Sex-dependent metabolism of ketamine and (2R,6R)-hydroxynorketamine in mice and humans

Adams, JD, Baillie, TA, Trevor, AJ, et al. (1981) Studies on the biotransformation of ketamine. 1—Identification of metabolites produced in vitro from rat liver microsomal preparations. Biomedical Mass Spectrometry 8(11): 527–538.
Google Scholar | Crossref | Medline Aguilar-Valles, A, De Gregorio, D, Matta-Camacho, E, et al. (2020) Antidepressant actions of ketamine engage cell-specific translation via eIF4E. Nature 590: 315–319.
Google Scholar | Crossref | Medline Barre, L, Fournel-Gigleux, S, Finel, M, et al. (2007) Substrate specificity of the human UDP-glucuronosyltransferase UGT2B4 and UGT2B7. Identification of a critical aromatic amino acid residue at position 33. FEBS Journal 274(5): 1256–1264.
Google Scholar | Crossref Berman, RM, Cappiello, A, Anand, A, et al. (2000) Antidepressant effects of ketamine in depressed patients. Biological Psychiatry 47(4): 351–354.
Google Scholar | Crossref | Medline | ISI Bowen, RS, Ferguson, DP, Lightfoot, JT (2011) Effects of aromatase inhibition on the physical activity levels of male mice. Journal of Steroids & Hormonal Science 1(1): 1–7.
Google Scholar | Medline Carrier, N, Kabbaj, M (2013) Sex differences in the antidepressant-like effects of ketamine. Neuropharmacology 70: 27–34.
Google Scholar | Crossref | Medline | ISI Casarotto, PC, Girych, M, Fred, SM, et al. (2021) Antidepressant drugs act by directly binding to TRKB neurotrophin receptors. Cell 185: 1299–1313.
Google Scholar | Crossref Chang, L, Toki, H, Qu, Y, et al. (2018) No sex-specific differences in the acute antidepressant actions of (R)-ketamine in an inflammation model. International Journal of Neuropsychopharmacology 21(10): 932–937.
Google Scholar | Crossref | Medline Chang, T, Glazko, AJ (1974) Biotransformation and disposition of ketamine. International Anesthesiology Clinics 12(2): 157–177.
Google Scholar | Crossref | Medline Chen, BK, Luna, VM, LaGamma, CT, et al. (2020) Sex-specific neurobiological actions of prophylactic (R, S)-ketamine, (2R,6R)-hydroxynorketamine, and (2S,6S)-hydroxynorketamine. Neuropsychopharmacology 45(9): 1545–1556.
Google Scholar | Crossref | Medline Chen, WY, Huang, MC, Lin, SK (2014) Gender differences in subjective discontinuation symptoms associated with ketamine use. Substance Abuse Treatment, Prevention, and Policy 9: 39.
Google Scholar | Crossref | Medline Chou, D, Peng, HY, Lin, TB, et al. (2018) (2R,6R)-hydroxynorketamine rescues chronic stress-induced depression-like behavior through its actions in the midbrain periaqueductal gray. Neuropharmacology 139: 1–12.
Google Scholar | Crossref | Medline Coyle, CM, Laws, KR (2015) The use of ketamine as an antidepressant: A systematic review and meta-analysis. Human Psychopharmacology: Clinical and Experimental 30(3): 152–163.
Google Scholar | Crossref | Medline Daan, S, Damassa, D, Pittendrigh, CS, et al. (1975) An effect of castration and testosterone replacement on a circadian pacemaker in mice (Mus musculus). Proceedings of the National Academy of Sciences of the United States of America 72(9): 3744–3747.
Google Scholar | Crossref | Medline Derntl, B, Hornung, J, Sen, ZD, et al. (2019) Interaction of sex and age on the dissociative effects of ketamine action in young healthy participants. Frontiers in Neuroscience 13: 616.
Google Scholar | Crossref | Medline Desta, Z, Moaddel, R, Ogburn, ET, et al. (2012) Stereoselective and regiospecific hydroxylation of ketamine and norketamine. Xenobiotica 42(11): 1076–1087.
