Metabolism and metabolomics of ketamine: a toxicological approach

References

• Liu Y, Lin D, Wu B, et al. Ketamine abuse potential and use disorder. Brain Res Bull. 2016;126:68–73.
   PubMed Web of Science ®Google Scholar
• Domino EF, Chodoff P, Corssen G. Pharmacologic effects of ci-581, a new dissociative anesthetic, in man. Clin Pharmacol Ther. 1965;6:279–291.
   PubMed Web of Science ®Google Scholar
• Hijazi Y, Bolon M, Boulieu R. Stability of ketamine and its metabolites norketamine and dehydronorketamine in human biological samples. Clin Chem. 2001;47:1713–1715.
   Web of Science ®Google Scholar
• Fischer MM. Ketamine hydrochloride in severe bronchospasm. Anaesthesia. 1977;32:771–772.
   PubMed Web of Science ®Google Scholar
• Barash PG, Cullen BF, Stoelting RK, et al. Clinical anesthesia. 7th ed. Philadelphia (PA): Lippincott Williams & Wilkins; 2013.
   Google Scholar
• James K, Briggs S, Lewis R, et al. Introduction to specialist therapeutics. In: Tomlin M, editor. Pharmacology & pharmacokinetics: a basic reader. London: Springer London; 2010. p. 53–66.
   Google Scholar
• Niesters M, Martini C, Dahan A. Ketamine for chronic pain: risks and benefits. Br J Clin Pharmacol. 2014;77:357–367.
   PubMed Web of Science ®Google Scholar
• Petrakis IL, Limoncelli D, Gueorguieva R, et al. Altered NMDA glutamate receptor antagonist response in individuals with a family vulnerability to alcoholism. Am J Psychiatry. 2004;161:1776–1782.
   PubMed Web of Science ®Google Scholar
• Krupitsky EM, Burakov AM, Dunaevsky IV, et al. Single versus repeated sessions of ketamine-assisted psychotherapy for people with heroin dependence. J Psychoactive Drugs. 2007;39:13–19.
   PubMed Web of Science ®Google Scholar
• Mills IH, Park GR, Manara AR, et al. Treatment of compulsive behaviour in eating disorders with intermittent ketamine infusions. QJM. 1998;91:493–503.
   PubMed Web of Science ®Google Scholar
• Murrough JW. Ketamine as a novel antidepressant: from synapse to behavior. Clin Pharmacol Therap. 2012;91:303–309.
   PubMed Web of Science ®Google Scholar
• Duman RS, Aghajanian GK. Synaptic dysfunction in depression: potential therapeutic targets. Science. 2012;338:68–72.
   PubMed Web of Science ®Google Scholar
• Li N, Lee B, Liu RJ, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329:959–964.
   PubMed Web of Science ®Google Scholar
• Coyle CM, Laws KR. The use of ketamine as an antidepressant: a systematic review and meta-analysis. Hum Psychopharmacol. 2015;30:152–163.
   PubMed Web of Science ®Google Scholar
• Corssen G, Domino EF. Dissociative anesthesia: further pharmacologic studies and first clinical experience with the phencyclidine derivative CI-581. Anesth Analg. 1966;45:29–40.
   PubMed Web of Science ®Google Scholar
• Domino EF, Chodoff P, Corssen G. Pharmacologic effects of CI-581, a new dissociative anesthetic, in man. Clin Pharmacol Ther. 1965;6:279–291.
   PubMed Web of Science ®Google Scholar
• Roberts JR, Hedges JR. Roberts and Hedges’: clinical procedures in emergency medicine. 6th ed. Philadelphia (PA): Elsevier Saunders; 2014.
   Google Scholar
• White PF, Way WL, Trevor AJ. Ketamine–its pharmacology and therapeutic uses. Anesthesiology. 1982;56:119–136.
   PubMed Web of Science ®Google Scholar
• Smith KM, Larive LL, Romanelli F. Club drugs: methylenedioxymethamphetamine, flunitrazepam, ketamine hydrochloride, and gamma-hydroxybutyrate. Am J Health Syst Pharm. 2002;59:1067–1076.
