In vitro Phase I and Phase II metabolism of α-pyrrolidinovalerophenone (α-PVP), methylenedioxypyrovalerone (MDPV) and methedrone by human liver microsomes and human liver cytosol
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The aim of the present study was to identify the in vitro Phase I and Phase II metabolites of three new psychoactive substances: α-pyrrolidinovalerophenone (α-PVP), methylenedioxypyrovalerone (MDPV), and methedrone, using human liver microsomes and human liver cytosol. Accurate-mass spectra of metabolites were obtained using liquid chromatography-quadrupole time-of-flight mass spectrometry. Six Phase I metabolites of α-PVP were identified, which were formed involving reduction, hydroxylation, and pyrrolidine ring opening reactions. The lactam compound was the major metabolite observed for α-PVP. Two glucuronidated metabolites of α-PVP, not reported in previous in vitro studies, were further identified. MDPV was transformed into 10 Phase I metabolites involving reduction, hydroxylation, and loss of the pyrrolidine ring. Also, six glucuronidated and two sulphated metabolites were detected. The major metabolite of MDPV was the catechol metabolite. Methedrone was transformed into five Phase I metabolites, involving N- and O-demethylation, hydroxylation, and reduction of the ketone group. Three metabolites of methedrone are reported for the first time. In addition, the contribution of individual human CYP enzymes in the formation of the detected metabolites was investigated.
KeywordsCathinones Quadrupole time-of-flight mass spectrometry In vitro metabolism MDPV Methedrone α-PVP New psychoactive substances
The authors thank Walid Maho and Steven Andries for technical assistance. This study was financially supported by the EU through the FP7 (2007-2013) project under grant agreement no. 316665 (A-TEAM). N.N. and A.L.N.vN. acknowledge University of Antwerp and FWO Flanders for their respective postdoctoral fellowships.
- 7.Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, Rothman RB, Goldberg SR, Lupica CR, Sitte HH, Brandt SD, Tella SR, Cozzi NV, Schindler CW (2013) Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive “bath salts” products. Neuropsychopharmacology 38:552–562CrossRefGoogle Scholar
- 14.Hasegawa K, Suzuki O, Wurita A, Minakata K, Yamagishi I, Nozawa H, Gonmori K, Watanabe K (2014) Post-mortem distribution of α-pyrrolidinovalerophenone and its metabolite in body fluids and solid tissues in a fatal poisoning case measured by LC-MS/MS with the standard addition method. Forensic Toxicol 32:225–234CrossRefGoogle Scholar
- 20.Strano-Rossi S, Cadwallader AB, de la Torre X, Botrè F (2010) Toxicological determination and in vitro metabolism of the designer drug methylenedioxypyrovalerone (MDPV) by gas chromatography/mass spectrometry and liquid chromatography/quadrupole time-of-flight mass spectrometry. Rapid Commun Mass Spectrom 24:2706–2714CrossRefGoogle Scholar
- 21.Meyer MR, Du P, Schuster F, Maurer HH (2010) Studies on the metabolism of the α-pyrrolidinophenone designer drug methylenedioxy-pyrovalerone (MDPV) in rat and human urine and human liver microsomes using GC-MS and LC-high-resolution MS and its detectability in urine by GC-MS. J Mass Spectrom 45:1426–1442CrossRefGoogle Scholar
- 23.Shima N, Katagi M, Kamata H, Matsuta S, Sasaki K, Kamata T, Nishioka H, Miki A, Tatsuno M, Zaitsu K, Ishii A, Sato T, Tsuchihashi H, Suzuki K (2014) Metabolism of the newly encountered designer drug α- pyrrolidinovalerophenone in humans: identification and quantitation of urinary metabolites. Forensic Toxicol 32:59–67CrossRefGoogle Scholar
- 35.Meyer MR, Wilhelm J, Peters FT, Maurer HH (2010) Beta-keto amphetamines: studies on the metabolism of the designer drug mephedrone and toxicological detection of mephedrone, butylone, and methylone in urine using gas chromatography-mass spectrometry. Anal Bioanal Chem 397:1225–1233CrossRefGoogle Scholar