Simultaneous population pharmacokinetic modelling of ketamine and three major metabolites in patients with treatment-resistant bipolar depression

Zhao, Xiaochen; Venkata, Swarajya Lakshmi Vattem; Moaddel, Ruin; Luckenbaugh, Dave A.; Brutsche, Nancy E.; Ibrahim, Lobna; Zarate Jr, Carlos A.; Mager, Donald E.; Wainer, Irving W.

doi:10.1111/j.1365-2125.2012.04198.x

Cited by 139Treatment of Major DepressionPharmacogenetics and Drug MetabolismPharmaceutical studies and practices

Simultaneous population pharmacokinetic modelling of ketamine and three major metabolites in patients with treatment-resistant bipolar depression

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Zhao, Xiaochen, Venkata, Swarajya Lakshmi Vattem, Moaddel, Ruin, Luckenbaugh, Dave A., Brutsche, Nancy E., Ibrahim, Lobna, Zarate Jr, Carlos A., Mager, Donald E. +1 more·2012·British Journal of Clinical Pharmacology

DOI 10.1111/j.1365-2125.2012.04198.xPMC PMC3630750

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Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • (R,S)‐ketamine is a phencyclidine derivative that was initially developed as an anaesthetic agent and which is currently being studied in the treatment of pain and depression. After administration, the drug is extensively N‐demethylated to (R,S)‐norketamine. The pharmacokinetics of ketamine and norketamine have been extensively studied in volunteers and patients after the administration of anaesthetic and sub‐anaesthetic doses. However, ketamine and norketamine are extensively transformed into a series of diastereomeric hydroxyketamines and hydroxynorketamines and (R,S)‐dehydronorketamine metabolites. The plasma kinetics of these metabolites have not been elucidated. WHAT THIS STUDY ADDS • The current study expands the characterization of the disposition kinetics of (R,S)‐ketamine and (R,S)‐norketamine and presents a population pharmacokinetic analysis of (R)‐ketamine, (S)‐ketamine, (R)‐norketamine, (S)‐norketamine, (R)‐dehydronorketamine, (S)‐ dehydronorketamine and (2S,6S;2R,6R)‐hydroxynorketamine and the serum concentration–time profiles of multiple ketamine metabolites observed in the plasma of patients after a single 40 min infusion of a sub‐anaesthetic dose of the drug. The data demonstrate that while norketamine is an initial metabolite, it is not the major circulating metabolite and suggest that the determination of the downstream metabolites of ketamine may play a role in the pharmacological effects of the drug. AIM To construct a population pharmacokinetic (popPK) model for ketamine (Ket), norketamine (norKet), dehydronorketamine (DHNK), hydroxynorketamine (2S,6S;2R,6R)‐HNK) and hydroxyketamine (HK) in patients with treatment‐resistant bipolar depression. METHOD Plasma samples were collected at 40, 80, 110, 230 min on day 1, 2 and 3 in nine patients following a 40 min infusion of (R,S)‐Ket (0.5 mg kg−1) and analyzed for Ket, norKet and DHNK enantiomers and (2S,6S;2R,6R)‐HNK, (2S,6S;2R,6R)‐HK and (2S,6R;2R,6S)‐HK. A compartmental popPK model was constructed that included all quantified analytes, and unknown parameters were estimated with an iterative two‐stage algorithm in ADAPT5. RESULTS Ket, norKet, DHNK and (2S,6S;2R,6R)‐HNK were present during the first 230 min post infusion and significant concentrations (>5 ng ml−1) were observed on day 1. Plasma concentrations of (2S,6S;2R,6R)‐HK and (2S,6R;2R,6S)‐HK were below the limit of quantification. The average (S) : (R) plasma concentrations for Ket and DHNK were <1.0 while no significant enantioselectivity was observed for norKet. There were large inter‐patient variations in terminal half‐lives and relative metabolite concentrations; at 230 min (R,S)‐DHNK was the major metabolite in four out of nine patients, (R,S)‐norKet in three out of nine patients and (2S,6S;2R,6R)‐HNK in two out of nine patients. The final PK model included three compartments for (R,S)‐Ket, two compartments for (R,S)‐norKet and single compartments for DHNK and HNK. All PK profiles were well described, and parameters for (R,S)‐Ket and (R,S)‐norKet were in agreement with prior estimates. CONCLUSION This represents the first PK analysis of (2S,6S;2R,6R)‐HNK and (R,S)‐DHNK. The results demonstrate that while norKet is the initial metabolite, it is not the main metabolite suggesting that future Ket studies should include the analysis of the major metabolites.