   PubMed Web of Science ®Google Scholar
• Mion G, Villevieille T. Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings). CNS Neurosci Therap. 2013;19:370–380.
   PubMed Web of Science ®Google Scholar
• Baker AK, Hoffmann VL, Meert TF. Dextromethorphan and ketamine potentiate the antinociceptive effects of mu- but not delta- or kappa-opioid agonists in a mouse model of acute pain. Pharmacol, Biochem, Behav. 2002;74:73–86.
   PubMed Web of Science ®Google Scholar
• Pawson P, Forsyth S. Chapter 5, Anesthetic agents. In: Maddison JE, Page SW, Church DB, editors. Small animal clinical pharmacology. 2nd ed. Edinburgh: W.B. Saunders; 2008. p. 83–112.
   Google Scholar
• Welters ID, Hafer G, Menzebach A, et al. Ketamine inhibits transcription factors activator protein 1 and nuclear factor-kappaB, interleukin-8 production, as well as CD11b and CD16 expression: studies in human leukocytes and leukocytic cell lines. Anesth Analg. 2010;110:934–941.
   PubMed Web of Science ®Google Scholar
• Durieux ME. Inhibition by ketamine of muscarinic acetylcholine receptor function. Anesth Analg. 1995;81:57–62.
   PubMed Web of Science ®Google Scholar
• Udesky JO, Spence NZ, Achiel R, et al. The role of nicotinic inhibition in ketamine-induced behavior. Anesth Analg. 2005;101:407–411.
   PubMed Web of Science ®Google Scholar
• Paul RK, Singh NS, Khadeer M, et al. (R,S)-Ketamine metabolites (R,S)-norketamine and (2S,6S)-hydroxynorketamine increase the mammalian target of rapamycin function. Anesthesiology. 2014;121:149–159.
   PubMed Web of Science ®Google Scholar
• Yamakage M, Hirshman CA, Croxton TL. Inhibitory effects of thiopental, ketamine, and propofol on voltage-dependent Ca2+ channels in porcine tracheal smooth muscle cells. Anesthesiology. 1995;83:1274–1282.
   Web of Science ®Google Scholar
• Peltoniemi MA, Hagelberg NM, Olkkola KT, et al. Ketamine: a review of clinical pharmacokinetics and pharmacodynamics in anesthesia and pain therapy. Clin Pharmacokinetics. 2016;55:1059–1077.
   PubMed Web of Science ®Google Scholar
• White PF, Schuttler J, Shafer A, et al. Comparative pharmacology of the ketamine isomers. Studies in volunteers. Br J Anaesth. 1985;57:197–203.
   PubMed Web of Science ®Google Scholar
• Himmelseher S, Pfenninger E, Georgieff M. The effects of ketamine-isomers on neuronal injury and regeneration in rat hippocampal neurons. Anesth Analg. 1996;83:505–512.
   PubMed Web of Science ®Google Scholar
• Klepstad P, Maurset A, Moberg ER, et al. Evidence of a role for NMDA receptors in pain perception. Euro J Pharmacol. 1990;187:513–518.
   PubMed Web of Science ®Google Scholar
• Karch SB, Drummer OH. Karch's pathology of drug abuse. 5th ed. Boca Raton (FL): CRC Press, Taylor & Francis Group; 2016.
   Google Scholar
• Schmid RL, Sandler AN, Katz J. Use and efficacy of low-dose ketamine in the management of acute postoperative pain: a review of current techniques and outcomes. Pain. 1999;82:111–125.
   PubMed Web of Science ®Google Scholar
• Dinis-Oliveira RJ. Metabolomics of drugs of abuse: a more realistic view of the toxicological complexity. Bioanalysis. 2014;6:3155–3159.
   PubMed Web of Science ®Google Scholar
• Aroke EN, Dungan JR. Pharmacogenetics of anesthesia: an integrative review. Nurs Res. 2016;65:318–330.
