Psychoactive substances as substrates or inhibitors of enzymes in drug metabolism and transport

Abstract

In contrast to therapeutic drugs, drugs of abuse (DOA) are marketed without (pre)clinical studies. In order to expand the knowledge surrounding toxicokinetics of DOA, the affinity and/or inhibition potential of selected DOA towards human metabolic enzymes such as monooxygenases or monoamine oxidases (MAO) and an efflux transporter, the breast cancer resistance protein (BCRP), was investigated using mass spectrometry techniques. FMO3 was identified as main enzyme involved in the N-oxygenation of N,N-diallyltryptamine and methamphetamine. Furthermore, a broad range of alpha-methyltryptamine-derived new psychoactive substances but also phenethylamines of the 2C-series were identified as MAO inhibitors. Finally, the BCRP ATPase was shown to be potently stimulated or inhibited by 3,4-BDB or WIN 55,212-2, respectively, comparable to model substrates or inhibitors.