Pharmacokinetics, absolute bioavailability and tolerability of ketamine after intranasal administration to dexmedetomidine sedated dogs


Autoři: Lise Vlerick aff001;  Mathias Devreese aff002;  Kathelijne Peremans aff003;  Robrecht Dockx aff003;  Siska Croubels aff002;  Luc Duchateau aff005;  Ingeborgh Polis aff001
Působiště autorů: Small Animal Department, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium aff001;  Department of Pharmacology, Toxicology and Biochemistry, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium aff002;  Department of Veterinary Medical Imaging and Small Animal Orthopaedics, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium aff003;  Department of Psychiatry and Medical Psychology, Ghent Experimental Psychiatry (GHEP) lab, Ghent University, Ghent, Belgium aff004;  Biometrics Research Centre, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium aff005
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: 10.1371/journal.pone.0227762

Souhrn

Intranasal ketamine has recently gained interest in human medicine, not only for its sedative, anaesthetic or analgesic properties, but also in the management of treatment resistant depression, where it has been shown to be an effective, fast acting alternative treatment. Since several similarities are reported between human psychiatric disorders and canine anxiety disorders, intranasal ketamine could serve as an alternative treatment for anxiety disordered dogs. However, to the authors knowledge, intranasal administration of ketamine and its pharmacokinetics have never been described in dogs. Therefore, this study aimed to examine the pharmacokinetics, absolute bioavailability and tolerability of intranasal ketamine administration compared with intravenous administration. Seven healthy, adult laboratory Beagle dogs were included in this randomized crossover study. The dogs received 2 mg/kg body weight ketamine intravenously (IV) or intranasally (IN), with a two-week wash-out period. Prior to ketamine administration, dogs were sedated intramuscularly with dexmedetomidine. Venous blood samples were collected at fixed times until 480 min post-administration and ketamine plasma concentrations were determined by liquid chromatography-tandem mass spectrometry. Cardiovascular parameters and sedation scores were recorded at the same time points. Non-compartmental pharmacokinetic analysis revealed a rapid (Tmax = 0.25 ± 0.14 h) and complete IN bioavailability (F = 147.65 ± 49.97%). Elimination half-life was similar between both administration routes (T1/2el IV = 1.47 ± 0.24 h, T1/2el IN = 1.50 ± 0.97 h). Heart rate and sedation scores were significantly higher at 5 and 10 min following IV administration compared to IN administration, but not at the later time-points.

Klíčová slova:

Dogs – Drug administration – Heart rate – Pharmacokinetics – Routes of administration – Sedation – Sedatives – Intranasal administration


Zdroje

1. Sarrau S, Jourdan J, Dupuis-Soyris F, Verwaerde P. Effects of postoperative ketamine infusion on pain control and feeding behaviour in bitches undergoing mastectomy. J Small Anim Pract. 2007;48(12):670–6. doi: 10.1111/j.1748-5827.2007.00362.x 17725589

2. Wagner AE, Walton J a, Hellyer PW, Gaynor JS, Mama KR. Use of low doses of ketamine administered by constant rate infusion as an adjunct for postoperative analgesia in dogs. J Am Vet Med Assoc. 2002;221(1):72–5. doi: 10.2460/javma.2002.221.72 12420827

3. Andrade C. Intranasal drug delivery in neuropsychiatry: focus on intranasal ketamine for refractory depression. J Clin Psychiatry [Internet]. 2015;76(5):e628–31. Available from: http://www.psychiatrist.com/jcp/article/Pages/2015/v76n05/v76n0514.aspx doi: 10.4088/JCP.15f10026 26035196

4. Illum L. Nasal drug delivery—Possibilities, problems and solutions. J Control Release. 2003;87(1–3):187–98. doi: 10.1016/s0168-3659(02)00363-2 12618035

5. Roelofse J a, Shipton E a, de la Harpe CJ, Blignaut RJ, Med D, Harpe CJ De, et al. Intranasal sufentanil/midazolam versus ketamine/midazolam for analgesia/sedation in the pediatric population prior to undergoing multiple dental extractions under general anesthesia: a prospective, double-blind, randomized comparison. Anesth Prog [Internet]. 2004;51(4):114–21. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2007493&tool=pmcentrez&rendertype=abstract 15675259

6. Weber F, Wulf H, el Saeidi G. Premedication with nasal s-ketamine and midazolam provides good conditions for induction of anesthesia in preschool children. Can J Anesth [Internet]. 2003;50(5):470–5. Available from: http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=emed6&NEWS=N&AN=2003281847 doi: 10.1007/BF03021058 12734155

7. Pandey R, Bahetwar S, Saksena A, Chandra G. A Comparative Evaluation of Drops versus Atomized Administration of Intranasal Ketamine for the Procedural Sedation of Young Uncooperative Pediatric Dental Patients: A Prospective Crossover Trial. J Clin Pediatr Dent. 2015;36(1):79–84.