Google Scholar | Crossref | Medline Diazgranados, N, Ibrahim, L, Brutsche, NE, et al. (2010) A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Archives of General Psychiatry 67(8): 793–802.
Google Scholar | Crossref | Medline Dinis-Oliveira, RJ (2017) Metabolism and metabolomics of ketamine: A toxicological approach. Forensic Sciences Research 2(1): 2–10.
Google Scholar | Crossref | Medline Elmer, GI, Tapocik, JD, Mayo, CL, et al. (2020) Ketamine metabolite (2R,6R)-hydroxynorketamine reverses behavioral despair produced by adolescent trauma. Pharmacology Biochemistry and Behavior 196: 172973.
Google Scholar | Crossref | Medline Farmer, CA, Gilbert, JR, Moaddel, R, et al. (2020) Ketamine metabolites, clinical response, and gamma power in a randomized, placebo-controlled, crossover trial for treatment-resistant major depression. Neuropsychopharmacology 45(8): 1398–1404.
Google Scholar | Crossref | Medline Fava, M, Freeman, MP, Flynn, M, et al. (2020) Correction: Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Molecular Psychiatry 25(7): 1604.
Google Scholar | Crossref | Medline Franceschelli, A, Sens, J, Herchick, S, et al. (2015) Sex differences in the rapid and the sustained antidepressant-like effects of ketamine in stress-naive and “depressed” mice exposed to chronic mild stress. Neuroscience 290: 49–60.
Google Scholar | Crossref | Medline | ISI Freeman, MP, Papakostas, GI, Hoeppner, B, et al. (2019) Sex differences in response to ketamine as a rapidly acting intervention for treatment resistant depression. Journal of Psychiatric Research 110: 166–171.
Google Scholar | Crossref | Medline Fukumoto, K, Fogaca, MV, Liu, RJ, et al. (2019) Activity-dependent brain-derived neurotrophic factor signaling is required for the antidepressant actions of (2R,6R)-hydroxynorketamine. Proceedings of the National Academy of Sciences of the United States of America 116(1): 297–302.
Google Scholar | Crossref | Medline Gochfeld, M (2017) Sex differences in human and animal toxicology. Toxicologic Pathology 45(1): 172–189.
Google Scholar | SAGE Journals | ISI Grunebaum, MF, Galfalvy, HC, Choo, TH, et al. (2019) Ketamine metabolite pilot study in a suicidal depression trial. Journal of Psychiatric Research 117: 129–134.
Google Scholar | Crossref | Medline Highland, JN, Morris, PJ, Zanos, P, et al. (2018) Mouse, rat, and dog bioavailability and mouse oral antidepressant efficacy of (2R,6R)-hydroxynorketamine. Journal of Psychopharmacology 33(1): 12–24.
Google Scholar | SAGE Journals Highland, JN, Zanos, P, Riggs, LM, et al. (2021) Hydroxynorketamines: Pharmacology and potential therapeutic applications. Pharmacological Reviews 73(2): 763–791.
Google Scholar | Crossref | Medline Idris, AI (2012) Ovariectomy/orchidectomy in rodents. Methods in Molecular Biology 816: 545–551.
Google Scholar | Crossref | Medline Kandel, SE, Han, LW, Mao, Q, et al. (2017) Digging deeper into CYP3A testosterone metabolism: Kinetic, regioselectivity, and stereoselectivity differences between CYP3A4/5 and CYP3A7. Drug Metabolism and Disposition 45(12): 1266–1275.
Google Scholar | Crossref | Medline Kharasch, ED, Labroo, R (1992) Metabolism of ketamine stereoisomers by human liver microsomes. Anesthesiology 77(6): 1201–1207.
Google Scholar | Crossref | Medline Krauser, JA, Voehler, M, Tseng, LH, et al. (2004) Testosterone 1 beta-hydroxylation by human cytochrome P450 3A4. European Journal of Biochemistry 271(19): 3962–3969.
Google Scholar | Crossref | Medline Krotkiewski, M, Kral, JG, Karlsson, J (1980) Effects of castration and testosterone substitution on body composition and muscle metabolism in rats. Acta Physiologica Scandinavica 109(3): 233–237.
