Therapeutic Drug Monitoring
April 1, 2002
Thomas Kræmer, Hans H. Maurer
232 citations
Amphetamines and related designer drugs are metabolized primarily by cytochrome P450 enzymes, with many N-alkylated derivatives acting as prodrugs that convert to active amphetamine or methamphetamine. The review covers MDA, MDMA, MDE, BDB, MBDB, and several N-alkylated amphetamines including methamphetamine, benzphetamine, and selegiline. It summarizes findings from English-language publications between 1995 and 2000 on metabolite identification, cytochrome P450-dependent metabolism, and pharmacokinetic or toxicokinetic data. The implications of these toxicokinetic pathways for forensic toxicology and interpretation in legal cases are discussed.
Journal of Mass Spectrometry
June 1, 2003
Frank T. Peters, Simone Schaëfer, Roland F. Staack et al.
171 citations
A method was developed to screen for and simultaneously quantify classical stimulants (amphetamine, methamphetamine, ethylamphetamine, MDA, MDMA, MDEA, BDB, MBDB) and newer designer drugs (4-methylthioamphetamine, p-methoxyamphetamine, p-methoxymethamphetamine, and several piperazine derivatives) along with two metabolites in human blood plasma. The technique uses gas chromatography/mass spectrometry with selected-ion monitoring after solid-phase extraction and derivatization. The method was linear from 5 to 1000 µg/L for all analytes, with a limit of quantification of 5 µg/L. Accuracy and precision met required limits except for MDBP. The assay was validated and applicable for confirming immunoassay results positive for amphetamines or ecstasy-type designer drugs.
Therapeutic Drug Monitoring
March 19, 2004
Hans H. Maurer, Thomas Kræmer, Dietmar Springer et al.
147 citations
Designer drugs such as MDMA, MDEA, MDA, and various piperazine and pyrrolidinophenone compounds, often used as rave drugs, produce euphoria, energy, and sociability. Despite their reputation as safe, studies in rats and primates along with human epidemiological investigations indicate potential risks, including serotonin syndrome, liver toxicity, neurotoxicity, and psychological problems. Metabolites may contribute to some toxic effects, so understanding metabolism is crucial for risk assessment. The enzyme CYP2D6, which is polymorphically expressed, catalyzes the major metabolic steps of piperazine- and pyrrolidinophenone-derived designer drugs, though it remains unclear whether this genetic polymorphism is clinically relevant.
Therapeutic Drug Monitoring
August 1, 1996
Hans H. Maurer
111 citations
Designer drugs of the methylenedioxyphenylalkylamine type, such as MDA, MDMA, MDE, BDB, and MBDB, are increasingly abused. Their metabolism in humans involves two overlapping pathways: O-dealkylation of the methylenedioxy group to dihydroxy derivatives followed by methylation of one hydroxy group, and successive side-chain degradation to N-dealkyl and deaminooxo metabolites. MDA, MDMA, and MDE are further metabolized to glycine conjugates of 3,4-disubstituted benzoic acids. A gas chromatography–mass spectrometry (GC-MS) screening procedure was developed to detect these drugs and their metabolites in urine after acid hydrolysis, isolation at pH 8-9, and acetylation. Using mass chromatography with characteristic fragment ions, the method can detect abuse or intoxication at 5-50 ng/ml.
Pharmacogenomics
February 1, 2011
Markus R. Meyer, Hans H. Maurer
107 citations
The effects of drugs of abuse and other foreign substances depend on an individual's genetic makeup and the specific enzymes that break down those substances. This article summarizes current knowledge about the enzymes—such as cytochrome P450, glucuronyltransferases, esterases, and reductases—involved in metabolizing frequently abused opioids (oxycodone, hydrocodone, methadone, fentanyl, buprenorphine, tramadol, heroin, morphine, codeine), anesthetics (GHB, propofol, ketamine, phencyclidine), cognitive enhancers (methylphenidate, modafinil), plant-derived hallucinogens (LSD, salvinorin A, psilocybin, psilocin), and nicotine. Understanding these metabolic pathways helps predict drug interactions, explain individual differences in drug response, assess toxicity, and improve drug testing interpretation.