8. Yeaman F, Meek R, Egerton-Warburton D, Rosengarten P, Graudins A. Sub-dissociative-dose intranasal ketamine for moderate to severe pain in adult emergency department patients. EMA—Emerg Med Australas. 2014;26(3):237–42.

9. Shimonovich S, Gigi R, Shapira A, Sarig-Meth T, Nadav D, Rozenek M, et al. Intranasal ketamine for acute traumatic pain in the Emergency Department: a prospective, randomized clinical trial of efficacy and safety. BMC Emerg Med [Internet]. 2016;16(1):43. Available from: http://bmcemergmed.biomedcentral.com/articles/10.1186/s12873-016-0107-0 27829367

10. Afridi SK, Giffin NJ, Kaube H, Goadsby PJ. A randomized controlled trial of intranasal ketamine in migraine with prolonged aura. Neurology. 2013;80(7):642–7. doi: 10.1212/WNL.0b013e3182824e66 23365053

11. Huge V, Lauchart M, Magerl W, Schelling G, Beyer A, Thieme D, et al. Effects of low-dose intranasal (S)-ketamine in patients with neuropathic pain. Eur J Pain [Internet]. 2010;14(4):387–94. Available from: http://dx.doi.org/10.1016/j.ejpain.2009.08.002 19733106

12. Riediger C, Haschke M, Bitter C, Fabbro T, Schaeren S, Urwyler A, et al. The analgesic effect of combined treatment with intranasal S-ketamine and intranasal midazolam compared with morphine patient-controlled analgesia in spinal surgery patients: a pilot study. J Pain Res. 2015;8:87–94. doi: 10.2147/JPR.S75928 25709497

13. Graudins A, Meek R, Egerton-Warburton D, Oakley E, Seith R. The PICHFORK (Pain in Children Fentanyl or Ketamine) Trial: A randomized controlled trial comparing intranasal ketamine and fentanyl for the relief of moderate to severe pain in children with limb injuries. Ann Emerg Med [Internet]. 2015;65(3):248–254.e1. Available from: http://dx.doi.org/10.1016/j.annemergmed.2014.09.024 25447557

14. Lapidus KAB, Levitch CF, Perez AM, Brallier JW, Parides MK, Soleimani L, et al. A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol Psychiatry [Internet]. 2014;76(12):970–6. Available from: doi: 10.1016/j.biopsych.2014.03.026 24821196

15. Daly EJ, Singh JB, Fedgchin M, Cooper K, Lim P, Shelton RC, et al. Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression. JAMA Psychiatry. 2017;75(2):139–48.

16. Canuso CM, Singh JB, Fedgchin M, Alphs L, Lane R, Lim P, et al. Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study. Am J Psychiatry. 2018;175(7):620–30. doi: 10.1176/appi.ajp.2018.17060720 29656663

17. Vermeire S, Audenaert K, Dobbeleir A, de Meester R, Vandermeulen E, Waelbers T, et al. Regional cerebral blood flow changes in dogs with anxiety disorders, measured with SPECT. Brain Imaging Behav. 2009;3(4):342–9.

18. Deckersbach T, Dougherty DD, Rauch SL. Functional Imaging of Mood and Anxiety Disorders. J Neuroimaging [Internet]. 2006;16(1):1–10. Available from: doi: 10.1177/1051228405001474 16483270

19. Eren I, Tükel R, Polat A, Karaman R, Ünal S. Evaluation of regional cerebral blood flow changes in panic disorder with Tc99m-HMPAO SPECT. Psychiatry Res Neuroimaging. 2003;123:135–43.

