Urinary Excretion Rates of Ketamine and Norketamine Following ...
Urinary Excretion Rates of Ketamine and Norketamine Following ... Urinary Excretion Rates of Ketamine and Norketamine Following ...
Journal of Analytical Toxicology, Vol. 28, July/August 2005 The LC-MS-APCI procedure is easier and faster (the derivati- zation step is omitted). The GC-MS-NCI method is character- ized by a very low LOD for norketamine. In cases where urine samples were collected a long time after ketamine administra- tion, the GC-MS-NCI method seems to be most suitable. Using both methods provides the toxicologist with a high level of confidence in their results. Both methods are very expensive and the procedures are time consuming. Therefore, they are not complementary, but can be regarded as alternative. Both can be used as independent screening methods for ketamine and norketamine, and can also be used for confirmation and quantitation of these analytes. Using the GC-MS-NCI method, norketamine can be detected for an extended period of time. Finding norketamine in a urine sample is forensically important because its status as a bio- transformation product reduces the likelihood of it as a con- taminant. Most authors have detected ketamine in urine up to 48-72 h after administration of a single dose (36). Our study confirmed these findings because ketamine was detected up to 48 h after a single therapeutic dose to children. Multiple-doses of ke- tamine (Case 2, Table I) extended its elimination time to 11 days. This is consistent with the report by Jansen et al. (37) who described that frequently repeated dose of ketamine prolonged its elimination. In our study norketamine was detected in urine samples up to 14 days after administration of a single intra- venous dose of ketamine to children. Negrusz et al. (34) re- ported that after a single intramuscular dose of ketamine, nor- ketamine remained in urine of nonhuman primates throughout the entire 35-day study period in four out of five animals. The detection times of ketamine and/or its metabolite vary a lot in both studies, but the subjects and the routes of ketamine ad- ministration are different. Both routes are different than in recreational ketamine use or in a ketamine-facilitated sexual as- sault scenario when the drug is taken orally. Variability be- tween individuals and species, as well as various routes of ke- tamine administration, highly influence its metabolism and elimination. Ketamine elimination in Rhesus monkey is similar to human elimination (38,39). The pharmacokinetics in chil- dren is not very different than in adults, although in children more norketamine is formed after intravenous and intramus- cular administrations (40,41). Ketamine is eliminated two times faster in children (42). Oral administration of ketamine pro- duces higher plasma levels of norketamine due to first pass metabolism (43). This study suggests that in cases of oral ingestion of ke- tamine, the parent compound and its major metabolite can be detected in urine for the same or longer time with the use of the described chromatographic methods. To detect a non-medical use of ketamine, urine samples should be collected up to several days after the suspected ad- ministration. Ketamine and its metabolite remain in human urine for an extended period of time. Conclusions Recently, an increased number of reports of illicit use of ketamine have been observed. Ketamine is abused by teenagers as a club drug and also used as a date-rape drug. This paper pre- sents the elimination of ketamine and its major metabolite, norketamine, in urine after single (and in one case multiple) in- travenous dose of ketamine in six