2B6.1 and b5. Metabolism of R- and S-ketamine enantiomers, and racemic RS-ketamine to norketamine enantiomers, was determined using stereoselective high-pressure liquid chromatography–mass spectrometry. Michaelis–Menten kinetic parameters were determined. Results For ketamine enantiomers and racemate, metabolism (intrinsic clearance) was generally wild-type CYP2B6.1 > CYP2B6.4 > CYP2B6.26, CYP2B6.19, CYP2B6.17, CYP2B6.6 > CYP2B6.5, CYP2B6.7 > CYP2B6.9. CYP2B6.16 and CYP2B6.18 were essentially inactive. Activity of several CYP2B6 variants was less than half that of CYP2B6.1. CYP2B6.9 was 15 to 35% that of CYP2B6.1. The order of metabolism was wild-type POR.1 > POR.28, P228L > POR.5. CYP2B6 variants had more influence than POR variants on ketamine metabolism. Neither CYP2B6 nor POR variants affected the stereoselectivity of ketamine metabolism (S > R). Conclusions Genetic variants of CYP2B6 and P450 oxidoreductase have diminished ketamine N-demethylation activity, without affecting the stereoselectivity of metabolism. These results suggest candidate genetic polymorphisms of CYP2B6 and P450 oxidoreductase for clinical evaluation to assess consequences for ketamine pharmacokinetics, elimination, bioactivation, and therapeutic effects.

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Pérez-Pereira, Ariana, Alexandra Maia, Virgínia Gonçalves, Cláudia Ribeiro, and Maria Elizabeth Tiritan. "Enantioselective Monitoring of Biodegradation of Ketamine and Its Metabolite Norketamine by Liquid Chromatography." Chemosensors 9, no. 9 (August 30, 2021): 242. http://dx.doi.org/10.3390/chemosensors9090242.

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Ketamine (K) and its main metabolite, norketamine (NK), are chiral compounds that have been found in effluents from wastewater treatment plants (WWTPs) and aquatic environments. Little is known about their enantioselective biodegradation during sewage treatment; however, this information is pivotal for risk assessment, the evaluation of WWTP performance and wastewater epidemiological studies. The aim of this study was to investigate the biodegradation pattern of the enantiomers of K by activated sludge (AS) from a WWTP. For that, an enantioselective liquid chromatography with diode array detection (LC-DAD) method was developed and validated to quantify the enantiomers of K and NK. Both K and NK enantiomers were separated, in the same chromatographic run, using a Lux® 3 µm cellulose-4 analytical column under isocratic elution mode. The method was demonstrated to be linear (r2 > 0.99) and precise (<11.3%). Accuracy ranged between 85.9 and 113.6% and recovery ranged between 50.1 and 86.9%. The limit of quantification was 1.25 µg/mL for the enantiomers of NK and 2.5 µg/mL for K. The method was applied to monitor the biodegradation assay of the enantiomers of K by AS for 14 days. K was poorly biodegraded, less than 15% for both enantiomers, and enantioselectivity in the biodegradation was not observed. The metabolite NK and other possible degradation products were not detected. This work reports, for the first time, the behavior of both enantiomers of K in biodegradation studies.

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Hijazi, Youssef, Magali Bolon, and Roselyne Boulieu. "Stability of Ketamine and Its Metabolites Norketamine and Dehydronorketamine in Human Biological Samples." Clinical Chemistry 47, no. 9 (September 1, 2001): 1713–15. http://dx.doi.org/10.1093/clinchem/47.9.1713.

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Legrand, T., S. Roy, C. Monchaud, C. Grondin, M. Duval, and E. Jacqz-Aigrain. "Determination of ketamine and norketamine in plasma by micro-liquid chromatography–mass spectrometry." Journal of Pharmaceutical and Biomedical Analysis 48, no. 1 (September 2008): 171–76. http://dx.doi.org/10.1016/j.jpba.2008.05.008.

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Jen, Hsiu-Ping, Yuan-Chien Tsai, Hsiu-Li Su, and You-Zung Hsieh. "On-line preconcentration and determination of ketamine and norketamine by micellar electrokinetic chromatography." Journal of Chromatography A 1111, no. 2 (April 2006): 159–65. http://dx.doi.org/10.1016/j.chroma.2005.05.019.

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Porpiglia, Nadia, Giacomo Musile, Federica Bortolotti, Elio Franco De Palo, and Franco Tagliaro. "Chiral separation and determination of ketamine and norketamine in hair by capillary electrophoresis." Forensic Science International 266 (September 2016): 304–10. http://dx.doi.org/10.1016/j.forsciint.2016.06.017.

