Cathinone metabolism and biliary excretion in an ex-vivo pig liver model: example of 4-Cl-PVP and eutylone

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English. <b>Objective:</b> Recently, the pig liver model perfused ex vivo using a normothermic machine perfusion (NMP) has been proposed as a suitable model to study xenobiotic metabolism and biliary excretion. The aim of our study is to describe the metabolism of NPS such as cathinones (with a focus on 4-Cl-PVP and eutylone) in blood and bile, using a normothermic perfused pig liver model.<br/><b>Methods:</b> Livers (n&nbsp;=&nbsp;4) from male large white pigs, 3-4&nbsp;months of age and weighing approximately 75-80&nbsp;kg, were harvested and reperfused onto an NMP (LiverAssist®, XVIVO) using autologous whole blood at 38&nbsp;°C. 4-Cl-PVP and eutylone were administered as a bolus in the circulating blood at T0 with the aim of achieving a concentration of 1&nbsp;μg/mL in the reperfusion system. The assays were carried out on plasma and bile between&nbsp;0 and 120&nbsp;min after cathinone administration using an targeted and untargeted approaches based on liquid chromatography coupled with high resolution mass spectrometry (Q-Exactive Thermo Scientific®).<br/><b>Results:</b> In plasma, the concentration of 4-Cl-PVP and eutylone decreased rapidly with elimination half-lives of 4&nbsp;min and 0.25&nbsp;min, respectively. Their phase&nbsp;I and phase&nbsp;II metabolites were detected in plasma as early as 1&nbsp;min. In bile, 4-Cl-PVP and eutylone were detected with maximum intensity between&nbsp;0 and 30&nbsp;min post-administration, and the main metabolites found in plasma were found in bile. Phase&nbsp;II derivatives showed increasing biliary excretion over time up to 120&nbsp;min.<br/><b>Conclusion:</b> The pig liver model perfused ex vivo using an NMP represent a promising model in pharmaco-toxicology, particularly for toxicokinetic investigations of cathinones. This model may be of interest in the absence of authentic cases of cathinone consumption or other NPS consumption to identify relevant metabolites consumption markers. In addition, the possibility of collecting bile in this model represents an additional advantage for studying biliary excretion of NPS and their metabolites in forensic toxicology.