children. Sensitive, accurate, and precise GC-MS-NCI and LC-MS-APCI methods for detec- tion of ketamine in urine were applied to urine samples. As shown, the detection window of the analytes is highly de- pendent on the method used for the analysis, and is also affected by the interindividual variability. Ketamine was detected up to two days with the use of the GC-MS-NCI method or up to 11 days with the use of the LC-MS-APCI method. Norketamine was detected in urine up to 14 days with the GC-MS-NCI method and up to 6 days with the LC-MS-APCI method. These results are important for the forensic toxicology com- munity because they demonstrate the length of time after ke- tamine administration that a person may continue to test pos- itive for the drug or metabolite. The authors suggest that urine samples should be collected up to several days after suspected consumption of ketamine for non-medical purposes. References 1. T. Bowdle, A. Horita, E.D. Kharash. The Pharmacologic Basis of Anesthesiology. Churchill Livingstone, New York, NY 1994. 2. M. Fisher. Ketamine hydrochloride in severe bronchospasm. Anaesthesia 32:771-772 (1977). 3. J.W. Dundee, R.SJ. Clarke, and W. McCaughey. Clinical Anaes- thetic Pharmocology. Churchill Livingstone, 1991, pp. 165-171. 4. B.K. Basak. Pharmacology for Anesthesiologist. Technomic Pub- lishing Company, Westport, CT, 1981, pp. 29-32. 5. K. Kelly. The Little Book ofKetamine. Ronin Publishing, Berkeley, CA, 1999. 6. I.H. Mills, G.R. Park, A.R. Manara, and R.J. Merriman. lreatment of compulsive behavior in eating disorders with intermittent ke- tamine infusions. Q. J. Med. 91" 493-503 (1998). 7. K.L.R. Jansen and R. Darracot-Cankovic. The non-medical use of ketamine, part two: A review of problem use and dependence. J. Psychoactive Drugs 33:151-158 (2001). 8. P.F. White, W.L. Way, and A.J. Trevor. Ketamine--its pharma- cology and therapeutic uses. Anesthesiology 56:119-136 (1982). 9. D.L. Reich and G. Siivay. Ketamine: an update on the first twenty- five years of clinical experience. Can. J. Anaesth. 36:186-197 (1989). 10. K.A. Moore, E.M. Kilbane, R. Jones, G.W. Kunsman, B. Levine, and M. Smith. Tissue distribution of ketamine in a mixed drug fatality. J. Forensic Sci. 42(6): 1183-1185 (1997). 11. M.M. Kochhar. The identification of ketamine and its metabolites in biologic fluids by gas-chromatography-mass spectrometry. Clin. ToxicoL 11 (2): 265-275 (1977). 12. S.N. Ahmed and L. Petchkovsky. Abuse of ketamine. Br. J. Psychi- atry 137:303 (1980). 13. R.S. Blacher. The near death experience. J. Am. Mecl. Assoc. 244: 30 (1980). 14. P.F. White, J. Ham, and W.L. Way. Pharmacology of ketamine iso- mers in surgical patients. Anesthesiology52:231-239 (1980). 15. J.R. Gill and M. Stajic. Ketamine in non-hospital and hospital deaths in New York City. ]. Forensic Sci. 45:655-658 (2000). 16. T. Chang and A.J. Glazko. A gas chromatographic assay for ke- tamine in human plasma. Anesthesiology36:401404 (1972). 17. K.A. Moore, J. Sklerov, B. Levine, and A.J. Jacobs. Urine conce- trations of ketamine and norketamine following illegal comsump- tion. J. Anal ToxicoL 25(7): 583-588 (2001). 381