   Web of Science ®Google Scholar
• Li Y, Jackson KA, Slon B, et al. CYP2B6*6 allele and age substantially reduce steady-state ketamine clearance in chronic pain patients: impact on adverse effects. British J Clin Pharmacol. 2015;80:276–284.
   PubMed Web of Science ®Google Scholar
• Johnson BA. Addiction medicine: science and practice. London: Springer; 2011.
   Google Scholar
• Qi X, Evans AM, Wang J, et al. Inhibition of morphine metabolism by ketamine. Drug Metabolism Disposition: Biol Fate Chem. 2010;38:728–731.
   PubMed Web of Science ®Google Scholar
• Idvall J, Aronsen KF, Stenberg P, et al. Pharmacodynamic and pharmacokinetic interactions between ketamine and diazepam. Euro J Clin Pharmacol. 1983;24:337–343.
   PubMed Web of Science ®Google Scholar
• Fanta S, Kinnunen M, Backman JT, et al. Population pharmacokinetics of S-ketamine and norketamine in healthy volunteers after intravenous and oral dosing. Eur J Clin Pharmacol. 2015;71:441–447.
   Google Scholar
• Malinovsky JM, Servin F, Cozian A, et al. Ketamine and norketamine plasma concentrations after i.v., nasal and rectal administration in children. Br J Anaesth. 1996;77:203–207.
   PubMed Web of Science ®Google Scholar
• Little B, Chang T, Chucot L, et al. Study of ketamine as an obstetric anesthetic agent. Am J Obstetrics Gynecol. 1972;113:247–260.
   PubMed Web of Science ®Google Scholar
• Dayton PG, Stiller RL, Cook DR, et al. The binding of ketamine to plasma proteins: emphasis on human plasma. Euro J Clin Pharmacol. 1983;24:825–831.
   PubMed Web of Science ®Google Scholar
• Moffat AC, Osselton MD, Widdop B, et al. Clarke's analysis of drugs and poisons. 4th ed. London: Pharmaceutical Press; 2011.
   Google Scholar
• Taylor E. Chapter 24, Ketamine. In: Bissonnette B, editor. Pediatric anesthesia: basic principles-state of the art-future. Shelton (CT): People's Medical Publishing House; 2011. p. 376–386.
   Google Scholar
• Domino EF, Zsigmond EK, Domino LE, et al. Plasma levels of ketamine and two of its metabolites in surgical patients using a gas chromatographic mass fragmentographic assay. Anesth Analg. 1982;61:87–92.
   PubMed Web of Science ®Google Scholar
• Grant IS, Nimmo WS, McNicol LR, et al. Ketamine disposition in children and adults. Br J Anaesth. 1983;55:1107–1111.
   PubMed Web of Science ®Google Scholar
• Dallimore D, Anderson BJ, Short TG, et al. Ketamine anesthesia in children–exploring infusion regimens. Paediatr Anaesth. 2008;18:708–714.
   Web of Science ®Google Scholar
• Adamowicz P, Kala M. Urinary excretion rates of ketamine and norketamine following therapeutic ketamine administration: method and detection window considerations. J Anal Toxicol. 2005;29:376–382.
   Web of Science ®Google Scholar
• Chang T, Savory A, Albin M, et al. Metabolic disposition of tritium-labelled ketamine. Clin Res. 1970;18:597–601.
   Google Scholar
• Wieber J, Gugler R, Hengstmann JH, et al. Pharmacokinetics of ketamine in man. Anaesthesist. 1975;24:260–263.
   PubMed Web of Science ®Google Scholar
• Chang T, Glazko AJ. Biotransformation and disposition of ketamine. Int Anesthesiol Clin. 1974;12:157–177.
   PubMedGoogle Scholar
• Jansen KL. A review of the nonmedical use of ketamine: use, users and consequences. J Psychoactive Drugs. 2000;32:419–433.