20. Etkin A, Wager TD. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry. 2007;164(10):1476–88. doi: 10.1176/appi.ajp.2007.07030504 17898336

21. Fitzgerald PB, Laird AR, Maller J, Daskalakis ZJ. A Meta-Analytic Study of Changes in Brain Activation in Depression. Hum Brain Mapp. 2008;29:683–95. doi: 10.1002/hbm.20426 17598168

22. Järnum H, Simon F, Steffensen EG, Fründ E. Longitudinal MRI study of cortical thickness, perfusion, and metabolite levels in major depressive disorder. Acta Psychiatr Scand. 2011;124:435–46. doi: 10.1111/j.1600-0447.2011.01766.x 21923809

23. Rogers MA, Kasai K, Koji M, Fukuda R, Iwanami A, Nakagome K, et al. Executive and prefrontal dysfunction in unipolar depression: A review of neuropsychological and imaging evidence. Neurosci Res. 2004;50(1):1–11. doi: 10.1016/j.neures.2004.05.003 15288493

24. Rowland LM, Beason-held L, Tamminga CA, Holcomb HH. The interactive effects of ketamine and nicotine on human cerebral blood flow. Psychopharmacology (Berl). 2010;208:575–84.

25. Holcomb HH, Lathi AC, Medoff DR, Weiler M, Tamminga CA. Sequential Regional Cerebral Blood Flow Brain Scans Using PET with H 215 O Demonstrate Ketamine Actions in CNS Dynamically. Neuropsychopharmacology. 2001;25(2):165–72. doi: 10.1016/S0893-133X(01)00229-9 11425500

26. Holcomb HH, Lahti AC, Medoff DR, Cullen T, Tamminga CA. Effects of Noncompetitive NMDA Receptor Blockade on Anterior Cingulate Cerebral Blood Flow in Volunteers with Schizophrenia. Neuropsychopharmacology. 2005;30:2275–82. doi: 10.1038/sj.npp.1300824 16034443

27. Pollak TA, De Simoni S, Barimani B, Zelaya FO, Stone JM, Mehta MA. Phenomenologically distinct psychotomimetic effects of ketamine are associated with cerebral blood flow changes in functionally relevant cerebral foci: A continuous arterial spin labelling study. Psychopharmacology (Berl). 2015;232(24):4515–24.

28. Waelbers T, Polis I, Vermeire S, Dobbeleir A, Eersels J, De Spiegeleer B, et al. Effect of ketamine on the regional cerebral blood flow and binding index of the 5-HT2A receptor radioligand 123I-R91150 in the canine brain. J Vet Behav Clin Appl Res [Internet]. 2015;10(4):332–7. Available from: http://dx.doi.org/10.1016/j.jveb.2015.03.009

29. Vlerick L, Peremans K, Dockx R, Audenaert K, Baeken C, De Spiegeleer B, et al. The influence of subanaesthetic ketamine on regional cerebral blood flow in healthy dogs measured with 99mTc-HMPAO SPECT. PLoS One [Internet]. 2018;1–15. Available from: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209316

30. Vlerick L, Peremans K, Dockx R, Audenaert K, Baeken C, Saunders JH, et al. The long-term effects of single and repeated subanaesthetic ketamine administration on regional cerebral blood flow in healthy dogs measured with 99mTc-HMPAO SPECT. Psychiatry Res—Neuroimaging [Internet]. 2019;285(January):18–24. Available from: https://doi.org/10.1016/j.pscychresns.2019.01.005

31. Vermeire S, Audenaert K, Dobbeleir A, De Meester R, De Vos F, Peremans K. Evaluation of the brain 5-HT2A receptor binding index in dogs with anxiety disorders, measured with 123I-5I-R91150 and SPECT. J Nucl Med [Internet]. 2009;50(2):284–9. Available from: http://jnm.snmjournals.org/content/50/2/284.full.pdf doi: 10.2967/jnumed.108.055731 19164223

32. Mintun MA, Sheline YI, Moerlein SM, Vlassenko AG, Huang Y, Snyder AZ. Decreased hippocampal 5-HT2A receptor binding in major depressive disorder: In vivo measurement with [18F]altanserin positron emission tomography. Biol Psychiatry. 2004;55(3):217–24. doi: 10.1016/j.biopsych.2003.08.015 14744461

33. Yatham LN, Liddle PF, Shiah I-S, Scarrow G, Lam RW, Adam MJ, et al. Brain Serotonin 2 Receptors in Major Depression. Arch Gen Psychiatry. 2000;57:850–8. doi: 10.1001/archpsyc.57.9.850 10986548

34. Beata C, Beaumont-Graff E, Diaz C, Marion M, Massal N, Marlois N, et al. Effects of alpha-casozepine (Zylkene) versus selegiline hydrochloride (Selgian, Anipryl) on anxiety disorders in dogs. J Vet Behav Clin Appl Res. 2007;2(5):175–83.