18. S.B. Karch. Karch's Pathology of Drug Abuse. 3rd ed. CRC Press, London, U.K. 2002, pp 467-471. 19. P.J. Delgarno and D. Shewan. Illicit use of ketamine in Scotland. J. Psychoactive Drugs. 28:191-199 (1996). 20. P.A. Gill. Non-medical use of ketamine. Br. Med. J. 306:1340 (1993). 21. K. Skovmand. Swedes alarmed at ketamine misuse. The Lancet. 348:122 (1996). 22. A.L. Weiner, L. Vieira, C.A. McKay, and J.M. Bayer. Ketamine abusers presenting to the emergency department: a case series. J. Emerg. Med. 18:447-451 (2000). 23. D.T.W. Chan and M.F. Chan. Simultaneous determination of am- phetamine-type stimulants, benzodiazepines and eetamine in ec- stasy tablets. Forensic Sci. Int. 136(1): 98 (2003). 24. M.A. EISohly and S.J. Salamone. Prevalance of drugs used in cases of alleged sexual assault. J. Anal. Toxicol. 23:141-146 (1999). 25. L.E. Ledray. The clinical care and documentation for victims of drug-facilitated sexual assault. J. Emerg. Nuts. 27:301-305 (2001). 26. R.H. Schwartz, R. Milteer, and M.A. LeBeau. Drug-facilitated sexual assault ('date rape'). South. Med. J. 93:558-561 (2000). 27. R. Sams and P. Pizzo. Detection and identyfication of ketamine and its metabolites in horse urine. J. AnaL Toxicol. 11(2): 58-62 (1987). 28. J.D. Adams, T.A. Baillie, A.J. Trevor, and N. Castagnoli. Studies on the bioformation of ketamine. 1. Identification of metabolites pro- duced in vitro from rat liver microsomal preparations. Biomed. Mass Spectrom. 8(11): 527-538 (1981 ). 29. H.A. Adams, B. Weber, M.B. Bachmann, M. Guerin, and G. Hempelmann. The simultaneous determination of ketamine and midazolam using high presure liquid chromatography and UV detection (HPLC/UV). Anaesthesist. 41 (10): 619-624 (1992). 30. S.S. Seay, D.P. Aucoin, and K.L. Tyczkowska. Rapid high-perfor- mance liquid chromatographic method for the determination of ke- tamine and its metabolite dehydronorketamine in equine serum. J. Chromatogr. 620(2): 281-287 (1993). 31. S. Bolze and R. Boulieu. HPLC determination of ketamine, norke- tamine, and dehydronorketamine in plasma with high-purity re- versed-phase sorbent. Clin. Chem. 44(3): 560-564 (1998). 382 Journal of Analytical Toxicology, Vol. 28, July/August 2005 32. Y. Hijazi, M. Bolon, and R. Boulieu. Stability of ketamine and its metabolites norketamine and dehydronorketamine in human bio- logical samples. Clin. Chem. 47(9): 1713-1715 (2001). 33. J.Y. Cheng and V.K. Mok. Rapid determination of ketamine in urine by liquid chromatography-tandem mass spectrometry for a high throughput laboratory. Forensic Sci. Int. 142(1): 9-15 (2004). 34. A. Negrusz, P. Adamowicz, B.K. Saini, D.E. Webster, M.P. Juhascik, Ch.M. Moore, and R.F. Schlemmer. Detection of ketamine and nor- ketamine in urine of nonhuman primates after a single dose of ke- tamine using microplate enzyme-linked immunosrobent assay (ELISA) and NCI-GC-MS. J. Anal. Toxicol. in press. 35. S.L. Chou, M.H. Yang, Y.C. Ling, and Y.S. Giang. Gas chromatog- raphy-isotope dilution mass spectrometry proceeded by liquid- liquid extraction and chemical derivatization for the determination of ketamine and norketamine in urine. J. Chromatogr. B 799: 37-50 (2004). 36. C. Dollery. Therapeutic Drugs. Volume 2. Churchil Livingstone, London, U.K., 1999, pp K3-K7. 37. K.L.R. Jansen. A review of the non-medical use of ketamine: use, users and consequences. J. Psychoactive Drugs. 32(4): 419-433 (2000). 38. T. Chang and A.J. Glazko. Biotransformation and disposition of ke- tamine. Int. AnesthesioL Clin. 12(2): 157-177 (1974). 39. C. Prys-Robert and C.C. Hug, Jr. Pharmocokinetics of Anaesthesia. Blackwell Scientific Publications, London, U.K., 1984, pp. 235-245. 40. I.S. Grant and W.S. Nimmo. Ketamine disposition in children and adults. Br. J. Anaesth. 55(11): 1107-1111 (1983). 41. M. Wood and A.J. Wood. Drugs and Anesthesia: Pharmacology for Anesthesiologists. Williams & Wilkins, Baltimore, MD, 1990, pp 193-196. 42. D.A. Hass and D.G. Harper. Ketamine: a review of its pharmaco- logic properties and use in ambulatory anesthesia. Anesth. Prog. 39:61-68 (1992). 43. I.S. Grant, W.S. Nimmo, and J.A. Clements. Pharmacokinetics and analgesics effects of I.M. and oral ketamine. Br. J. Anaesth. 53: 805-810 (1981).