   PubMed Web of Science ®Google Scholar
• Hijazi Y, Boulieu R. Contribution of CYP3A4, CYP2B6, and CYP2C9 isoforms to N-demethylation of ketamine in human liver microsomes. Drug Metabolism Disposition: Biol Fate Chem. 2002;30:853–858.
   PubMed Web of Science ®Google Scholar
• Yanagihara Y, Kariya S, Ohtani M, et al. Involvement of CYP2B6 in n-demethylation of ketamine in human liver microsomes. Drug Metabolism Disposition: Biol Fate Chem. 2001;29:887–890.
   PubMed Web of Science ®Google Scholar
• Leung LY, Baillie TA. Comparative pharmacology in the rat of ketamine and its two principal metabolites, norketamine and (Z)-6-hydroxynorketamine. J Med Chem. 1986;29:2396–2399.
   PubMed Web of Science ®Google Scholar
• Shimoyama M, Shimoyama N, Gorman AL, et al. Oral ketamine is antinociceptive in the rat formalin test: role of the metabolite, norketamine. Pain. 1999;81:85–93.
   PubMed Web of Science ®Google Scholar
• Ebert B, Mikkelsen S, Thorkildsen C, et al. Norketamine, the main metabolite of ketamine, is a non-competitive NMDA receptor antagonist in the rat cortex and spinal cord. Euro J Pharmacol. 1997;333:99–104.
   PubMed Web of Science ®Google Scholar
• Moore KA, Kilbane EM, Jones R, et al. Tissue distribution of ketamine in a mixed drug fatality. J Forensic Sci. 1997;42:1183–1185.
   PubMed Web of Science ®Google Scholar
• Schmitz A, Theurillat R, Lassahn PG, et al. CE provides evidence of the stereoselective hydroxylation of norketamine in equines. Electrophoresis. 2009;30:2912–2921.
   Web of Science ®Google Scholar
• Adams JD, Jr., Baillie TA, Trevor AJ, et al. Studies on the biotransformation of ketamine. 1-Identification of metabolites produced in vitro from rat liver microsomal preparations. Biomed Mass Spectrom. 1981;8:527–538.
   PubMedGoogle Scholar
• Turfus SC, Parkin MC, Cowan DA, et al. Use of human microsomes and deuterated substrates: an alternative approach for the identification of novel metabolites of ketamine by mass spectrometry. Drug Metabolism Disposition: Biol Fate Chem. 2009;37:1769–1778.
   PubMed Web of Science ®Google Scholar
• Leung LY, Baillie TA. Studies on the biotransformation of ketamine. II–Quantitative significance of the N-demethylation pathway in rats in vivo determined by a novel stable isotope technique. Biomed Environ Mass Spectrom. 1989;18:401–404.
   Google Scholar
• Curran HV, Monaghan L. In and out of the K-hole: a comparison of the acute and residual effects of ketamine in frequent and infrequent ketamine users. Addiction. 2001;96:749–760.
   PubMed Web of Science ®Google Scholar
• Woolf TF, Adams JD. Biotransformation of ketamine, (Z)-6-hydroxyketamine, and (E)-6-hydroxyketamine by rat, rabbit, and human liver microsomal preparations. Xenobiotica; Fate Foreign Compd Biol Syst. 1987;17:839–847.
   PubMed Web of Science ®Google Scholar
• Katzung BG, Masters SB, Trevor AJ. Basic & clinical pharmacology. 12th ed. New York (NY): McGraw-Hill; 2012.
   Google Scholar
• Parkin MC, Turfus SC, Smith NW, et al. Detection of ketamine and its metabolites in urine by ultra high pressure liquid chromatography-tandem mass spectrometry. J Chromatography B, Anal Technol Biomed Life Sci. 2008;876:137–142.
   PubMed Web of Science ®Google Scholar
• Lo JN, Cumming JF. Interaction between sedative premedicants and ketamine in man in isolated perfused rat livers. Anesthesiology. 1975;43:307–312.
   Web of Science ®Google Scholar
• Domino EF, Domino SE, Smith RE, et al. Ketamine kinetics in unmedicated and diazepam-premedicated subjects. Clin Pharmacol Therap. 1984;36:645–653.