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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 Zhao et al., 2012
The Abstract (page not provided) reports plasma sampling beginning at 40 minutes after the start of a 0.5 mg/kg, 40-minute ketamine infusion and detects norketamine, DHNK, and (2S,6S;2R,6R)-HNK. The Discussion (page not provided) identifies the two named HNKs as predominant in earlier CRPS-patient data, not in this study’s bipolar-depression patients; among the other HNKs measured in this study, it names (2S,5R;2R,5S)-HNK as most predominant. (LLM, conf=0.88)
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A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.
Zarate, C. A., Singh, J. B., Carlson, P. J., Brutsche, N. E., Ameli, R., Luckenbaugh, D. A., Charney, D. S., & Manji, H. K. (2006) · Archives of General Psychiatry · doi:10.1001/archpsyc.63.8.856 · Cited by 3,766 · see citing works
Self-citation
A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression
Diazgranados, N., Ibrahim, L., Brutsche, N. E., Newberg, A., Kronstein, P., Khalife, S., Kammerer, W. A., Quezado, Z., Luckenbaugh, D. A., Salvadore, G., et al. (2010) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2010.90 · Cited by 963 · see citing works
Self-citation
Ketamine
Kohrs, R., & Durieux, M. E. (1998) · Anesthesia & Analgesia · doi:10.1097/00000539-199811000-00039 · Cited by 635 · see citing works
Rapid Resolution of Suicidal Ideation After a Single Infusion of an <i>N</i> -Methyl- <scp>D</scp> -Aspartate Antagonist in Patients With Treatment-Resistant Major Depressive Disorder
DiazGranados, N., Ibrahim, L. A., Brutsche, N. E., Ameli, R., Henter, I. D., Luckenbaugh, D. A., Machado-Vieira, R., & Zarate, C. A. (2010) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.09m05327blu · Cited by 564 · see citing works
Self-citation
Taming the Ketamine Tiger
Domino, E. F., & Warner, D. S. (2010) · Anesthesiology · doi:10.1097/aln.0b013e3181ed09a2 · Cited by 520 · see citing works
Intraoperative Ketamine Reduces Perioperative Opiate Consumption in Opiate-dependent Patients with Chronic Back Pain Undergoing Back Surgery
Loftus, R. W., Yeager, M. P., Clark, J. A., Brown, J. R., Abdu, W. A., Sengupta, D. K., & Beach, M. L. (2010) · Anesthesiology · doi:10.1097/aln.0b013e3181e90914 · Cited by 471 · see citing works
Ketamine produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1
Sigtermans, M. J., van Hilten, J. J., Bauer, M. C. R., Arbous, M. S., Marinus, J., Sarton, E. Y., & Dahan, A. (2009) · Pain · doi:10.1016/j.pain.2009.06.023 · Cited by 468 · see citing works
The use of ketamine in complex regional pain syndrome: possible mechanisms
Schwartzman, R. J., Alexander, G. M., & Grothusen, J. R. (2011) · Expert Review of Neurotherapeutics · doi:10.1586/ern.11.31 · Cited by 225 · see citing works
Plasma concentration profiles of ketamine and norketamine after administration of various ketamine preparations to healthy Japanese volunteers
Yanagihara, Y., Ohtani, M., Kariya, S., Uchino, K., Hiraishi, T., Ashizawa, N., Aoyama, T., Yamamura, Y., Yamada, Y., & Iga, T. (2002) · Biopharmaceutics & Drug Disposition · doi:10.1002/bdd.336 · Cited by 219 · see citing works
Pharmacokinetics of ketamine in man.
Wieber, J., Gugler, R., Hengstmann, J. H., & Dengler, H. J. (1975) · PubMed · Cited by 176 · see citing works
Ketamine
Kohrs, R., & Durieux, M. E. (1998) · Anesthesia & Analgesia · doi:10.1213/00000539-199811000-00039 · Cited by 153 · see citing works
S(+)-ketamine Effect on Experimental Pain and Cardiac Output
Sigtermans, M. J., Dahan, A., Mooren, R. A. G., Bauer, M., Kest, B., Sarton, E. Y., & Olofsen, E. (2009) · Anesthesiology · doi:10.1097/aln.0b013e3181b437b1 · Cited by 151 · see citing works
Stereoselective pharmacokinetics of ketamine: R(–)-Ketamine inhibits the elimination of S(+)-ketamine
Ihmsen, H., Geißlinger, G., & Schüttler, J. (2001) · Clinical Pharmacology & Therapeutics · doi:10.1067/mcp.2001.119722 · Cited by 147 · see citing works
PHARMACOKINETICS AND PHARMACODYNAMICS OF KETAMINE ENANTIOMERS IN SURGICAL PATIENTS USING A STEREOSELECTIVE ANALYTICAL METHOD
Geißlinger, G., Hering, W., Thomann, P. E., KNOLL, R., Kamp, H.-D., & Brune, K. (1993) · British Journal of Anaesthesia · doi:10.1093/bja/70.6.666 · Cited by 142 · see citing works
Comparative pharmacology in the rat of ketamine and its two principal metabolites, norketamine and (Z)-6-hydroxynorketamine
Leung, L. Y., & Baillie, T. A. (1986) · Journal of Medicinal Chemistry · doi:10.1021/jm00161a043 · Cited by 135 · see citing works
Population pharmacokinetic—pharmacodynamic modeling of ketamine‐induced pain relief of chronic pain
Dahan, A., Olofsenl, E., Sigtermans, M. J., Noppers, I. M., Niesters, M., Aarts, L. P. H. J., Bauer, M., & Sarton, E. Y. (2010) · European Journal of Pain · doi:10.1016/j.ejpain.2010.06.016 · Cited by 120 · see citing works
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
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. (2010) · Talanta · doi:10.1016/j.talanta.2010.08.005 · Cited by 108 · see citing works
Self-citation
Enantioselective capillary electrophoresis for identification and characterization of human cytochrome P450 enzymes which metabolize ketamine and norketamine in vitro
Portmann, S., Kwan, H. Y., Theurillat, R., Schmitz, A., Mevissen, M., & Thormann, W. (2010) · Journal of Chromatography A · doi:10.1016/j.chroma.2010.06.028 · Cited by 101 · see citing works
Effects of norketamine enantiomers in rodent models of persistent pain
HOLTMANJR, J., Crooks, P. A., JOHNSONHARDY, J., HOJOMAT, M., Kleven, M. S., & Wala, E. P. (2008) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2008.05.011 · Cited by 73 · see citing works
PHARMACOKINETICS OF KETAMINE IN MAN
WlEBER, J., Gugler, R., Hengstmann, J. H., & Dengler, H. J. (1976) · Survey of Anesthesiology · doi:10.1097/00132586-197606000-00004 · Cited by 73 · see citing works
HPLC determination of ketamine, norketamine, and dehydronorketamine in plasma with a high-purity reversed-phase sorbent
Bolze, S., & Boulieu, R. (1998) · Clinical Chemistry · doi:10.1093/clinchem/44.3.560 · Cited by 71 · see citing works
Modeling the norketamine metabolite in children and the implications for analgesia
HERD, D. W., Anderson, B. J., & Holford, N. H. G. (2007) · Pediatric Anesthesia · doi:10.1111/j.1460-9592.2007.02257.x · Cited by 60 · see citing works
Use of Human Microsomes and Deuterated Substrates: An Alternative Approach for the Identification of Novel Metabolites of Ketamine by Mass Spectrometry
Turfus, S. C., Parkin, M. C., Cowan, D., Halket, J. M., Smith, N. W., Braithwaite, R. A., Elliot, S. P., Steventon, G. B., & Kicman, A. T. (2009) · Drug Metabolism and Disposition · doi:10.1124/dmd.108.026328 · Cited by 57 · see citing works
Enantioselective analysis of ketamine and its metabolites in equine plasma and urine by CE with multiple isomer sulfated β‐CD
Theurillat, R., Knobloch, M., Schmitz, A., Lassahn, P., Mevissen, M., & Thormann, W. (2007) · Electrophoresis · doi:10.1002/elps.200600820 · Cited by 51 · see citing works
Low-dose ketamine for analgesia in the ED: a retrospective case series
Lester, L., Braude, D. A., Nilès, C., & Crandall, C. S. (2010) · The American Journal of Emergency Medicine · doi:10.1016/j.ajem.2009.07.023 · Cited by 49 · see citing works
EFFECTS OF PROTEIN CALORIE MALNUTRITION ON THE PHARMACOKINETICS OF KETAMINE IN RATS
Williams, M. L., Mager, D. E., Parenteau, H. I., Gudi, G. S., Tracy, T. S., Mulheran, M., & Wainer, I. W. (2004) · Drug Metabolism and Disposition · doi:10.1124/dmd.32.8.786 · Cited by 35 · see citing works
Self-citation
Stereoselective pharmacokinetics of ketamine and norketamine after constant rate infusion of a subanesthetic dose of racemic ketamine or S-ketamine in Shetland ponies
Larenza, M. P., Peterbauer, C., Landoni, M. F., Levionnois, O., Schatzmann, U., Spadavecchia, C., & Thormann, W. (2009) · American Journal of Veterinary Research · doi:10.2460/ajvr.70.7.831 · Cited by 32 · see citing works
Enantioselective pharmacokinetics of (R)‐ and (S)‐ketamine after a 5‐day infusion in patients with complex regional pain syndrome
Goldberg, M. E., Torjman, M. C., Schwartzman, R. J., Mager, D. E., & Wainer, I. W. (2010) · Chirality · doi:10.1002/chir.20890 · Cited by 30 · see citing works
Self-citation
Pharmacokinetics of S(+) ketamine derived from target controlled infusion
White, M. J., de Graaf, P., Renshof, B., van Kan, E., & Dzoljic, M. (2006) · British Journal of Anaesthesia · doi:10.1093/bja/aei316 · Cited by 27 · see citing works
Advances in Translational Neuropathic Research: Example of Enantioselective Pharmacokinetic–Pharmacodynamic Modeling of Ketamine-induced Pain Relief in Complex Regional Pain Syndrome
Sabia, M., Hirsh, R. A., Torjman, M. C., Wainer, I. W., Cooper, N., Domsky, R., & Goldberg, M. E. (2011) · Current Pain and Headache Reports · doi:10.1007/s11916-011-0185-3 · Cited by 14 · see citing works
Self-citation