Analytical and Bioanalytical Chemistry
June 24, 2015
Achim T. Caspar, Andreas G. Helfer, Julian A. Michely et al.
69 citations
25I-NBOMe, a potent hallucinogenic drug that activates 5-HT2A receptors, is extensively metabolized in rats. After administration to male Wistar rats, 68 metabolites were identified in urine using liquid chromatography-high-resolution tandem mass spectrometry. The main metabolic pathways include O-demethylation, O,O-bis-demethylation, hydroxylation, and combinations, followed by glucuronidation and sulfation. Detection of intake is possible through metabolites using LC-MS methods but not by GC-MS standard urine screening. Initial tests indicate that CYP1A2 and CYP3A4 are involved in hydroxylation, while CYP2C9 and CYP2C19 mediate O-demethylation, suggesting potential drug-drug interactions.
Journal of Analytical Toxicology
November 1, 2003
Frank T. Peters, Nele Samyn, Martin Wahl et al.
65 citations
The pharmacological effects of amphetamine, methamphetamine, MDA, MDMA, and MDEA depend on their mirror-image molecular forms (enantiomers), which differ in how they act in the body. Analysis of plasma from clinical toxicology cases and from drivers suspected of drug impairment showed that concentrations of most enantiomers were lower in routine screening samples than in intoxication or driving-under-the-influence cases. Drivers under the influence had higher levels of both amphetamine enantiomers than intoxicated patients. Differences in the ratio of R to S enantiomers for several drugs between groups suggest these ratios can help distinguish recent from past use. In one MDMA poisoning, the R form cleared more slowly (half-life 6.0 hours) than the S form (4.1 hours), and the ratio of R to S rose over time.
Clinical Chemistry
August 11, 2005
Frank T. Peters, Nele Samyn, C. T. J. Lamers et al.
49 citations
An assay was developed to measure the enantiomers of the designer drugs MDA, MDMA, and MDEA in small plasma volumes (0.2 mL or less). After extraction and derivatization, the enantiomers were separated by gas chromatography and detected by mass spectrometry within 17 minutes. The method was linear for MDA at 1–50 μg/L and for MDMA and MDEA at 5–250 μg/L per enantiomer, with extraction yields of 82.1%–95.3%. Applied to samples from a controlled study after a single 75 mg dose of racemic MDMA, the assay showed that R-(−)-MDMA concentrations significantly exceeded those of S-(+)-MDMA, with ratios always above 1.0 and increasing over time. S-(+)-MDA concentrations exceeded those of R-(−)-MDA, with ratios also increasing but remaining below 1.0.
Journal of Pharmaceutical and Biomedical Analysis
November 27, 2016
Achim T. Caspar, Simon D. Brandt, Andreas E. Stoever et al.
43 citations
25B-NBOMe and 25C-NBOMe, potent 5-HT2A receptor agonists linked to hallucinogenic effects and severe intoxications, are extensively metabolized in rats and humans. Using LC-HR-MS/MS, 66 metabolites were identified for 25B-NBOMe and 69 for 25C-NBOMe, primarily through O-demethylation, O,O-bis-demethylation, hydroxylation, and subsequent glucuronidation and sulfation. After low-dose administration to rats, both substances were detectable mainly via their metabolites using LC-based screening approaches. In an authentic human urine sample from an acute intoxication, 25B-NBOMe and its metabolites were detected by GC-MS as well. Initial screening showed CYP1A2 and CYP3A4 involvement in hydroxylation, and CYP2C9 and CYP2C19 in O-demethylation.
Chemical Research in Toxicology
May 22, 2009
Markus R. Meyer, Hans H. Maurer
39 citations
The designer drugs MDMA, MDEA, and MBDB are chiral compounds whose metabolism is enantioselective, favoring the S-enantiomer. This study investigated whether the elimination of their catecholamine metabolites via O-methylation by catechol-O-methyltransferase (COMT) is also enantioselective. Using human liver cytosol and microsomes, the S-enantiomers of all three catecholamines were preferentially O-methylated by both soluble and membrane-bound COMT. The membrane-bound COMT had 10-fold higher affinity for substrates, while the soluble form had 10-fold higher turnover rate. All tested catechols uncompetitively inhibited dopamine methylation. Enantioselective elimination may contribute to different pharmacokinetic properties of the enantiomers.
