ADME profile of phencyclidine (PCP) analogues: emerging dissociative hallucinogens 3-MeO-PCP (CAS: 72242-03-6) and 4-MeO-PCP (CAS: 2201-35-6)-a multi-in silico approach for comprehensive prediction of absorption, distribution, metabolism and excretion relevant to clinical and forensic toxicology.

A computational workflow predicted the absorption, distribution, metabolism, and excretion (ADME) profiles of two methoxy-substituted phencyclidine analogues, 3-MeO-PCP and 4-MeO-PCP, for clinical and forensic use. Both analogues are predicted to have high passive permeability, gastrointestinal absorption, and blood-brain barrier access. They are expected to distribute extensively into tissues, with high plasma protein binding (around 70-80%) and large volumes of distribution. Metabolism is primarily by CYP3A4, CYP2D6, and CYP2C19, involving O-demethylation followed by glucuronidation, suggesting potential for drug-drug interactions and genotype effects. 4-MeO-PCP shows a higher theoretical propensity for bioactivation. These predictions guide targeted bioanalysis and matrix selection when in vivo data are limited.

Study at a glance

Abstract

A multi-platform in silico workflow was applied to characterize the ADME profile of the methoxy-substituted phencyclidines 3-MeO-PCP and 4-MeO-PCP for clinical toxicological and forensic use. Predictions from ACD/Percepta, SwissADME, pkCSM, ADMETlab 3.0, DruMAP 2.0 and XenoSite were triangulated under OECD (Q)SAR principles with explicit applicability-domain checks. Both analogues were predicted to exhibit high passive permeability, high gastrointestinal absorption, and blood-brain barrier access. Distribution outputs consistently indicated extensive tissue partitioning, high plasma protein binding (~ 70-80%), and large apparent volumes of distribution. Metabolic liability was assigned primarily to CYP3A4, CYP2D6 and CYP2C19, with early O-demethylation to phenolic metabolites followed by rapid glucuronidation; modelled CYP values support clinically relevant drug-drug interaction and genotype effects. XenoSite suggested a higher theoretical bioactivation propensity for 4-MeO-PCP via arene-oxide/quinone-methide manifolds. Excretion modules predicted renal transporter involvement, while total clearance and half-life estimates showed method-dependent dispersion. The consolidated profile supports targeted bioanalysis (phenolic O-glucuronides; adduct screening in severe cases), informs matrix selection and exposure back-extrapolation, and prioritizes validation studies (recombinant CYP phenotyping, transporter assays, protein/brain binding). The workflow generalizes to related dissociatives and provides a transparent, regulator-aligned template for rapid ADME risk triage when in vivo data are limited.