- Page 1 and 2: [ TechnicalNote Journal of Analytic
- Page 3 and 4: tamine was an artifact of the analy
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18. S.B. Karch. Karch's Pathology <strong>of</strong> Drug Abuse. 3rd ed. CRC Press,<br />
London, U.K. 2002, pp 467-471.<br />
19. P.J. Delgarno <strong>and</strong> D. Shewan. Illicit use <strong>of</strong> ketamine in Scotl<strong>and</strong>. J.<br />
Psychoactive Drugs. 28:191-199 (1996).<br />
20. P.A. Gill. Non-medical use <strong>of</strong> ketamine. Br. Med. J. 306:1340<br />
(1993).<br />
21. K. Skovm<strong>and</strong>. Swedes alarmed at ketamine misuse. The Lancet.<br />
348:122 (1996).<br />
22. A.L. Weiner, L. Vieira, C.A. McKay, <strong>and</strong> J.M. Bayer. <strong>Ketamine</strong><br />
abusers presenting to the emergency department: a case series. J.<br />
Emerg. Med. 18:447-451 (2000).<br />
23. D.T.W. Chan <strong>and</strong> M.F. Chan. Simultaneous determination <strong>of</strong> am-<br />
phetamine-type stimulants, benzodiazepines <strong>and</strong> eetamine in ec-<br />
stasy tablets. Forensic Sci. Int. 136(1): 98 (2003).<br />
24. M.A. EISohly <strong>and</strong> S.J. Salamone. Prevalance <strong>of</strong> drugs used in cases<br />
<strong>of</strong> alleged sexual assault. J. Anal. Toxicol. 23:141-146 (1999).<br />
25. L.E. Ledray. The clinical care <strong>and</strong> documentation for victims <strong>of</strong><br />
drug-facilitated sexual assault. J. Emerg. Nuts. 27:301-305 (2001).<br />
26. R.H. Schwartz, R. Milteer, <strong>and</strong> M.A. LeBeau. Drug-facilitated<br />
sexual assault ('date rape'). South. Med. J. 93:558-561 (2000).<br />
27. R. Sams <strong>and</strong> P. Pizzo. Detection <strong>and</strong> identyfication <strong>of</strong> ketamine <strong>and</strong><br />
its metabolites in horse urine. J. AnaL Toxicol. 11(2): 58-62 (1987).<br />
28. J.D. Adams, T.A. Baillie, A.J. Trevor, <strong>and</strong> N. Castagnoli. Studies on<br />
the bi<strong>of</strong>ormation <strong>of</strong> ketamine. 1. Identification <strong>of</strong> metabolites pro-<br />
duced in vitro from rat liver microsomal preparations. Biomed.<br />
Mass Spectrom. 8(11): 527-538 (1981 ).<br />
29. H.A. Adams, B. Weber, M.B. Bachmann, M. Guerin, <strong>and</strong><br />
G. Hempelmann. The simultaneous determination <strong>of</strong> ketamine<br />
<strong>and</strong> midazolam using high presure liquid chromatography <strong>and</strong> UV<br />
detection (HPLC/UV). Anaesthesist. 41 (10): 619-624 (1992).<br />
30. S.S. Seay, D.P. Aucoin, <strong>and</strong> K.L. Tyczkowska. Rapid high-perfor-<br />
mance liquid chromatographic method for the determination <strong>of</strong> ke-<br />
tamine <strong>and</strong> its metabolite dehydronorketamine in equine serum.<br />
J. Chromatogr. 620(2): 281-287 (1993).<br />
31. S. Bolze <strong>and</strong> R. Boulieu. HPLC determination <strong>of</strong> ketamine, norke-<br />
tamine, <strong>and</strong> dehydronorketamine in plasma with high-purity re-<br />