35. Sherman BL, Mills DS. Canine Anxieties and Phobias: An Update on Separation Anxiety and Noise Aversions. Vet Clin North Am—Small Anim Pract. 2008;38(5):1081–106. doi: 10.1016/j.cvsm.2008.04.012 18672155

36. Landsberg GM, Melese P, Sherman BL, Neilson JC, Zimmerman A, Clarke TP. Effectiveness of fluoxetine chewable tablets in the treatment of canine separation anxiety. J Vet Behav Clin Appl Res. 2008;3(1):12–9.

37. Takeuchi Y, Houpt KA, Scarlett JM. Evaluation of treatments for separation anxiety in dogs. J Am Vet Med Assoc. 2000;217(3):342–5. doi: 10.2460/javma.2000.217.342 10935036

38. Marjani M, Akbarinejad V, Bagheri M. Comparison of intranasal and intramuscular ketamine-midazolam combination in cats. Vet Anaesth Analg. 2015;42(2):178–81. doi: 10.1111/vaa.12183 24986665

39. Weiland LC, Kluge K, Kutter APN, Kronen PW. Clinical evaluation of intranasal medetomidine–ketamine and medetomidine–S(+)-ketamine for induction of anaesthesia in rabbits in two centres with two different administration techniques. Vet Anaesth Analg [Internet]. 2017;44(1):98–105. Available from: doi: 10.1111/vaa.12408 27374385

40. Orr H, Roughan J, Flecknell P. Assessment of ketamine and medetomidine anaesthesia in the domestic rabbit. Vet Anaesth Analg [Internet]. 2005;32(5):271–9. Available from: http://www.embase.com/search/results?subaction=viewrecord&from=export&id=L41467465 doi: 10.1111/j.1467-2995.2005.00211.x 16135208

41. Canpolat İ, Karabulut E, Cakir S. The efficacy of intranasal administation of dexmedetomidine, ketamine and morphine combination to rabbit. Int J Dev Res. 2016;6(7):8634–6.

42. Gurney M, Cripps P, Mosing M. Subcutaneous pre-anaesthetic medication with acepromazine-buprenorphine is effective as and less painful than the intramuscular route. J Small Anim Pract. 2009;50(9):474–7. doi: 10.1111/j.1748-5827.2009.00786.x 19769668

43. Devreese M, Rodrigo D, Schauvliege S, Gasthuys F, De Backer P, Croubels S. Quantification of ketamine and norketamine in bovine plasma by liquid chromatography-tandem mass spectrometry. J Iran Chem Soc [Internet]. 2015;12(8):1357–62. Available from: http://dx.doi.org/10.1007/s13738-015-0601-4

44. Malinovsky JM, Servin F, Cozian a, Lepage JY, Pinaud M. Ketamine and norketamine plasma concentrations after i.v., nasal and rectal administration in children. Br J Anaesth. 1996;77(2):203–7. doi: 10.1093/bja/77.2.203 8881626

45. Yanagihara Y, Ohtani M, Kariya S, Uchino K, Hiraishi T, Ashizawa N, et al. Plasma concentration profiles of ketamine and norketamine after administration of various ketamine preparations to healthy Japanese volunteers. Biopharm Drug Dispos. 2003;24(1):37–43. doi: 10.1002/bdd.336 12516077

46. Wong YC, Zuo Z. Intranasal delivery-Modification of drug metabolism and brain disposition. Pharm Res. 2010;27(7):1208–23. doi: 10.1007/s11095-010-0127-5 20372990

47. Romagnoli N, Bektas RN, Kutter AP, Barbarossa A, Roncada P, Hartnack S, et al. Pharmacokinetics of ketamine and norketamine enantiomers after racemic or S-ketamine IV bolus administration in dogs during sevoflurane anaesthesia. Res Vet Sci [Internet]. 2017;112(December 2016):208–13. Available from: http://dx.doi.org/10.1016/j.rvsc.2017.05.005