Flagged first, then by citations

2 of the 32 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

Kohrs R, Durieux ME. Ketamine: teaching an old drug new tricks. Anesth Analg 1998; 87: 1186-93.

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Abdallah, C. G., Adams, T. G., Kelmendi, B., Esterlis, I., Sanacora, G., & Krystal, J. H. (2016) · Depression and Anxiety · doi:10.1002/da.22501 · Cited by 206 · see citing works
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Moaddel, R., Abdrakhmanova, G., Kozak, J., Jozwiak, K., Toll, L., Jimenez, L., Rosenberg, A., Tran, T., Xiao, Y., Zarate, C. A., et al. (2013) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2012.11.023 · Cited by 176 · see citing works
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Kamp, J., van Velzen, M., Olofsen, E., Boon, M., Dahan, A., & Niesters, M. (2019) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2019.1689958 · Cited by 70 · see citing works
Ketamine and its metabolites: Potential as novel treatments for depression
Zhang, K., Yao, Y., & Hashimoto, K. (2022) · Neuropharmacology · doi:10.1016/j.neuropharm.2022.109305 · Cited by 69 · see citing works
Ketamine and serotonergic psychedelics: An update on the mechanisms and biosignatures underlying rapid-acting antidepressant treatment
Johnston, J. N., Kadriu, B., Allen, J., Gilbert, J. R., Henter, I. D., & Zarate, C. A. (2023) · Neuropharmacology · doi:10.1016/j.neuropharm.2023.109422 · Cited by 68 · see citing works
Efficacy and safety of oral ketamine for the relief of intractable chronic pain: A retrospective 5‐year study of 51 patients
Marchetti, F., Coutaux, A., Bellanger, A., Magneux, C., Bourgeois, P., & Mion, G. (2014) · European Journal of Pain · doi:10.1002/ejp.624 · Cited by 68 · see citing works
Role of Cytochrome P4502B6 Polymorphisms in Ketamine Metabolism and Clearance
Rao, L. K., Flaker, A. M., Friedel, C. C., & Kharasch, E. D. (2016) · Anesthesiology · doi:10.1097/aln.0000000000001392 · Cited by 67 · see citing works
Ketamine-induced changes in plasma brain-derived neurotrophic factor (BDNF) levels are associated with the resting-state functional connectivity of the prefrontal cortex
Woelfer, M., Li, M., Colic, L., Liebe, T., Di, X., Biswal, B., Murrough, J., Lessmann, V., Brigadski, T., & Walter, M. (2020) · The World Journal of Biological Psychiatry · doi:10.1080/15622975.2019.1679391 · Cited by 64 · see citing works
Metaplastic Effects of Subanesthetic Ketamine on CA1 Hippocampal Function
Izumi, Y., & Zorumski, C. F. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2014.08.002 · Cited by 63 · see citing works
Drug Pharmacokinetics Determined by Real‐Time Analysis of Mouse Breath
Li, X., Sinues, P., Dallmann, R., Bregy, L., Hollmén, M., Proulx, S. T., Brown, S. A., Detmar, M. J., Kohler, M., & Zenobi, R. (2015) · Angewandte Chemie International Edition · doi:10.1002/anie.201503312 · Cited by 62 · see citing works
Bridging Rapid and Sustained Antidepressant Effects of Ketamine
Kim, J.-W., Suzuki, K., Kavalali, E. T., & Monteggia, L. M. (2023) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2023.02.003 · Cited by 59 · see citing works
Treatment-Resistant Major Depression: Rationale for NMDA Receptors as Targets and Nitrous Oxide as Therapy
Zorumski, C. F., Nagele, P., Mennerick, S., & Conway, C. R. (2015) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2015.00172 · Cited by 57 · see citing works
Default mode network connectivity change corresponds to ketamine’s delayed glutamatergic effects
Li, M., Woelfer, M., Čolić, L., Safron, A., Chang, C. E., Heinze, H., Speck, O., Mayberg, H. S., Biswal, B. B., Salvadore, G., et al. (2018) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-018-0942-y · Cited by 57 · see citing works
Quantitative chiral and achiral determination of ketamine and its metabolites by LC–MS/MS in human serum, urine and fecal samples
Hasan, M., Hofstetter, R. K., Fassauer, G. M., Link, A., Siegmund, W., & Oswald, S. (2017) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2017.02.035 · Cited by 55 · see citing works
Ketamine Pharmacokinetics
Kamp, J., Olofsen, E., Henthorn, T. K., van Velzen, M., Niesters, M., Dahan, A., & for the Ketamine Pharmacokinetic Study Group (2020) · Anesthesiology · doi:10.1097/aln.0000000000003577 · Cited by 55 · see citing works
Pharmacotherapy
Feeney, A., & Papakostas, G. I. (2023) · Psychiatric Clinics of North America · doi:10.1016/j.psc.2023.02.003 · Cited by 54 · see citing works
The role of eEF2 kinase in the rapid antidepressant actions of ketamine
(2020) · Advances in Pharmacology · doi:10.1016/bs.apha.2020.04.005 · Cited by 52 · see citing works
Ketamine and Active Ketamine Metabolites Regulate STAT3 and the Type I Interferon Pathway in Human Microglia: Molecular Mechanisms Linked to the Antidepressant Effects of Ketamine
Ho, M., Zhang, C., Zhang, L., Li, H., & Weinshilboum, R. M. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.01302 · Cited by 50 · see citing works
Ketamine and ketamine metabolites as novel estrogen receptor ligands: Induction of cytochrome P450 and AMPA glutamate receptor gene expression
Ho, M.-F., Correia, C., Ingle, J. N., Kaddurah-Daouk, R., Wang, L., Kaufmann, S. H., & Weinshilboum, R. M. (2018) · Biochemical Pharmacology · doi:10.1016/j.bcp.2018.03.032 · Cited by 49 · see citing works