   PubMed Web of Science ®Google Scholar
• Sweeney BP, Bromilow J. Liver enzyme induction and inhibition: implications for anaesthesia. Anaesthesia. 2006;61:159–177.
   PubMed Web of Science ®Google Scholar
• Gantenbein M, Abat C, Attolini L, et al. Ketamine effects on bupivacaine local anaesthetic activity and pharmacokinetics of bupivacaine in mice. Life Sci. 1997;61:2027–2033.
   PubMed Web of Science ®Google Scholar
• Loch JM, Potter J, Bachmann KA. The influence of anesthetic agents on rat hepatic cytochromes P450 in vivo. Pharmacology. 1995;50:146–153.
   PubMed Web of Science ®Google Scholar
• Noppers I, Olofsen E, Niesters M, et al. Effect of rifampicin on S-ketamine and S-norketamine plasma concentrations in healthy volunteers after intravenous S-ketamine administration. Anesthesiology. 2011;114:1435–1445.
   PubMed Web of Science ®Google Scholar
• Peltoniemi MA, Saari TI, Hagelberg NM, et al. Exposure to oral S-ketamine is unaffected by itraconazole but greatly increased by ticlopidine. Clin Pharmacol Ther. 2011;90:296–302.
   PubMed Web of Science ®Google Scholar
• Hagelberg NM, Peltoniemi MA, Saari TI, et al. Clarithromycin, a potent inhibitor of CYP3A, greatly increases exposure to oral S-ketamine. Eur J Pain. 2010;14:625–629.
   PubMed Web of Science ®Google Scholar
• Li Y, Coller JK, Hutchinson MR, et al. The CYP2B6*6 allele significantly alters the N-demethylation of ketamine enantiomers in vitro. Drug Metabolism Disposition: Biol Fate Chem. 2013;41:1264–1272.
   PubMed Web of Science ®Google Scholar
• Chan WH, Sun WZ, Ueng TH. Induction of rat hepatic cytochrome P-450 by ketamine and its toxicological implications. J Toxicol Environ Health Part A. 2005;68:1581–1597.
   PubMed Web of Science ®Google Scholar
• Marietta MP, White PF, Pudwill CR, et al. Biodisposition of ketamine in the rat: self-induction of metabolism. J Pharmacol Exp Therap. 1976;196:536–544.
   PubMed Web of Science ®Google Scholar
• Rofael HZ. Effect of ketamine pretreatment on cocaine-mediated hepatotoxicity in rats. Toxicol Lett. 2004;152:213–222.
   Web of Science ®Google Scholar
• Chang HC, Chen TL, Chen RM. Cytoskeleton interruption in human hepatoma HepG2 cells induced by ketamine occurs possibly through suppression of calcium mobilization and mitochondrial function. Drug Metabolism Disposition: Biol Fate Chem. 2009;37:24–31.
   PubMed Web of Science ®Google Scholar
• Chen JT, Chen RM. Mechanisms of ketamine-involved regulation of cytochrome P450 gene expression. Expert Opin Drug Metabol Toxicol. 2010;6:273–281.
   PubMed Web of Science ®Google Scholar
• Dinis-Oliveira RJ. Oxidative and non-oxidative metabolomics of ethanol. Curr Drug Metabolism. 2016;17:327–335.
   PubMed Web of Science ®Google Scholar
• Ueng TH, Ueng YF, Tsai JN, et al. Induction and inhibition of cytochrome P-450-dependent monooxygenases in hamster tissues by ethanol. Toxicology. 1993;81:145–154.
   PubMed Web of Science ®Google Scholar
• Rofael HZ, Abdel-Rahman MS. The role of ketamine on plasma cocaine pharmacokinetics in rat. Toxicol Lett. 2002;129:167–176.
   PubMed Web of Science ®Google Scholar
• Wu LT, Schlenger WE, Galvin DM. Concurrent use of methamphetamine, MDMA, LSD, ketamine, GHB, and flunitrazepam among American youths. Drug Alcohol Depend. 2006;84:102–113.
