Ketamine analogues: Comparative toxicokinetic in vitro–in vivo extrapolation and quantification of 2-fluorodeschloroketamine in forensic blood and hair samples
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Ketamine analogues : Comparative toxicokinetic in vitro–in vivo extrapolation and quantification of 2-fluorodeschloroketamine in forensic blood and hair samples. / Davidsen, Anders Bork; Mardal, Marie; Holm, Niels Bjerre; Andreasen, Anna Katrine; Johansen, Sys Stybe; Noble, Carolina; Dalsgaard, Petur Weihe; Linnet, Kristian.
I: Journal of Pharmaceutical and Biomedical Analysis, Bind 180, 113049, 20.02.2020.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Ketamine analogues
T2 - Comparative toxicokinetic in vitro–in vivo extrapolation and quantification of 2-fluorodeschloroketamine in forensic blood and hair samples
AU - Davidsen, Anders Bork
AU - Mardal, Marie
AU - Holm, Niels Bjerre
AU - Andreasen, Anna Katrine
AU - Johansen, Sys Stybe
AU - Noble, Carolina
AU - Dalsgaard, Petur Weihe
AU - Linnet, Kristian
PY - 2020/2/20
Y1 - 2020/2/20
N2 - Recently, the new psychoactive substance (NPS) ketamine analogue 2-fluoro-deschloroketamine (2FDCK) was observed in driving-under-the-influence-of-drugs whole blood samples and in a forensic hair investigation case in Denmark. The molecular structure variations among the NPS subgroups may alter the metabolic fate and drug potency, thereby posing a threat for drug users. This study reports quantification of 2FDCK in whole blood samples and forensic hair and compares the following toxicokinetic parameters: unbound fraction (fu) and in vitro–in vivo-extrapolation (IVIVE) of hepatic clearance for ketamine, norketamine, 2FDCK, methoxetamine and deschloroketamine. The fu was investigated with ultrafiltration, while clearance studies were conducted at 1 μM with pooled human liver microsomes. Samples were analysed by liquid chromatography and mass spectrometry. For the first time, 2FDCK was determined in a concentration range between 0.005 and 0.48 mg/kg in blood samples. Segmental hair analysis demonstrated 2FDCK at concentrations from 0.007 to 0.034 ng/mg throughout the three investigated segments. Toxicokinetic comparison of the five compounds gave a fu between 0.54 and 0.84, with ketamine being the most bound and deschloroketamine being the least bound, in accordance with the logP of the compounds. Conversely, a negative correlation was observed between the molecular weight of the halogen in the ortho-position and IVIVE hepatic clearance. The IVIVE of hepatic clearance, CLparallel-tube, gave values from 18.1 to 5.44 mL/min/kg for ketamine and methoxetamine, respectively. The deschloroketamine IVIVE was disregarded due to low drug elimination under the experimental conditions used. This study provides a basis for toxicokinetic understanding of ketamine analogues.
AB - Recently, the new psychoactive substance (NPS) ketamine analogue 2-fluoro-deschloroketamine (2FDCK) was observed in driving-under-the-influence-of-drugs whole blood samples and in a forensic hair investigation case in Denmark. The molecular structure variations among the NPS subgroups may alter the metabolic fate and drug potency, thereby posing a threat for drug users. This study reports quantification of 2FDCK in whole blood samples and forensic hair and compares the following toxicokinetic parameters: unbound fraction (fu) and in vitro–in vivo-extrapolation (IVIVE) of hepatic clearance for ketamine, norketamine, 2FDCK, methoxetamine and deschloroketamine. The fu was investigated with ultrafiltration, while clearance studies were conducted at 1 μM with pooled human liver microsomes. Samples were analysed by liquid chromatography and mass spectrometry. For the first time, 2FDCK was determined in a concentration range between 0.005 and 0.48 mg/kg in blood samples. Segmental hair analysis demonstrated 2FDCK at concentrations from 0.007 to 0.034 ng/mg throughout the three investigated segments. Toxicokinetic comparison of the five compounds gave a fu between 0.54 and 0.84, with ketamine being the most bound and deschloroketamine being the least bound, in accordance with the logP of the compounds. Conversely, a negative correlation was observed between the molecular weight of the halogen in the ortho-position and IVIVE hepatic clearance. The IVIVE of hepatic clearance, CLparallel-tube, gave values from 18.1 to 5.44 mL/min/kg for ketamine and methoxetamine, respectively. The deschloroketamine IVIVE was disregarded due to low drug elimination under the experimental conditions used. This study provides a basis for toxicokinetic understanding of ketamine analogues.
KW - In vitro-in vivo extrapolation
KW - Ketamine
KW - Ketamine analogue
KW - Microsome
KW - New psychoactive substance
KW - Toxicokinetics
U2 - 10.1016/j.jpba.2019.113049
DO - 10.1016/j.jpba.2019.113049
M3 - Journal article
C2 - 31881397
AN - SCOPUS:85076701310
VL - 180
JO - Journal of Pharmaceutical and Biomedical Analysis
JF - Journal of Pharmaceutical and Biomedical Analysis
SN - 0731-7085
M1 - 113049
ER -
ID: 233780902