Current Neuropharmacology
November 3, 2016
Julian A. Michely, Sascha K. Manier, Achim T. Caspar et al.
36 citations
Two new psychoactive substances, 3-MeO-PCP and 3-MeOPCPy, are metabolized in rat and human liver microsomes through multiple pathways including hydroxylation, O-demethylation, and glucuronidation. Specific cytochrome P450 enzymes (CYP 2B6, 2C19, 2C9, 2D6) catalyze initial metabolic steps. Because only polymorphically expressed enzymes are involved, pharmacogenomic variations may affect metabolism, though clinical data are needed to confirm relevance. Standard urine screening approaches using GC-MS, LC-MSn, and LC-HR-MS/MS can detect intake of both drugs via identified metabolites.
Clinical Chemistry
March 2, 2007
Frank T. Peters, Nele Samyn, Thomas Kræmer et al.
36 citations
A gas chromatography–mass spectrometry method using negative-ion chemical ionization was developed to separately measure the left- and right-handed forms (enantiomers) of amphetamine, methamphetamine, MDA, MDMA, and MDEA in oral fluid. After adding a buffer and a derivatizing agent, the enantiomers were extracted and analyzed. The method was linear from 5–250 μg/L per enantiomer for MDA and from 25–1250 μg/L per enantiomer for the other drugs. Recoveries and precision were acceptable except for MDEA. When applied to samples from a controlled MDMA study and real driving-under-the-influence cases, the oral fluid concentrations and enantiomer ratios did not reliably predict plasma levels.
Clinical Chemistry
October 7, 2011
Andrea E. Schwaninger, Markus R. Meyer, Allan J. Barnes et al.
33 citations
After oral MDMA (ecstasy) intake, human urine contains mostly sulfate and glucuronide conjugates of MDMA metabolites, with sulfates present at higher concentrations than glucuronides. More than 90% of the metabolites DHMA and HMMA were excreted as conjugates. HMMA sulfate had the longest detection window in urine. The ratio of HMMA sulfate to glucuronide was 2.0, and the ratio of DHMA 3-sulfate to 4-sulfate was 5.3 during the first 24 hours, matching predictions from earlier lab experiments. These findings can improve direct urine analysis for MDMA and its metabolites in clinical and forensic toxicology.
Biochemical Pharmacology
September 29, 2011
Andrea E. Schwaninger, Markus R. Meyer, Allan J. Barnes et al.
23 citations
The R- and S-enantiomers of MDMA are eliminated differently in human urine. After controlled oral doses of 1.0 and 1.6 mg/kg, urine from ten participants was analyzed. Over five days, a median of 21% of the measured compounds were excreted as R-stereoisomers and 17% as S-stereoisomers. Significantly more R-enantiomers of MDMA, DHMA, and HMMA sulfate were excreted, while more S-stereoisomers of HMMA and HMMA glucuronide were excreted. No significant differences appeared for MDA and DHMA sulfate. The ratio of R- to S-stereoisomers changed steadily over the first 48 hours, suggesting it could help estimate time of MDMA ingestion in clinical and forensic toxicology.
Analytical and Bioanalytical Chemistry
July 19, 2019
Lea Wagmann, Lilian H. J. Richter, Tobias Kehl et al.
Nine LSD derivatives—ALD-52, 1P-LSD, 1B-LSD, ETH-LAD, 1P-ETH-LAD, AL-LAD, ECPLA, LSZ, and LSM-775—are metabolized in pooled human liver S9 fractions primarily through N-dealkylation and hydroxylation, mainly catalyzed by CYP1A2 and CYP3A4. ALD-52, 1P-LSD, and 1B-LSD undergo deacylation to LSD. Many metabolites are structurally identical, complicating differentiation in urinalysis. However, after administering expected recreational doses to rats, neither parent drugs nor metabolites were detectable in urine using standard screening approaches.