The neurophysiology of ketamine: an integrative review
McMillan, R. L., & Muthukumaraswamy, S. D. (2020) · Reviews in the Neurosciences · doi:10.1515/revneuro-2019-0090 · Cited by 49 · see citing works
Analgesic Response to Intravenous Ketamine Is Linked to a Circulating microRNA Signature in Female Patients With Complex Regional Pain Syndrome
Douglas, S. R., Shenoda, B. B., Qureshi, R., Saçan, A., Alexander, G. M., Perreault, M. J., Barrett, J. E., Aradillas, E., Schwartzman, R. J., & Ajit, S. K. (2015) · Journal of Pain · doi:10.1016/j.jpain.2015.05.008 · Cited by 47 · see citing works
Effect of Ketamine on Limbic GABA and Glutamate: A Human In Vivo Multivoxel Magnetic Resonance Spectroscopy Study
Silberbauer, L., Spurny‐Dworak, B., Handschuh, P. A., Klöbl, M., Bednařík, P., Reiter, B., Ritter, V., Trost, P., Konadu, M. E., Windpassinger, M., et al. (2020) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2020.549903 · Cited by 42 · see citing works
Antidepressant mechanisms of ketamine: Focus on GABAergic inhibition
Lüscher, B., Feng, M., & Jefferson, S. J. (2020) · Advances in pharmacology · doi:10.1016/bs.apha.2020.03.002 · Cited by 41 · see citing works
Pharmacogenetic and drug interaction aspects on ketamine safety in its use as antidepressant ‐ implications for precision dosing in a global perspective
Langmia, I. M., Just, K. S., Yamoune, S., Müller, J. P., & Stingl, J. (2022) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.15467 · Cited by 41 · see citing works
A meta-analysis of the effects of ketamine on suicidal ideation in depression patients
Shen, Z., Gao, D., Lv, X., Wang, H., & Yue, W. (2024) · Translational Psychiatry · doi:10.1038/s41398-024-02973-1 · Cited by 41 · see citing works
The distribution and clearance of (2S,6S)‐hydroxynorketamine, an active ketamine metabolite, in Wistar rats
Moaddel, R., Sanghvi, M., Dossou, K. S. S., Ramamoorthy, A., Green, C., Bupp, J. E., Swezey, R. R., O’Loughlin, K. G., & Wainer, I. W. (2015) · Pharmacology Research & Perspectives · doi:10.1002/prp2.157 · Cited by 41 · see citing works
Self-citation
Dose-response characteristics of intravenous ketamine on dissociative stereotypy, locomotion, sensorimotor gating, and nociception in male Sprague-Dawley rats
Radford, K. D., Park, T. Y., Lee, B. H., Moran, S., Osborne, L. A., & Choi, K. H. (2016) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2016.12.014 · Cited by 40 · see citing works
(2R,6R)-Hydroxynorketamine promotes dendrite outgrowth in human inducible pluripotent stem cell-derived neurons through AMPA receptor with timing and exposure compatible with ketamine infusion pharmacokinetics in humans
Collo, G., Cavalleri, L., Chiamulera, C., & Pich, E. M. (2018) · Neuroreport · doi:10.1097/wnr.0000000000001131 · Cited by 38 · see citing works
A Phase 1 Assessment of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of (2 R ,6 R )‐Hydroxynorketamine in Healthy Volunteers
Raja, S. M., Guptill, J. T., Mack, M., Peterson, M., Byard, S. J., Twieg, R. J., Jordan, L., Rich, N., Castledine, R. A., Bourne, S. L., et al. (2024) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.3391 · Cited by 37 · see citing works
Self-citation
The role of glutamatergic modulation in the mechanism of action of ketamine, a prototype rapid-acting antidepressant drug
Pałucha-Poniewiera, A. (2018) · Pharmacological Reports · doi:10.1016/j.pharep.2018.02.011 · Cited by 36 · see citing works
Inhibition of the l-arginine–nitric oxide pathway mediates the antidepressant effects of ketamine in rats in the forced swimming test
Zhang, G.-F., Wang, N., Shi, J., Shixia, X., Li, X., Ji, M., Zuo, Z., Zhou, Z., & Yang, J. (2013) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2013.05.010 · Cited by 36 · see citing works
The modulation of BDNF expression and signalling dissects the antidepressant from the reinforcing properties of ketamine: Effects of single infusion vs. chronic self-administration in rats
Caffino, L., Chio, M. D., Giannotti, G., Vènniro, M., Mutti, A., Padovani, L., Cheung, D., Fumagalli, G. F., Yew, D. T. W., Fumagalli, F., et al. (2015) · Pharmacological Research · doi:10.1016/j.phrs.2015.12.014 · Cited by 36 · see citing works
Sex-dependent metabolism of ketamine and ( 2R,6R )-hydroxynorketamine in mice and humans
Highland, J. N., Farmer, C., Zanos, P., Lovett, J., Zarate, C. A., Moaddel, R., & Gould, T. D. (2021) · Journal of Psychopharmacology · doi:10.1177/02698811211064922 · Cited by 35 · see citing works
Self-citation
Assessment of Ketamine Binding of the Serotonin Transporter in Humans with Positron Emission Tomography
Spies, M., James, G. M., Berroterán-Infante, N., Ibeschitz, H., Kranz, G. S., Unterholzner, J., Godbersen, M., Gryglewski, G., Hienert, M., Jungwirth, J., et al. (2018) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyx085 · Cited by 34 · see citing works
Ketamine – A New Antidepressant Drug with Anti-Inflammatory Properties
Jóźwiak-Bębenista, M., Sokołowska, P., Wiktorowska‐Owczarek, A., Kowalczyk, E., & Sienkiewicz, M. (2023) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.123.001823 · Cited by 32 · see citing works
A single dose of vortioxetine, but not ketamine or fluoxetine, increases plasticity-related gene expression in the rat frontal cortex
du Jardin, K. G., Müller, H. K., Sánchez, C., Wegener, G., & Elfving, B. (2016) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2016.05.029 · Cited by 31 · see citing works
