The 2,5-dimethoxyamphetamines — a new class of designer drugs : studies on the metabolite identification, toxicological analysis, involvement of cytochrome P450 isoforms in main metabolic steps, and inhibition potentials on cytochrome P450 2D6

摘要

In the presented studies, the metabolism and the toxicological analysis in urine of the amphetamine-derived designer drugs DOB, DOC, DOI, DOM, MDOB and TMA-2 were investigated. Furthermore, CYP isoform dependence of the main metabolic steps and the inhibition potential of the parent drugs on CYP2D6 were elucidated to predict possible drug-drug interactions and influence of genetic polymorphisms. The 2,5-dimethoxyamphetamines were mainly metabolized by O-demethylation in position 2 and 5 of the ring, respectively, and by deamination followed by reduction to the corresponding alcohol. A further metabolic step was the hydroxylation of the side chains. Phase II reactions consisted of partial glucuronidation and/or sulfation. Combinations of these steps could also be detected. The target analytes for the toxicological analysis were the derivatized hydroxy metabolite of DOM or the O-demethyl metabolites of DOB, DOC, DOI, MDOB and TMA-2. CYP2D6 was identified to be the only CYP isoform involved in the main metabolic steps. In addition, the studied drugs act also as inhibitor of CYP2D6. It could be shown, that the mode of inhibition of none of the studied drugs was irreversible, but competitive for all drugs.