Toxicokinetics and analytical toxicology of the phenmetrazine-derived new psychoactive substance 3,4-methylenedioxyphenmetrazine studied by means of in vitro systems

Compounds derived from known drugs are usually brought on the new psychoactive substance (NPS) market without any previous toxicological risk assessment. The European Union Drugs Agency issued an EU early notification for 3,4-methylenedioxyphenmetrazine (MDPM) in 2024. It is structurally related to the stimulants amphetamine, 3,4-methylenedioxymethamphetamine (MDMA), and phenmetrazine and expected to have similar effects. So far, no scientific reports are available describing its toxicokinetic and analytical profile. This study aimed to provide such data to allow a thorough risk assessment and to ease its analytical detectability in forensic and clinical toxicology and doping control. Data reported include the in vitro plasma protein binding, the in vitro half-life and in vitro metabolism of MDPM by human liver microsomes and S9 fraction (pHLS9) and by HepaRG cells. A monooxygenase mapping and the in vitro cytochrome P450 inhibition of MDPM was elucidated. Results showed that HepaRG cells and pHLS9 formed the same MDPM metabolites via demethylenation and O-methylation and that MDPM has a low plasma protein binding and is a low-turnover drug. Monooxygenase mapping revealed that the demethylenation was exclusively CYP2D6-mediated. MDPM showed strong inhibition of CYP2D6 and moderate inhibition of CYP1A2 and CYP3A4. Polymorphisms or the simultaneous intake of substances that are also CYP2D6 substrates can have a considerable impact on the toxicity of MDPM. Based on in vitro data, the demethylenyl-methyl metabolite of MDPM and the parent compound are recommended as analytical urine screening targets.