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Anal Bioanal Chem (2015) 407:15451557 DOI 10.1007/s00216-014-8414-3
PAPER IN FOREFRONT
Lefetamine, a controlled drug and pharmaceutical leadof new designer drugs: synthesis, metabolism, and detectability in urine and human liver preparations using GC-MS, LC-MSn,
and LC-high resolution-MS/MS
Carina S. D. Wink & Golo M. J. Meyer & Josef Zapp &
Hans H. Maurer
Received: 20 October 2014 /Revised: 8 December 2014 /Accepted: 13 December 2014 /Published online: 11 January 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract Lefetamine (N,N-dimethyl-1,2-diphenylethylamine, L-SPA) was marketed as an opioid analgesic in Japan and Italy. After being widely abused, it became a controlled substance. It seems to be a pharmaceutical lead for designer drugs because N-ethyl-1,2-diphenylethylamine (NEDPA) and N-iso-propyl-1, 2-diphenylethylamine (NPDPA) were confiscated by the German police. In contrast to these derivatives, metabolism and detectability of lefetamine were not studied yet. Therefore, phase I and II metabolism should be elucidated and correlated to the derivatives. Also the detectability using the authors standard urine screening approaches (SUSA) needed to be checked. As lefetamine was commercially unavailable, it had to be synthesized first. For metabolism studies, a high dose of lefetamine was administered to rats and the urine samples worked up in different ways. Separation and analysis were achieved by gas chromatography-mass spec-trometry (GC-MS) and liquid chromatography-high resolution-tandem mass spectrometry (LC-HR-MS/MS). In accordance with NEPDA and NPDPA, the following metabolic steps could be proposed: N-oxidation, N-dealkylation, mono- and bis-hydroxylation of the benzene ring, and hydroxylation of the phenyl ring only after N-dealkylation. The dihydroxy metabolites were conjugated by methylation of one hydroxy group, and hydroxy metabolites by glucuronidation or sulfation. All initial metabolites could also be detected in human liver preparations. After a therapeutic lefetamine dose,
the bis-nor, bis-nor-hydroxy, nor-hydroxy, nor-di-hydroxy metabolites could be detected using the authors GC-MS SUSA and the nor-hydroxy-glucuronide by the LC-MSn SUSA. Thus, an intake of lefetamine should be detectable in human urine assuming similar pharmacokinetics.
Keywords Drugs of abuse . Lefetamine . Metabolism . GC-MS . LC-HR-MS/MS
Introduction
Lefetamine (N,N-dimethyl-1,2-diphenylethylamine, also named L-SPA) was synthesized as an opioid analgesic in Japan in the 1940s. After introduction in the market, several cases of abuse were reported in the 1950s and 1960s [1]. Nevertheless, it was marketed in Italy in the 1980s, where it was used for surgical or orthopedic...