Evaluation of Vancomycin Use in Late-Onset Neonatal Sepsis Using the Area Under the Concentration–Time Curve to the Minimum Inhibitory Concentration ≥400 Target
Bhongsatiern, J., Stockmann, C. R., Roberts, J. K., Tian, Y., Korgenski, K. E., Spigarelli, M. G., Desai, P. B., & Sherwin, C. M. T. (2015) · Therapeutic Drug Monitoring · doi:10.1097/ftd.0000000000000216 · Cited by 31 · see citing works
Population Pharmacokinetics and Pharmacodynamics of the Therapeutic and Adverse Effects of Ketamine in Patients With Treatment‐Refractory Depression
Abuhelwa, A. Y., Somogyi, A. A., Loo, C. K. A., Glue, P., Barratt, D. T., & Foster, D. J. R. (2022) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.2640 · Cited by 30 · see citing works
Enantioselective pharmacokinetics of (R)‐ and (S)‐ketamine after a 5‐day infusion in patients with complex regional pain syndrome
Goldberg, M. E., Torjman, M. C., Schwartzman, R. J., Mager, D. E., & Wainer, I. W. (2010) · Chirality · doi:10.1002/chir.20890 · Cited by 30 · see citing works
Self-citation
Pharmacokinetics of ketamine and three metabolites in Beagle dogs under sevoflurane vs. medetomidine comedication assessed by enantioselective capillary electrophoresis
Sandbaumhüter, F. A., Theurillat, R., Bektas, R. N., Kutter, A. P. N., Bettschart‐Wolfensberger, R., & Thormann, W. (2016) · Journal of Chromatography A · doi:10.1016/j.chroma.2016.07.060 · Cited by 27 · see citing works
Hydroxynorketamine Pharmacokinetics and Antidepressant Behavioral Effects of (2,6)- and (5R)-Methyl-(2R,6R)-hydroxynorketamines
Highland, J. N., Morris, P. J., Konrath, K. M., Riggs, L. M., Hagen, N. R., Zanos, P., Powels, C. F., Moaddel, R., Thomas, C. J., Wang, A. Q., et al. (2022) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.1c00761 · Cited by 27 · see citing works
Self-citation
Effects of medetomidine and its active enantiomer dexmedetomidine on N‐demethylation of ketamine in canines determined in vitro using enantioselective capillary electrophoresis
Sandbaumhüter, F. A., Theurillat, R., & Thormann, W. (2015) · Electrophoresis · doi:10.1002/elps.201500147 · Cited by 27 · see citing works
Acetylcholine and metacognition during sleep
Gott, J. A., Stücker, S., Kanske, P., Haaker, J., & Dresler, M. (2024) · Consciousness and Cognition · doi:10.1016/j.concog.2023.103608 · Cited by 25 · see citing works
The Antidepressant-Like Effects of a Clinically Relevant Dose of Ketamine Are Accompanied by Biphasic Alterations in Working Memory in the Wistar Kyoto Rat Model of Depression
McDonnell, C., Dunphy-Doherty, F., Rouine, J., Bianchi, M., Upton, N., Sokolowska, E., & Prenderville, J. A. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2020.599588 · Cited by 23 · see citing works
Association between dynamic resting-state functional connectivity and ketamine plasma levels in visual processing networks
Spies, M., Klöbl, M., Höflich, A. S., Hummer, A., Vanicek, T., Michenthaler, P., Kranz, G. S., Hahn, A., Winkler, D., Windischberger, C., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-46702-x · Cited by 22 · see citing works
Beyond NMDA Receptors: A Narrative Review of Ketamine’s Rapid and Multifaceted Mechanisms in Depression Treatment
Antos, Z., Żukow, X., Bursztynowicz, L., & Jakubów, P. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252413658 · Cited by 21 · see citing works
Clinical and pharmacokinetic evaluation of S-ketamine for intravenous general anaesthesia in horses undergoing field castration
Casoni, D. C., Spadavecchia, C., Wampfler, B., Thormann, W., & Levionnois, O. (2015) · Acta veterinaria Scandinavica · doi:10.1186/s13028-015-0112-4 · Cited by 21 · see citing works
Hydroxynorketamine: Implications for the NMDA Receptor Hypothesis of Ketamine’s Antidepressant Action
Aleksandrova, L. R., Wang, Y. T., & Phillips, A. G. (2017) · Chronic Stress · doi:10.1177/2470547017743511 · Cited by 21 · see citing works
Ketamine as Potential Treatment for Postpartum Depression: A Narrative Review
Chen-Li, D. C. J., Lui, L. M. W., Rosenblat, J. D., Lipsitz, O., Teopiz, K. M., Ho, R., Vinberg, M., Golts, M., Jawad, M. Y., Lee, Y. L., et al. (2022) · Annals of Clinical Psychiatry · doi:10.12788/acp.0082 · Cited by 20 · see citing works
Enantioselective CE–MS analysis of ketamine metabolites in urine
Sandbaumhüter, F. A., Aerts, J. T., Theurillat, R., Andrén, P. E., Thormann, W., & Jansson, E. T. (2022) · Electrophoresis · doi:10.1002/elps.202200175 · Cited by 20 · see citing works
Combined Recirculatory-compartmental Population Pharmacokinetic Modeling of Arterial and Venous Plasma S(+) and R(–) Ketamine Concentrations
Henthorn, T. K., Avram, M. J., Dahan, A., Gustafsson, L. L., Persson, J., Krejcie, T. C., & Olofsen, E. (2018) · Anesthesiology · doi:10.1097/aln.0000000000002265 · Cited by 20 · see citing works
Dextromethorphan and memantine after ketamine analgesia: a randomized control trial
Martin, E., Sorel, M., Morel, V., Marcaillou, F., Picard, P., Delage, N., Tiberghien-Chatelain, F., Crosmary, M.-C., Najjar, M., Colamarino, R., et al. (2019) · Drug Design Development and Therapy · doi:10.2147/dddt.s207350 · Cited by 18 · see citing works
Rapid-Acting Antidepressants
Kadriu, B., Subramanian, S., Deng, Z., Henter, I. D., Park, L. T., & Zarate, C. A. (2019) · Oxford University Press eBooks · doi:10.1093/med/9780190929565.003.0013 · Cited by 18 · see citing works
