Article Figures & Data
Figures
- Fig. 1.
Molecular structure of the ring-substituted amphetamines PMMA, PMA, and MDMA.
- Fig. 2.
Concentration-time profiles of PMMA (A and B) and MDMA (C and D) and their respective major (left) and minor (right) metabolites, in pHLMs, which were incubated with PMMA or MDMA (100 µM) at 37°C for 240 minutes. Each symbol and error bars denote the mean ± S.E.M. of three to four experiments (except for PMMA, 60 minutes; n = 2).
- Fig. 3.
Impact of CYP2D6 genotype on the concentration-time profile of PMMA (A) and the metabolites OH-MA (B), PMA (C), OH-A (D), and di-OH-MA (E), respectively, in HLMs. CYP2D6 UMs, pHLMs, or PM HLMs were incubated with PMMA (100 µM) at 37°C for 240 minutes. Each symbol and error bars denote the mean ± S.E.M. of three to four experiments (except for PMMA, 60 minutes in CYP2D6 PM; n = 2). *P < 0.05; **P < 0.01; ***P < 0.001 compared with pHLMs. †P < 0.05; ††P < 0.01; †††P < 0.001 for UMs compared with PMs.
- Fig. 4.
Impact of CYP2D6 genotype on the concentration-time profile of MDMA (A) and the metabolites MDA (B) and di-OH-MA (C), respectively, in HLMs. CYP2D6 UMs, pHLMs, or PM HLMs were incubated with MDMA (100 µM) at 37°C for 240 minutes. Each symbol and error bars denote the mean ± S.E.M. of n = three experiments. *P < 0.05; **P < 0.01 compared with pHLM. †P < 0.05; ††P < 0.01; †††P < 0.001 for UM compared with PMs.
- Fig. 5.
Proposed pathway for the metabolism of PMMA in humans. The figure is based on the present study in HLMs and in blood samples from fatal PMMA intoxications and on previously published studies in rodents and humans. The major enzymes presumed to be involved in PMMA metabolism are included in cursive. (Maurer et al., 2000a; Easton et al., 2003; Staack et al., 2003, 2004a,b; de la Torre and Farre, 2004; Staack and Maurer, 2005; Kuwayama et al., 2009; Rohanova and Balikova, 2009a,b; Páleníček et al., 2011). di-OH-A, dihydroxyamphetamine, di-OH-MA, dihydroxymethamphetamine; HM-A, 4-hydroxy-3-methoxyamphetamine, HM-MA, 4-hydroxy-3-methoxymethamphetamine; HLM, human liver microsomes; OH-A, 4-hydroxyamphetamine; OH-MA, 4-hydroxymethamphetamine; PMA, para-methoxyamphetamine; PMMA, para-methoxymethamphetamine; SULT, sulfotransferase; UGT, uridine diphosphate glucuronosyltransferase.
Tables
- TABLE 1
Method performance: lower limit of quantification (LLOQ), calibration range, between-assay precision (RSD), and accuracy (bias)
Analyte LLOQ Calibration Range QC Low QC Medium QC High Mean RSD Bias Mean RSD Bias Mean RSD Bias µM µM PMMA 0.025 1–150 2.1 11% 3% 23 20% 13% 100 10% −1% PMA 0.01 0.01–3 0.028 23% −6% 0.71 25% −12% 7.1 20% −12% MDMA 0.05 1–150 4.6 12% 13% 44 15% 9% 111 9% 11% MDA 0.025 0.025–7.5 0.069 19% −6% 1.8 10% −10% 18 22% −10% Methamphetamine 0.05 1–150 4.1 10% 3% 39 12% −2% 101 8% 1% Amphetamine 0.05 0.05–15 0.070 19% −4% 1.8 6% −9% 18 7% −8% OH-MA 0.1 0.1–100 0.13 18% −9% 3.6 13% −9% 37 17% −8% OH-A 0.01 0.01–1.7 0.013 31% −15% 0.41 14% 0% 3.5 17% −15% Di-OH-MA 0.01 0.01–3 0.030 20% 2% 0.79 13% −1% 6.6 14% −17% Oxilofrine 0.01 0.01–1.5 0.015 17% −3% 0.41 12% −2% 2.6 16% −36% HM-MA 0.01 0.01–1.5 0.015 19% −3% 0.40 22% 0% 3.6 13% −11% HM-A 0.005 0.005–0.76 0.0077 19% 10% 0.20 8% 2% 2.0 14% −2% di-OH-MA, 3,4-dihydroxymethamphetamine; HM-A, 4-hydroxy-3-methoxyamphetamine; HM-MA, 4-hydroxy-3-methoxymethamphetamine; OH-A, 4-hydroxyamphetamine; OH-MA, 4-hydroxymethamphetamine.
- TABLE 2
Individual blood concentrations of PMMA and metabolites in three fatal PMMA intoxicationsa
Concentration 1 2 3 Unbound Hydrolyzed Unbound Hydrolyzed Unbound Hydrolyzed µM PMMA 6.9 7.4 26.4 PMA 0.02 0.2 2.5 OH-MA 0 0.09 0.4 2.7 1.9 23.1 OH-A 0 0.03 0 0.05 0.3 1.1 Oxilofrine 0 0 0 0.01 0 0.02 HM-MA 0 0 0 0 0.03 0.3 HM-A 0 0 0 0 0 0.02 aFatal PMMA intoxications in which no methamphetamine, amphetamine, or MDMA was detected in femoral blood since these drugs have several metabolites in common with PMMA. OH-MA, 4-hydroxymethamphetamine; OH-A, 4-hydroxyamphetamine; HM-MA, 4-hydroxy-3-methoxymethamphetamine; HM-A, 4-hydroxy-3-methoxyamphetamine.
Data Supplement
- Supplemental Data -
Supplemental Table 1 - Characteristics of the pooled and the individual donor HLMa
Supplemental Table 2 - Instrumental parameters
Supplemental Table 3 - Extraction recovery and matrix effects of quality control (QC) samples and internal standards (IS) in human liver microsomesa
- Supplemental Data -
In this issue
PMMA Metabolism and CYP2D6 Genetics
