@article {Vevelstaddmd.117.077263, author = {Merete Vevelstad and Elisabeth Leere Oiestad and Elisabeth Nerem and Marianne Arnestad and Inger Lise Bogen}, title = {Studies on para-methoxymethamphetamine (PMMA) metabolite pattern and influence of CYP2D6 genetics in human liver microsomes and authentic samples from fatal PMMA intoxications}, elocation-id = {dmd.117.077263}, year = {2017}, doi = {10.1124/dmd.117.077263}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Para-methoxymethamphetamine (PMMA) has caused numerous fatal poisonings worldwide and appears to be more toxic than other ring-substituted amphetamines. Systemic metabolism is suggested to be important for PMMA neurotoxicity, possibly through activation of minor catechol metabolites to neurotoxic conjugates. The aim of this study was to examine the metabolism of PMMA in humans, and for this purpose we used human liver microsomes (HLM) and blood samples from three cases of fatal PMMA intoxication. We also examined the impact of CYP2D6 genetics on PMMA metabolism using genotyped HLM isolated from CYP2D6 poor, population average and ultrarapid metabolizers. In HLM, PMMA was metabolized mainly to 4-hydroxymethamphetamine (OH-MA), while low concentrations of para-methoxyamphetamine (PMA), 4-hydroxyamphetamine (OH-A), dihydroxymethamphetamine (di-OH-MA) and oxilofrine were formed. The metabolite profile in the fatal PMMA intoxications were in accordance with the HLM study, with OH-MA and PMA being the major metabolites, while OH-A, oxilofrine, HM-MA and HM-A were detected in low concentrations. A significant influence of CYP2D6 genetics on PMMA metabolism in HLM was found. The catechol metabolite di-OH-MA has previously been suggested to be involved in PMMA toxicity. Our studies show that the formation of di-OH-MA from PMMA was 2-7 times lower than from an equimolar dose of the less toxic drug MDMA, and do not support the hypothesis of catechol metabolites as major determinants of fatal PMMA toxicity. Altogether, the present study revealed the metabolite pattern of PMMA in humans and demonstrated a great impact of CYP2D6 genetics on human PMMA metabolism.}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/early/2017/10/04/dmd.117.077263}, eprint = {https://dmd.aspetjournals.org/content/early/2017/10/04/dmd.117.077263.full.pdf}, journal = {Drug Metabolism and Disposition} }