48. Sandbaumhüter FA, Theurillat R, Bektas RN, Kutter APN, Bettschart-Wolfensberger R, Thormann W. Pharmacokinetics of ketamine and three metabolites in Beagle dogs under sevoflurane vs. medetomidine comedication assessed by enantioselective capillary electrophoresis. J Chromatogr A [Internet]. 2016;1467:436–44. Available from: doi: 10.1016/j.chroma.2016.07.060 27485149

49. Pypendop BH, Ilkiw JE. Pharmacokinetics of ketamine and its metabolite, norketamine, after intravenous administration of a bolus of ketamine to isoflurane-anesthetized dogs. Am J Vet Res. 2005;66(12):2034–8. doi: 10.2460/ajvr.2005.66.2034 16379643

50. Björkman S, Redke F. Clearance of Fentanyl, Alfentanil, Methohexitone, Thiopentone and Ketamine in Relation to Estimated Hepatic Blood Flow in Several Animal Species: Application to Prediction of Clearance in Man. J Pharm Pharmacol. 2000;52(9):1065–74. doi: 10.1211/0022357001774985 11045886

51. Murrell J. Pre-anaesthetic medication and sedation. In: Duke-Novakovski T, de Vries M, Seymour C, editors. BSAVA Manual of Canine and Feline Anaesthesia and Analgesia. third. Gloucester: British Small Animal Veterinary Association; 2016. p. 170–89.

52. Lawrence C, Prinzen F, de Lange S. The Effect of Dexmedetomidine on Nutrient Organ Blood Flow. Anesth Analg. 1996;83:1160–5. doi: 10.1097/00000539-199612000-00005 8942579

53. Bührer M, Mappes A, Lauber R, Stanski D, Maitre P. Dexmedetomidine decreases thiopental dose requirement and alters distribution pharmacokinetics. Anesthesiology. 1994;80(6):1216–27. doi: 10.1097/00000542-199406000-00008 7912044

54. Bergadano A, Andersen OK, Arendt-Nielsen L, Theurillat R, Thormann W, Spadavecchia C. Plasma levels of a low-dose constant-rate-infusion of ketamine and its effect on single and repeated nociceptive stimuli in conscious dogs. Vet J [Internet]. 2009;182(2):252–60. Available from: doi: 10.1016/j.tvjl.2008.06.003 18706837

55. Kaka U, Saifullah B, Abubakar AA, Goh YM, Fakurazi S, Kaka A, et al. Serum concentration of ketamine and antinociceptive effects of ketamine and ketamine-lidocaine infusions in conscious dogs. BMC Vet Res [Internet]. 2016;12(1):1–10. Available from: http://dx.doi.org/10.1186/s12917-016-0815-4

56. Kästner S. Injectable anaesthetics. In: Duke-Novakovski T, de Vries M, C S, editors. BSAVA Manual of Canine and Feline Anaesthesia and Analgesia. third. Gloucester: British Small Animal Veterinary Association; 2016. p. 190–206.

57. Charalambous M, Bhatti SFM, Van Ham L, Platt S, Jeffery ND, Tipold A, et al. Intranasal Midazolam versus Rectal Diazepam for the Management of Canine Status Epilepticus: A Multicenter Randomized Parallel-Group Clinical Trial. J Vet Intern Med. 2017;31(4):1149–58. doi: 10.1111/jvim.14734 28543780

58. Musulin SE, Mariani CL, Papich MG. Diazepam pharmacokinetics after nasal drop and atomized nasal administration in dogs. J Vet Pharmacol Ther. 2011;34(1):17–24. doi: 10.1111/j.1365-2885.2010.01186.x 21219339

59. Nielsen BN, Friis SM, Rømsing J, Schmiegelow K, Anderson BJ, Ferreirõs N, et al. Intranasal sufentanil/ketamine analgesia in children. Paediatr Anaesth. 2014;24(2):170–80. doi: 10.1111/pan.12268 24118506

60. Trivedi S, Kumar R, Tripathi AK, Mehta RK. A comparative study of dexmedetomidine and midazolam in reducing delirium caused by ketamine. J Clin Diagnostic Res. 2016;10(8):UC01–4.

61. Tobias JD. Dexmedetomidine and ketamine: An effective alternative for procedural sedation? Pediatr Crit Care Med. 2012;13(4):423–7. doi: 10.1097/PCC.0b013e318238b81c 22067985


Článek vyšel v časopise

PLOS One


2020 Číslo 1