The ADME profile of threo-4-methylmethylphenidate (4-Mmph, 4-MeTMP, CAS: 467468-40-2) as new psychoactive substance (NPS): Prediction of absorption, distribution, metabolism and excretion parameters using integrated in silico approach for clinical and forensic purposes

Abstract

Threo-4-methylmethylphenidate (4-Mmph, 4-MeTMP, CAS: 467468-40-2) is a stimulant that could be recognized as a new psychoactive substance. It is a derivative of methylphenidate, which is a medicament for treating attention deficit hyperactivity disorder. This study aims to use integrated in silico methods to predict the absorption, distribution, metabolism, and excretion (ADME) of 4-Mmph for the first time. The absorption potential of 4-Mmph indicates gastrointestinal absorption and potential brain penetration, however that it is neither a substrate nor an inhibitor of P-glycoprotein. The predictions of water solubility show a range of estimates, all indicating high gastrointestinal absorption. However, the Caco-2 permeability data are inconsistent between the methods, necessitating further experimental validation. Metabolism predictions focus on interactions with CYP450 enzymes, showing varied results across different tools. Consistent predictions are seen for CYP2C19 and CYP2C9, with low substrate and inhibitor activity. The predictions of CYP2D6 and CYP3A4 show discrepancies, highlighting the importance of using multiple tools for a complete metabolic profile. Potential phase I and phase II reactions are also indicated within this study. 4-Mmph is not identified as a substrate for the renal organic cation transporter OCT2, implying alternative renal excretion pathways.