Serotonergic transmission plays differentiated roles in the rapid and sustained antidepressant‐like effects of ketamine
Yin, Y., Yan, J., Wei, Q., Sun, S., Ding, Y., Zhang, L., & Li, Y. (2024) · British Journal of Pharmacology · doi:10.1111/bph.17324 · Cited by 18 · see citing works
Prediction of human efficacious antidepressant doses using the mouse forced swim test
Yuen, E., Swanson, S., & Witkin, J. M. (2017) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2017.09.002 · Cited by 18 · see citing works
Targeted mass spectrometry of ketamine and its metabolites cis-6-hydroxynorketamine and norketamine in human blood serum
Kurzweil, L., Danyeli, L. V., Şen, Z. D., Fejtová, A., Walter, M., & Gensberger‐Reigl, S. (2020) · Journal of Chromatography B · doi:10.1016/j.jchromb.2020.122214 · Cited by 17 · see citing works
Subchronic administration of (R,S)-ketamine induces ketamine ring hydroxylation in Wistar rats
Moaddel, R., Sanghvi, M., Ramamoorthy, A., Jóźwiak, K., Singh, N., Green, C., O’Loughlin, K. G., Torjman, M. C., & Wainer, I. W. (2016) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2016.03.030 · Cited by 17 · see citing works
Self-citation
Association of the delayed changes in glutamate levels and functional connectivity with the immediate network effects of S-ketamine
Danyeli, L. V., Şen, Z. D., Čolić, L., Kurzweil, L., Gensberger‐Reigl, S., Macharadze, T., Götting, F. N., Refisch, A., Liebe, T., Chand, T., et al. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02346-0 · Cited by 16 · see citing works
Ketamine Prevents Inflammation-Induced Reduction of Human Hippocampal Neurogenesis via Inhibiting the Production of Neurotoxic Metabolites of the Kynurenine Pathway
Mandal, G., Kirkpatrick, M., Alboni, S., Mariani, N., Pariante, C. M., & Borsini, A. (2024) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyae041 · Cited by 15 · see citing works
A PK–PD model of ketamine-induced high-frequency oscillations
Flores, F. J., Ching, S., Hartnack, K. E., Fath, A. B., Purdon, P. L., Wilson, M. A., & Brown, E. N. (2015) · Journal of Neural Engineering · doi:10.1088/1741-2560/12/5/056006 · Cited by 15 · see citing works
CYP 450 enzymes influence (R,S)-ketamine brain delivery and its antidepressant activity
Nguyen, T. M. L., McGowan, J. C., & Gardier, A. M. (2021) · Neuropharmacology · doi:10.1016/j.neuropharm.2021.108936 · Cited by 15 · see citing works
Molecular Mechanism and Clinical Relevance of Ketamine as Rapid‐Acting Antidepressant
Pešić, V., Petrović, J., & Jukić, M. M. (2016) · Drug Development Research · doi:10.1002/ddr.21335 · Cited by 15 · see citing works
Separation of hydroxynorketamine stereoisomers using capillary electrophoresis with sulfated β‐cyclodextrin and highly sulfated γ‐cyclodextrin
Sandbaumhüter, F. A., Theurillat, R., & Thormann, W. (2017) · Electrophoresis · doi:10.1002/elps.201700016 · Cited by 15 · see citing works
Cerebrospinal fluid exploratory proteomics and ketamine metabolite pharmacokinetics in human volunteers after ketamine infusion
Moaddel, R., Farmer, C., Yavi, M., Kadriu, B., Zhu, M., Fan, J., Chen, Q., Lehrmann, E., Fantoni, G., De, S., et al. (2023) · iScience · doi:10.1016/j.isci.2023.108527 · Cited by 14 · see citing works
Self-citation
Pharmacokinetic Modeling of Ketamine Enantiomers and Their Metabolites After Administration of Prolonged‐Release Ketamine With Emphasis on 2,6‐Hydroxynorketamines
Weiss, M., & Siegmund, W. (2022) · Clinical Pharmacology in Drug Development · doi:10.1002/cpdd.993 · Cited by 13 · see citing works
Stereochemical and structural effects of (2R,6R)-hydroxynorketamine on the mitochondrial metabolome in PC-12 cells
Faccio, A. T., Rupérez, F. J., Singh, N., Angulo, S., Tavares, M. F. M., Bernier, M., Barbas, C., & Wainer, I. W. (2018) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2018.03.008 · Cited by 13 · see citing works
Self-citation
Chiral Pharmacokinetics and Metabolite Profile of Prolonged-release Ketamine Tablets in Healthy Human Subjects
Hasan, M., Modeß, C., Roustom, T., Dokter, A., Grube, M., Link, A., Rey, H., Adler, S., Meissner, K., & Siegmund, W. (2021) · Anesthesiology · doi:10.1097/aln.0000000000003829 · Cited by 13 · see citing works
High Yielding Continuous-Flow Synthesis of Norketamine
Veguillas, M., Moore, J. C., Howie, R. A., Castledine, R. A., Bourne, S. L., Jenkins, G. N., Licence, P., Poliakoff, M., & George, M. W. (2022) · Organic Process Research & Development · doi:10.1021/acs.oprd.1c00407 · Cited by 13 · see citing works
NMDA Antagonists for Treatment-Resistant Depression
Farber, N. B. (2018) · Handbook of experimental pharmacology · doi:10.1007/164_2018_165 · Cited by 13 · see citing works
General Anesthetics: Aspects of Chirality, Pharmacodynamics, and Pharmacokinetics
Cizmáriková, R., Habala, L., & Valentová, J. (2025) · Pharmaceuticals · doi:10.3390/ph18020250 · Cited by 12 · see citing works
Perioperative ketamine for acute analgesia and beyond.
Porter, S. B. (2019) · PubMed Central · doi:10.2478/rjaic-2019-0010 · Cited by 11 · see citing works
Antidepressants enter cells, organelles, and membranes
Blumenfeld, Z., Bera, K., Ċastrén, E., & Lester, H. A. (2023) · Neuropsychopharmacology · doi:10.1038/s41386-023-01725-x · Cited by 10 · see citing works