   PubMed Web of Science ®Google Scholar
• Zhang M, Wen C, Zhang Y, et al. Serum metabolomics in rats models of ketamine abuse by gas chromatography-mass spectrometry. J Chromatography B, Anal Technol Biomed Life Sci. 2015;1006:99–103.
   Web of Science ®Google Scholar
• Wen C, Zhang M, Zhang Y, et al. Brain metabolomics in rats after administration of ketamine. Biomed Chromatography: BMC. 2016;30:81–84.
   Web of Science ®Google Scholar
• Weckmann K, Labermaier C, Asara JM, et al. Time-dependent metabolomic profiling of Ketamine drug action reveals hippocampal pathway alterations and biomarker candidates. Translational Psychiatry. 2014;4:e481.
   PubMed Web of Science ®Google Scholar
• Villaseñor A, Ramamoorthy A, Silva dos Santos M, et al. A pilot study of plasma metabolomic patterns from patients treated with ketamine for bipolar depression: evidence for a response-related difference in mitochondrial networks. Br J Pharmacol. 2014;171:2230–2242.
   Web of Science ®Google Scholar
• Rotroff DM, Corum DG, Motsinger-Reif A, et al. Metabolomic signatures of drug response phenotypes for ketamine and esketamine in subjects with refractory major depressive disorder: new mechanistic insights for rapid acting antidepressants. Translational Psychiatry. 2016;6:e894.
   PubMed Web of Science ®Google Scholar
• Koike H, Iijima M, Chaki S. Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression. Behav Brain Res. 2011;224:107–111.
   PubMed Web of Science ®Google Scholar
• Pan X, Zeng X, Hong J, et al. Effects of ketamine on metabolomics of serum and urine in Cynomolgus Macaques (Macaca fascicularis). J Am Assoc Lab Animal Sci. 2016;55:558–564.
   Web of Science ®Google Scholar
• Muetzelfeldt L, Kamboj SK, Rees H, et al. Journey through the K-hole: phenomenological aspects of ketamine use. Drug Alcohol Depend. 2008;95:219–229.
   PubMed Web of Science ®Google Scholar
• Jansen KL. Non-medical use of ketamine. BMJ. 1993;306:601–602.
   PubMed Web of Science ®Google Scholar
• Wolff K, Winstock AR. Ketamine : from medicine to misuse. CNS Drugs. 2006;20:199–218.
   PubMed Web of Science ®Google Scholar
• Gahlinger PM. Club drugs: MDMA, gamma-hydroxybutyrate (GHB), Rohypnol, and ketamine. Am Family Phys. 2004;69:2619–2626.
   PubMed Web of Science ®Google Scholar
• Dinis-Oliveira RJ, Magalhaes T. Forensic toxicology in drug-facilitated sexual assault. Toxicol Mechanisms Methods. 2013;23:471–478.
   PubMed Web of Science ®Google Scholar
• Jansen KL, Darracot-Cankovic R. The nonmedical use of ketamine, part two: A review of problem use and dependence. J Psychoactive Drugs. 2001;33:151–158.
   PubMed Web of Science ®Google Scholar
• Lora-Tamayo C, Tena T, Rodriguez A, et al. The designer drug situation in Ibiza. Forensic Sci Int. 2004;140:195–206.
   PubMed Web of Science ®Google Scholar
• van Velzen M, Dahan A. Ketamine metabolomics in the treatment of major depression. Anesthesiology. 2014;121:4–5.
   Web of Science ®Google Scholar
• Dinis-Oliveira RJ. Metabolomics of methadone: clinical and forensic toxicological implications and variability of dose response. Drug Metabolism Rev. 2016;48:568–576.
   PubMed Web of Science ®Google Scholar
• Dinis-Oliveira RJ. Metabolomics of Delta(9)-tetrahydrocannabinol: implications in toxicity. Drug Metabolism Rev. 2016;48:80–87.
   PubMed Web of Science ®Google Scholar