versed-phase sorbent. Clin. Chem. 44(3): 560-564 (1998).<br />
382<br />
Journal <strong>of</strong> Analytical Toxicology, Vol. 28, July/August 2005<br />
32. Y. Hijazi, M. Bolon, <strong>and</strong> R. Boulieu. Stability <strong>of</strong> ketamine <strong>and</strong> its<br />
metabolites norketamine <strong>and</strong> dehydronorketamine in human bio-<br />
logical samples. Clin. Chem. 47(9): 1713-1715 (2001).<br />
33. J.Y. Cheng <strong>and</strong> V.K. Mok. Rapid determination <strong>of</strong> ketamine in<br />
urine by liquid chromatography-t<strong>and</strong>em mass spectrometry for a<br />
high throughput laboratory. Forensic Sci. Int. 142(1): 9-15 (2004).<br />
34. A. Negrusz, P. Adamowicz, B.K. Saini, D.E. Webster, M.P. Juhascik,<br />
Ch.M. Moore, <strong>and</strong> R.F. Schlemmer. Detection <strong>of</strong> ketamine <strong>and</strong> nor-<br />
ketamine in urine <strong>of</strong> nonhuman primates after a single dose <strong>of</strong> ke-<br />
tamine using microplate enzyme-linked immunosrobent assay<br />
(ELISA) <strong>and</strong> NCI-GC-MS. J. Anal. Toxicol. in press.<br />
35. S.L. Chou, M.H. Yang, Y.C. Ling, <strong>and</strong> Y.S. Giang. Gas chromatog-<br />
raphy-isotope dilution mass spectrometry proceeded by liquid-<br />
liquid extraction <strong>and</strong> chemical derivatization for the determination<br />
<strong>of</strong> ketamine <strong>and</strong> norketamine in urine. J. Chromatogr. B 799:<br />
37-50 (2004).<br />
36. C. Dollery. Therapeutic Drugs. Volume 2. Churchil Livingstone,<br />
London, U.K., 1999, pp K3-K7.<br />
37. K.L.R. Jansen. A review <strong>of</strong> the non-medical use <strong>of</strong> ketamine: use,<br />
users <strong>and</strong> consequences. J. Psychoactive Drugs. 32(4): 419-433<br />
(2000).<br />
38. T. Chang <strong>and</strong> A.J. Glazko. Biotransformation <strong>and</strong> disposition <strong>of</strong> ke-<br />
tamine. Int. AnesthesioL Clin. 12(2): 157-177 (1974).<br />
39. C. Prys-Robert <strong>and</strong> C.C. Hug, Jr. Pharmocokinetics <strong>of</strong> Anaesthesia.<br />
Blackwell Scientific Publications, London, U.K., 1984, pp.<br />
235-245.<br />
40. I.S. Grant <strong>and</strong> W.S. Nimmo. <strong>Ketamine</strong> disposition in children <strong>and</strong><br />
adults. Br. J. Anaesth. 55(11): 1107-1111 (1983).<br />
41. M. Wood <strong>and</strong> A.J. Wood. Drugs <strong>and</strong> Anesthesia: Pharmacology for<br />
Anesthesiologists. Williams & Wilkins, Baltimore, MD, 1990, pp<br />
193-196.<br />
42. D.A. Hass <strong>and</strong> D.G. Harper. <strong>Ketamine</strong>: a review <strong>of</strong> its pharmaco-<br />
logic properties <strong>and</strong> use in ambulatory anesthesia. Anesth. Prog.<br />
39:61-68 (1992).<br />
43. I.S. Grant, W.S. Nimmo, <strong>and</strong> J.A. Clements. Pharmacokinetics <strong>and</strong><br />
analgesics effects <strong>of</strong> I.M. <strong>and</strong> oral ketamine. Br. J. Anaesth. 53:<br />
805-810 (1981).
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