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Metabolite Pattern and Influence of CYP2D6 Genetics in Human Liver Microsomes and Authentic Samples from Fatal PMMA Intoxications S

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Metabolite Pattern and Influence of CYP2D6 Genetics in Human Liver Microsomes and Authentic Samples from Fatal PMMA Intoxications S Supplemental material to this article can be found at: http://dmd.aspetjournals.org/content/suppl/2017/10/04/dmd.117.077263.DC1 1521-009X/45/12/1326–1335$25.00 https://doi.org/10.1124/dmd.117.077263 DRUG METABOLISM AND DISPOSITION Drug Metab Dispos 45:1326–1335, December 2017 Copyright ª 2017 by The American Society for Pharmacology and Experimental Therapeutics Studies on Para-Methoxymethamphetamine (PMMA) Metabolite Pattern and Influence of CYP2D6 Genetics in Human Liver Microsomes and Authentic Samples from Fatal PMMA Intoxications s Merete Vevelstad, Elisabeth Leere Øiestad, Elisabeth Nerem, Marianne Arnestad, and Inger Lise Bogen Department of Forensic Sciences, Oslo University Hospital (M.V., E.L.Ø., E.N., M.A., I.L.B.), and Institute of Clinical Medicine (M.V.), School of Pharmacy (E.L.Ø.), and Institute of Basic Medical Sciences (I.L.B.), University of Oslo, Oslo, Norway Received June 27, 2017; accepted September 29, 2017 ABSTRACT Downloaded from Para-methoxymethamphetamine (PMMA) has caused numer- and oxilofrine were formed. The metabolite profile in the fatal ous fatal poisonings worldwide and appears to be more toxic PMMA intoxications were in accordance with the HLM study, than other ring-substituted amphetamines. Systemic metabo- with OH-MA and PMA being the major metabolites, whereas lism is suggested to be important for PMMA neurotoxicity, OH-A, oxilofrine, HM-MA and HM-A were detected in low possibly through activation of minor catechol metabolites to concentrations. A significant influence of CYP2D6 genetics on neurotoxic conjugates. The aim of this study was to examine the PMMA metabolism in HLMs was found. The catechol metabolite metabolism of PMMA in humans; for this purpose, we used di-OH-MA has previously been suggested to be involved in dmd.aspetjournals.org human liver microsomes (HLMs) and blood samples from three PMMA toxicity. Our studies show that the formation of cases of fatal PMMA intoxication. We also examined the impact di-OH-MA from PMMA was two to seven times lower than of CYP2D6 genetics on PMMA metabolism by using genotyped from an equimolar dose of the less toxic drug MDMA, and HLMs isolated from CYP2D6 poor, population-average, do not support the hypothesis of catechol metabolites as and ultrarapid metabolizers. In HLMs, PMMA was metabo- major determinants of fatal PMMA toxicity. The present study lized mainly to 4-hydroxymethamphetamine (OH-MA), whereas revealed the metabolite pattern of PMMA in humans and low concentrations of para-methoxyamphetamine (PMA), 4-hydroxy- demonstrated a great impact of CYP2D6 genetics on human at ASPET Journals on October 1, 2021 amphetamine (OH-A), dihydroxymethamphetamine (di-OH-MA), PMMA metabolism. Introduction poisonings worldwide (WHO, 2015). In Norway, 27 fatal PMMA-related – Para-methoxymethamphetamine (4-methoxymethamphetamine, PMMA) intoxications were registered in an outbreak during 2010 2012 (Vevelstad is a toxic serotonergic designer drug that is structurally and pharmacologically et al., 2012, 2016b). closely related to para-methoxyamphetamine (4-methoxyamphetamine, The pharmacologic actions of PMMA are mainly related to increased PMA) and MDMA (3,4-methylenedioxymethamphetamine, “ecstasy”) serotonergic and noradrenergic synaptic transmission in the central (Fig. 1). Since the 1990s, PMMA has occasionally appeared on the illicit nervous system (Simmler et al., 2014). PMMA is a potent inhibitor of drug market in many countries as powder or tablets purported to be serotonin and noradrenaline uptake transporters, and it also induces the “ecstasy” or “amphetamine.” PMMA is unpopular among drug users release of serotonin and noradrenalin. At high concentrations, dopami- owing to its mainly unpleasant effects and high toxicity. It is regarded as nergic transport is also affected; however, the potency of PMMA for more toxic than MDMA and methamphetamine, and it has a narrow inhibition of dopamine uptake is low, with a dopamine/serotonin margin of safety (Steele et al., 1992; http://www.emcdda.europa.eu/ inhibition ratio of 0.04 in vitro (Simmler et al., 2014; Liechti, 2015). attachements.cfm/att_33350_EN_Risk33355.pdf). During the last 5 years, Based on previous studies demonstrating the inhibitory activity of PMA PMMAhasbeenassociatedwithatleast131fataland31nonfatal on the degrading enzyme monoamine oxidase A, PMMA is also presumed to exert potent inhibition of this enzyme, a characteristic contributing to drug toxicity (Green and El Hait, 1980; Freezer et al., https://doi.org/10.1124/dmd.117.077263. 