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This research aims to understand the phase I metabolism of the phencyclidine derivative 3‐Cl‐PCP and its role in a fatal intoxication.

May 26, 2026Drug Testing and Analysis0 citationsOpen Access

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Phase I Metabolism of Novel Phencyclidine Derivative 3‐Cl‐PCP: In Vitro Studies With Pooled Human Liver Microsomes and Investigation of a Post‐Mortem Case

JKJohannes Kutzler TVTobias Veit TKThomas Keller

Key Points

This research aims to understand the phase I metabolism of the phencyclidine derivative 3‐Cl‐PCP and its role in a fatal intoxication.
In vitro studies used pooled human liver microsomes and liquid chromatography–mass spectrometry for analysis.
Postmortem samples were collected from a fatal intoxication case for metabolite quantification.
Metabolites were tentatively identified using liquid chromatography-quadrupole time-of-flight mass spectrometry.
3‐Cl‐PCP concentrations in femoral blood were 830 ng/mL, with 4300 ng/mL in bile and 1200 ng/mL in urine.
Seven phase I metabolites were identified, with extensive glucuronidation of M1–M5 observed in urine.
Unchanged 3‐Cl‐PCP accumulated mainly in bile, emphasizing the need for targeted urine analysis.

Abstract

ABSTRACT Assessing fatalities linked to new psychoactive substances (NPS) often remains challenging. This study investigates a fatal intoxication involving the novel phencyclidine derivative 3‐chloro‐phencyclidine (3‐Cl‐PCP), analyzing its phase I metabolism aided by pooled human liver microsomes (pHLMs) and supported by in silico models. Postmortem samples (bile, urine, cardiac and femoral blood, and gastric contents) and three syringes were collected from a fatal intoxication case. Quantification was performed using liquid chromatography–tandem mass spectrometry (LC–MS/MS). In vitro metabolism studies employed pHLM incubation, with metabolites tentatively identified by liquid chromatography‐quadrupole time‐of‐flight mass spectrometry (LC‐QTOF‐MS). To evaluate phase II metabolism, urine and bile samples were measured with and without β‐glucuronidase treatment. 3‐Cl‐PCP concentrations ranged from 610 ng/mL in cardiac blood to 830 ng/mL in femoral blood. Higher levels were detected in urine (1200 ng/mL) and bile (4300 ng/mL). Seven phase I metabolites were tentatively identified in vitro and postmortem, primarily involving hydroxylation of the cyclohexyl (M1–M3) and piperidine (M4–M5) rings. Additionally, piperidine ring‐opened carboxyl (M6) and ring‐opened alcohol (M7) metabolites were tentatively identified. Post‐enzyme urine analysis revealed extensive glucuronidation of metabolites M1–M5, with M4 (hydroxyl piperidine) showing the highest abundance. Bile showed elevated abundance of unconjugated metabolites, particularly M6. Metabolites M4–M7 were detected in all investigated matrices. Unchanged 3‐Cl‐PCP predominantly accumulated in bile. Urine analysis should prioritize the parent compound along with the metabolites hydroxy cyclohexyl (M3), hydroxy piperidine (M4), and piperidine ring‐opened carboxyl (M6) and should include a prior β‐glucuronidase cleavage step.

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Phase I Metabolism of Novel Phencyclidine Derivative 3‐Cl‐PCP: In Vitro Studies With Pooled Human Liver Microsomes and Investigation of a Post‐Mortem Case

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