ADME profile of AP-238 - opioid designer drug (CAS: 140924-11-4): first application of multi-in silico approach methodology for comprehensive prediction of ADME profile (absorption, distribution, metabolism and excretion) important for clinical toxicology and forensic purposes

Abstract

AP-238 is a recently emerged opioid designer drug from the cinnamylpiperazine class, raising increasing concern in forensic and clinical toxicology due to its potential for abuse and limited ADME (absorption, distribution, metabolism, and excretion) profile. This study presents the first comprehensive prediction of the ADME parameters for AP-238 using a multi-in silico approach. Multiple in silico methods (SwissADME, ACD/Percepta, pkCSM, ADMETlab 3.0, ADMET Predictor 12.0, Simulation Plus, XenoSite, and DruMAP) were employed to estimate key ADME parameters. Results indicate high gastrointestinal absorption and blood-brain barrier permeability, suggesting strong psychoactive potential. AP-238 exhibits pH-dependent solubility and interacts variably with P-glycoprotein, which may affect its systemic and central nervous system exposure. Distribution modeling revealed moderate to extensive tissue penetration and significant plasma protein binding. Metabolic simulations identified 11 primary metabolites and involvement of major CYP isoforms (including CYP2B6, CYP2C19, CYP2D6, CYP3A4). Excretion predictions suggest a rapid elimination primarily via hepatic routes. This study provides critical pharmacokinetic insight into AP-238, supporting its early toxicological assessment and prioritization for further investigation. The applied in silico strategy demonstrates a rapid, ethical alternative to traditional ADME testing, particularly valuable in the context of novel synthetic opioids.