Google Scholar | Crossref | Medline Krystal, JH, Karper, LP, Seibyl, JP, et al. (1994) Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Archives of General Psychiatry 51(3): 199–214.
Google Scholar | Crossref | Medline Kurzweil, L, Danyeli, L, Sen, ZD, et al. (2020) Targeted mass spectrometry of ketamine and its metabolites cis-6-hydroxynorketamine and norketamine in human blood serum. Journal of Chromatography B 1152: 122214.
Google Scholar | Crossref | Medline Lankveld, DP, Driessen, B, Soma, LR, et al. (2006) Pharmacodynamic effects and pharmacokinetic profile of a long-term continuous rate infusion of racemic ketamine in healthy conscious horses. Journal of veterinary pharmacology and therapeutics 29(6): 477–488.
Google Scholar | Crossref | Medline Leung, LY, Baillie, TA (1986) Comparative pharmacology in the rat of ketamine and its two principal metabolites, norketamine and (Z)-6-hydroxynorketamine. Journal of Medicinal Chemistry 29(11): 2396–2399.
Google Scholar | Crossref | Medline Lofgren, S, Hagbjork, AL, Ekman, S, et al. (2004) Metabolism of human cytochrome P450 marker substrates in mouse: A strain and gender comparison. Xenobiotica 34(9): 811–834.
Google Scholar | Crossref | Medline Lumsden, EW, Troppoli, TA, Myers, SJ, et al. (2019) Antidepressant-relevant concentrations of the ketamine metabolite (2R,6R)-hydroxynorketamine do not block NMDA receptor function. Proceedings of the National Academy of Sciences of the United States of America 116(11): 5160–5169.
Google Scholar | Crossref | Medline Maenpaa, J, Pelkonen, O, Cresteil, T, et al. (1993) The role of cytochrome P450 3A (CYP3A) isoform(s) in oxidative metabolism of testosterone and benzphetamine in human adult and fetal liver. The Journal of Steroid Biochemistry and Molecular Biology 44(1): 61–67.
Google Scholar | Crossref | Medline Martignoni, M, Groothuis, GM, de Kanter, R (2006) Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opinion on Drug Metabolism & Toxicology 2(6): 875–894.
Google Scholar | Crossref | Medline Moaddel, R, Sanghvi, M, Dossou, KS, et al. (2015) The distribution and clearance of (2S,6S)-hydroxynorketamine, an active ketamine metabolite, in Wistar rats. Pharmacology Research & Perspectives 3(4): e00157.
Google Scholar | Crossref | Medline Moaddel, R, Venkata, SL, Tanga, MJ, et al. (2010) 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. Talanta 82(5): 1892–1904.
Google Scholar | Crossref | Medline Morgan, CJ, Perry, EB, Cho, HS, et al. (2006) Greater vulnerability to the amnestic effects of ketamine in males. Psychopharmacology 187(4): 405–414.
Google Scholar | Crossref | Medline Morris, PJ, Moaddel, R, Zanos, P, et al. (2017) Synthesis and N-methyl-d-aspartate (NMDA) receptor activity of ketamine metabolites. Organic Letters 19(17): 4572–4575.
Google Scholar | Crossref | Medline Murrough, JW, Perez, AM, Pillemer, S, et al. (2013) Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biological Psychiatry 74(4): 250–256.
Google Scholar | Crossref | Medline Niciu, MJ, Luckenbaugh, DA, Ionescu, DF, et al. (2014) Clinical predictors of ketamine response in treatment-resistant major depression. The Journal of Clinical Psychiatry 75(5): e417–e423.
Google Scholar | Crossref Pham, TH, Defaix, C, Xu, X, et al. (2018) Common neurotransmission recruited in (R,S)-ketamine and (2R,6R)-hydroxynorketamine-induced sustained antidepressant-like effects. Biological Psychiatry 84(1): e3–e6.
Google Scholar | Crossref | Medline Portmann, S, Kwan, HY, Theurillat, R, et al. (2010) Enantioselective capillary electrophoresis for identification and characterization of human cytochrome P450 enzymes which metabolize ketamine and norketamine in vitro. Journal of Chromatography A 1217(51): 7942–7948.

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