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Malinovsky, J. M., F. Servin, A. Cozian, J. Y. Lepage, and M. Pinaud. "Ketamine and norketamine plasma concentrations after i.v., nasal and rectal administration in children." British Journal of Anaesthesia 77, no. 2 (August 1996): 203–7. http://dx.doi.org/10.1093/bja/77.2.203.

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Göktaş, Eylem Funda, and Filiz Arıöz. "A review of chromatographic methods for ketamine and its metabolites norketamine and dehydronorketamine." Biomedical Chromatography 32, no. 1 (July 11, 2017): e4014. http://dx.doi.org/10.1002/bmc.4014.

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Tran, Benjamin Duy, Ganesh S. Moorthy, and Athena F. Zuppa. "Ketamine and norketamine stability in whole blood at ambient and 4°C conditions." Biomedical Chromatography 32, no. 3 (November 9, 2017): e4104. http://dx.doi.org/10.1002/bmc.4104.

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Yen, Yao-Te, Shih-Hao Tseng, Deng-Ying Huang, Yi-Shiuan Tsai, Li-Wen Lee, Pei-Lin Chen, Yuh-Lin Liu, and San-Chong Chyueh. "Identification of a novel norketamine precursor from seized powders: 2-(2-chlorophenyl)-2-nitrocyclohexanone." Forensic Science International 333 (April 2022): 111241. http://dx.doi.org/10.1016/j.forsciint.2022.111241.

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Biermann, Manfred, Guangrong Zheng, Marhaba Hojahmat, Nick V. Moskalev, and Peter A. Crooks. "Asymmetric synthesis of (S)- and (R)-norketamine via Sharpless asymmetric dihydroxylation/Ritter amination sequence." Tetrahedron Letters 56, no. 20 (May 2015): 2608–10. http://dx.doi.org/10.1016/j.tetlet.2015.04.050.

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Shimoyama, Megumi, Naohito Shimoyama, Laurel A. Gorman, Kathryn J. Elliott, and Charles E. Inturrisi. "Oral ketamine is antinociceptive in the rat formalin test: role of the metabolite, norketamine." Pain 81, no. 1 (May 1999): 85–93. http://dx.doi.org/10.1016/s0304-3959(98)00269-3.

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Watterson, J. H., and J. P. Donohue. "Relative Distribution of Ketamine and Norketamine in Skeletal Tissues Following Various Periods of Decomposition." Journal of Analytical Toxicology 35, no. 7 (September 1, 2011): 452–58. http://dx.doi.org/10.1093/anatox/35.7.452.

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Devreese, Mathias, Diego Rodrigo, Stijn Schauvliege, Frank Gasthuys, Patrick De Backer, and Siska Croubels. "Quantification of ketamine and norketamine in bovine plasma by liquid chromatography–tandem mass spectrometry." Journal of the Iranian Chemical Society 12, no. 8 (February 1, 2015): 1357–62. http://dx.doi.org/10.1007/s13738-015-0601-4.

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Bolze, Sébastien, and Roselyne Boulieu. "HPLC determination of ketamine, norketamine, and dehydronorketamine in plasma with a high-purity reversed-phase sorbent." Clinical Chemistry 44, no. 3 (March 1, 1998): 560–64. http://dx.doi.org/10.1093/clinchem/44.3.560.

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Abstract We developed an isocratic, selective, and very sensitive HPLC method for the determination of ketamine and its two main metabolites in plasma. The compounds were extracted from plasma by a liquid–liquid extraction with a dichloromethane:ethyl acetate mixture followed by an acidic back-extraction. Separation was achieved on a new stationary phase, Purospher RP-18 end-capped, with a mobile phase containing acetonitrile:0.03 mol/L phosphate buffer (23:77 by vol) adjusted to pH 7.2. Because of the high column efficiency and the significant improvement of peak symmetry, the quantification limit could be down to 5 μg/L for ketamine and norketamine (NK). The intraday and interday CVs ranged from 1.7% to 5.8% and 3.1% to 10.2% for all compounds respectively. The method is sensitive enough for monitoring ketamine, NK, and dehydroketamine in plasma during pharmacokinetic studies after an intravenous bolus of a low dose of ketamine.

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WEBER, FRANK, HINNERK WULF, MICHAEL GRUBER, and RALF BIALLAS. "S-ketamine and s-norketamine plasma concentrations after nasal and i.v. administration in anesthetized children." Pediatric Anesthesia 14, no. 12 (December 2004): 983–88. http://dx.doi.org/10.1111/j.1460-9592.2004.01358.x.

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Lua, Ahai C., and Huei R. Lin. "A Rapid and Sensitive ESI-MS Screening Procedure for Ketamine and Norketamine in Urine Samples*." Journal of Analytical Toxicology 28, no. 8 (November 1, 2004): 680–84. http://dx.doi.org/10.1093/jat/28.8.680.

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