2005; Stanley et al., 2007). PMMA toxicity is mainly related to the s This article has supplemental material available at dmd.aspetjournals.org. PMMA dose, and PMMA blood concentrations greater than 2.8 mMare ABBREVIATIONS: 2C-B, 4-bromo-2,5-dimethoxyphenethylamine; COMT, catechol-O-methyl-transferase; di-OH-A, 3,4-dihydroxyamphetamine (dihydroxyamphetamine, a-methyldopamine); di-OH-MA, 3,4-dihydroxymethamphetamine (dihydroxymethamphetamine, N-methyl-a-methyldop- amine); EM, extensive metabolizer; HLM, human liver microsome; HM-A, 4-hydroxy-3-methoxyamphetamine; HM-MA, 4-hydroxy-3-methoxy- methamphetamine; HPLC, high performance liquid chromatography; IS, internal standard; LC-MS, liquid chromatography mass spectrometry; MDA, 3,4-methylenedioxyamphetamine; MDMA, 3,4-methylenedioxymethamphetamine; ME, matrix effect; MQ water, Milli-Q water; NADPH, nicotinamide adenine dinucleotide phosphate; OH-A, 4-hydroxyamphetamine; OH-MA, 4-hydroxymethamphetamine; P450, cytochrome P450); pHLM, pooled human liver microsome; PM, poor metabolizer; PMA, para-methoxyamphetamine (4-methoxyamphetamine); PMMA, para- methoxymethamphetamine (4-methoxymethamphetamine); QC, quality control; SULT, sulfotransferase; UGT, uridine diphosphate glucuronosyl- transferase; UHPLC-MS/MS, ultra-high-performance liquid chromatography-tandem mass spectrometry; UM, ultrarapid metabolizer. 1326 PMMA Metabolism and CYP2D6 Genetics 1327 Perfetti et al., 2009). Di-OH-MA, which is well known as the main intermediate metabolite of MDMA (Segura et al., 2001; de la Torre et al., 2004), is reported to be formed in rats after administration of PMMA (Staack et al., 2003). The high toxicity of PMMA, compared with MDMA, requires additional research on PMMA’s metabolite pattern and pharmacoge- netics in humans. The existing knowledge of the metabolism of PMMA is limited to two microsomal studies (Staack et al., 2004b; Lai et al., 2015) and experimental studies in rats (Staack et al., 2003; Rohanova and Balikova, 2009a,b; Pálenícek et al., 2011). The aim of this study was to examine the metabolism of PMMA in human liver microsomes (HLMs) and in authentic blood samples from fatal PMMA intoxications. We also examined the impact of CYP2D6 genetics on PMMA metab- olism by using genotyped HLMs isolated from CYP2D6 poor metabolizers (PMs) and population-average (pHLMs) and ultrarapid metabolizers (UMs). Downloaded from Materials and Methods Drugs and Chemicals PMMA-hydrochloride was purchased from Cayman Chemicals (Ann Arbour, MI) and MDMA-hydrochloride from Chiron (Trondheim, Norway) and used for incubation solutions. The 13C-labeled internal standards (IS) 13C amphetamine, 13C methamphetamine, 6 6 dmd.aspetjournals.org 13 13 13 13 13 C6 MDMA, C6 MDA, C6 PMMA, C6 PMA, and C6 4-bromo-2,5- 13 dimethoxyphenethylamine ( C6 2C-B) were purchased from Chiron. Stock Fig. 1. Molecular structure of the ring-substituted amphetamines PMMA, PMA, solutions of IS were prepared in methanol, and a mixture of IS was prepared in and MDMA. MQ water in concentrations of 1–5 mM depending on the IS. To make analytical calibrators and quality control (QC) samples, amphetamine was purchased from Sigma-Aldrich (Saint Louis, MO) and Cerillant (Round Rock, considered lethal (Chen et al., 2012; Vevelstad et al., 2012, 2016a; TX); 4-hydroxymethamphetamine (OH-MA) from Sigma-Aldrich; di-OH-MA Kronstrand et al., 2015; WHO, 2015). PMMA toxicity usually manifests from Cayman Chemicals; PMMA, 4-hydroxy-3-methoxyamphetamine (HM-A) at ASPET Journals on October 1, 2021 as serotonin syndrome. Intoxication symptoms range from mild and 4-hydroxy-3-methoxymethamphetamine (HM-MA) from Lipomed (Arlesheim, hyperthermia, neuromuscular hyperactivity and confusion, to fatal Switzerland); methamphetamine and PMA from Cerillant and Lipomed); MDMA hyperthermia, convulsions, coma, respiratory distress, hypoglycemia, from Cerillant and Chiron; 3,4-methylenedioxyamphetamine (MDA) from cardiac arrest, and multiple organ failure (Chen et al., 2012; Vevelstad Cerillant and Alltech (Deerfield, IL); and 4-hydroxyephedrine (oxilofrine) and et al., 2012; Nicol et al., 2015). Fatal PMMA intoxications have also 4-hydroxyamphetamine (OH-A) from the National Measurement Institute (Syd- been associated with PMMA concentrations in the low “recreational ney, NSW, Australia). Formic acid was purchased from VWR (Oslo, Norway). range.” In the Norwegian outbreak of 27 fatal PMMA-related intoxica- NADPH regeneration solution A and B were purchased from Corning BV (Woburn, MA). Liquid chromatography-mass spectrometry (LC-MS)-grade tions, two cases had PMMA blood concentrations of 0.1 and 0.2 mM, methanol was purchased from Sigma-Aldrich and AnalaR ammonium formate respectively, with no other toxicologic contributor to death (Vevelstad from BDH Laboratory Supplies (Poole, England). Deionized water was obtained et al., 2012, 2016a). Similar concentration levels also have been reported from a Milli-Q UF Plus water purification system (Millipore, Bedford, MA). occasionally in other
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