Pharmacokinetics of ketamine and its major metabolites norketamine, hydroxynorketamine, and dehydronorketamine: a model-based analysis
Kamp, J., Jonkman, K., van Velzen, M., Aarts, L. P. H. J., Niesters, M., Dahan, A., & Olofsen, E. (2020) · British Journal of Anaesthesia · doi:10.1016/j.bja.2020.06.067 · Cited by 76 · see citing works
Pharmacokinetic Modeling of Ketamine Enantiomers and Their Metabolites After Administration of Prolonged‐Release Ketamine With Emphasis on 2,6‐Hydroxynorketamines
Weiss, M., & Siegmund, W. (2022) · Clinical Pharmacology in Drug Development · doi:10.1002/cpdd.993 · Cited by 13 · see citing works
Subchronic administration of (R,S)-ketamine induces ketamine ring hydroxylation in Wistar rats
Moaddel, R., Sanghvi, M., Ramamoorthy, A., Jóźwiak, K., Singh, N., Green, C., O’Loughlin, K. G., Torjman, M. C., & Wainer, I. W. (2016) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2016.03.030 · Cited by 17 · see citing works
Self-citation
Ketamine Metabolomics in the Treatment of Major Depression
van Velzen, M., & Dahan, A. (2014) · Anesthesiology · doi:10.1097/aln.0000000000000286 · Cited by 11 · see citing works
Pharmacokinetics and pharmacodynamics of intravenous and oral (S)‐ketamine: Investigating metabolite contribution to subjective effects
Otto, M. E., Jacobs, G. E., van Mechelen, J., Borghans, L. G. J. M., van Hasselt, J. G. C., & Aulin, L. B. S. (2026) · British Journal of Clinical Pharmacology · doi:10.1002/bcp.70503

