Ketamine analogues: Comparative toxicokinetic in vitro-in vivo extrapolation and quantification of 2-fluorodeschloroketamine in forensic blood and hair samples

J Pharm Biomed Anal. 2020 Feb 20:180:113049. doi: 10.1016/j.jpba.2019.113049. Epub 2019 Dec 18.

Abstract

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.

Keywords: In vitro-in vivo extrapolation; Ketamine; Ketamine analogue; Microsome; New psychoactive substance; Toxicokinetics.

Publication types

  • Comparative Study

MeSH terms

  • Chromatography, High Pressure Liquid
  • Forensic Toxicology / methods*
  • Hair / chemistry*
  • Humans
  • In Vitro Techniques
  • Ketamine / analogs & derivatives*
  • Ketamine / toxicity*
  • Limit of Detection
  • Liver / metabolism
  • Metabolic Clearance Rate
  • Models, Theoretical
  • Psychotropic Drugs / analysis
  • Psychotropic Drugs / blood*
  • Tandem Mass Spectrometry
  • Toxicokinetics
  • Ultrafiltration

Substances

  • Psychotropic Drugs
  • Ketamine