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Simultaneous population pharmacokinetic modelling of ketamine and three major metabolites in patients with treatment-resistant bipolar depression
Open accessAbstract
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 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
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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
Self-citationDiazgranados, 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
Self-citationKohrs, R., & Durieux, M. E. (1998) · Anesthesia & Analgesia · doi:10.1097/00000539-199811000-00039 · Cited by 635
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
Self-citationDomino, E. F., & Warner, D. S. (2010) · Anesthesiology · doi:10.1097/aln.0b013e3181ed09a2 · Cited by 520
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
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 471
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
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
Pharmacokinetics of ketamine in man.
Wieber, J., Gugler, R., Hengstmann, J. H., & Dengler, H. J. (1975) · PubMed · Cited by 176
Kohrs, R., & Durieux, M. E. (1998) · Anesthesia & Analgesia · doi:10.1213/00000539-199811000-00039 · Cited by 153
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
Ihmsen, H., Geißlinger, G., & Schüttler, J. (2001) · Clinical Pharmacology & Therapeutics · doi:10.1067/mcp.2001.119722 · Cited by 147
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
Leung, L. Y., & Baillie, T. A. (1986) · Journal of Medicinal Chemistry · doi:10.1021/jm00161a043 · Cited by 135
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
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
Self-citationPortmann, 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
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
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
Bolze, S., & Boulieu, R. (1998) · Clinical Chemistry · doi:10.1093/clinchem/44.3.560 · Cited by 71
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
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
Theurillat, R., Knobloch, M., Schmitz, A., Lassahn, P., Mevissen, M., & Thormann, W. (2007) · Electrophoresis · doi:10.1002/elps.200600820 · Cited by 51
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
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
Self-citationLarenza, 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
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
Self-citationPharmacokinetics 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
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
Self-citation
Research works printed but not linked: 2
- Trevor AJ, 1983, Stereoselective Metabolism of Ketamine Enantiomers, Phencyclidine and Related Arylcyclohexylamines: Present and Future Applications, 279
- 10.1016/S0009-9236(01)06321-4 · DOI
Cited by
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Zanos, P., Moaddel, R., Morris, P. J., Riggs, L. M., Highland, J. N., Georgiou, P., Pereira, E. F. R., Albuquerque, E. X., Thomas, C. J., Zarate, C. A., et al. (2018) · Pharmacological Reviews · doi:10.1124/pr.117.015198 · Cited by 1,260
Self-citationMcIntyre, R. S., Rosenblat, J. D., Nemeroff, C. B., Sanacora, G., Murrough, J. W., Berk, M., Brietzke, E., Dodd, S., Gorwood, P., Ho, R., et al. (2021) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2020.20081251 · Cited by 731
Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy
Peltoniemi, M. A., Hagelberg, N. M., Olkkola, K. T., & Saari, T. I. (2016) · Clinical Pharmacokinetics · doi:10.1007/s40262-016-0383-6 · Cited by 672
Zarate, C. A., Brutsche, N., Laje, G., Luckenbaugh, D. A., Venkata, S. L. V., Ramamoorthy, A., Moaddel, R., & Wainer, I. W. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.03.004 · Cited by 282
Self-citationKetamine: NMDA Receptors and Beyond
Zorumski, C. F., Izumi, Y., & Mennerick, S. (2016) · The Journal of Neuroscience · doi:10.1523/jneurosci.1547-16.2016 · Cited by 254
Metadata
- 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.
- 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
- 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
- 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 (medical) › 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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