Authors: Zhao, X., Venkata, S. L. V., Moaddel, R., Luckenbaugh, D. A., Brutsche, N. E., Ibrahim, L., Zarate Jr, C. A., Mager, D. E., & Wainer, I. W.
Affiliations: University at Buffalo, State University of New York (US)
National Institute on Aging (US)
National Institutes of Health (US)
Corresponding author: Wainer, Irving W.
ORCID: Zhao, Xiaochen
Moaddel, Ruin
Mager, Donald E.
Wainer, Irving W.
Venue: British Journal of Clinical Pharmacology
Publisher: Wiley
Published: 2012-07-10
Volume: 74
Issue: 2
Pages: 304-314
ISSN: 0306-5251 (ISSN-L)
1365-2125
DOI: 10.1111/j.1365-2125.2012.04198.x
PMC: PMC3630750
OpenAlex: W2158336114
Cited by: 137
References: 32
Citations by year: 2026: 4 · 2025: 10 · 2024: 10 · 2023: 12 · 2022: 12 · 2021: 12 · 2020: 8 · 2019: 10 · 2018: 12 · 2017: 11 · 2016: 11 · 2015: 14 · 2014: 5 · 2013: 1 · 2012: 3
FWCI: 5.40
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: British Journal of Clinical Pharmacology (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
National Institute of General Medical Sciences (GM 57980, R01GM057980)
Topics: Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
Keywords: ketamine, norketamine, dehydronorketamine, hydroxynorketamine, ketamine metabolites, population pharmacokinetic model, treatment-resistant bipolar depression, enantiomers, N-demethylation, plasma concentration-time curve, drug disposition kinetics
MeSH terms: Adult, Algorithms, Antidepressive Agents, Biotransformation, Bipolar Disorder, Double-Blind Method, Drug Resistance, Female, Humans, Hydroxylation, Infusions, Parenteral, Ketamine, Male, Middle Aged, Models, Biological, Cross-Over Studies, Young Adult

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Simultaneous population pharmacokinetic modelling of ketamine and three major metabolites in patients with treatment-resistant bipolar depression

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