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Forensic Toxicology
Published in: Forensic Toxicology 2/2018

Open Access 01-07-2018 | Original Article

Metabolism of α-PHP and α-PHPP in humans and the effects of alkyl chain lengths on the metabolism of α-pyrrolidinophenone-type designer drugs

Authors: Shuntaro Matsuta, Noriaki Shima, Hidenao Kakehashi, Hiroe Kamata, Shihoko Nakano, Keiko Sasaki, Tooru Kamata, Hiroshi Nishioka, Akihiro Miki, Kei Zaitsu, Hitoshi Tsuchihashi, Munehiro Katagi

Published in: Forensic Toxicology | Issue 2/2018

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Abstract

Purpose

This study aims to investigate the urinary metabolites of two common α-pyrrolidinophenones (PPs), α-pyrrolidinohexiophenone (α-PHP) and α-pyrrolidinoheptanophenone (α-PHPP). This report also aims to discuss the effects of alkyl chain lengths on the metabolism of PPs.

Methods

Urinary metabolites of α-PHP and α-PHPP have been investigated by analyzing urine samples from their users (n = 13 each) by liquid chromatography–high-resolution tandem mass spectrometry using reference standards of the metabolites synthesized in our laboratory.

Results and conclusions

For both drugs, metabolites via reduction of the keto moiety (1-OH metabolites) and via oxidation of the pyrrolidine ring (2″-oxo metabolites) were identified, and those via oxidation of the terminal (ω) or penultimate (ω-1) positions of the alkyl chain were tentatively identified. Quantitative analysis indicated oxidation of the pyrrolidine ring to be the major metabolic pathway for α-PHP (side chain R: hexyl), but ω or ω-1 oxidation was the major metabolic pathway for α-PHPP (R: heptyl). Comparison of their metabolic profiles with those of analogs with a longer or shorter side chain (studied previously for R: butyl, pentyl, and octyl) revealed that the alkyl chain length strongly influences the metabolic pathway. In addition, to the best of our knowledge, this is the first report describing the quantification of metabolites of α-PHP and α-PHPP in authentic urine specimens collected from the users using their reference standards synthesized.
Appendix
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Literature
1.
Baumann MH, Ayestas MA Jr, Partilla JS, Sink JR, Shulgin AT, Daley PF, Brandt SD, Rothman RB, Ruoho AE, Cozzi NV (2012) The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue. Neuropsycopharmacology 37:1192–1203CrossRef
2.
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. Neuropsycopharmacology 38:552–562CrossRef
3.
Kakizaki A, Tanaka S, Numazawa S (2014) New recreational drug 1-phenyl-2-(1-pyrrolidinyl)-1-pentanone (α-PVP) activates central nervous system via dopaminergic neuron. J Toxicol Sci 39:1–6CrossRef
4.
Marusich JA, Antonazzo KR, Willey JL, Blough BE, Partilla JS, Baumann MH (2014) Pharmacology of novel synthesic stimulants structurally related to the “bath salts” constituent 3,4-methylenedioxypyrovalerone (MDPV). Neuropharmacology 87:206–213CrossRefPubMedPubMedCentral
5.
Tsujikawa K, Yamamuro T, Kuwayama K, Kanamori T, Iwata YT, Inoue H (2015) Instability of the hydrochloride salts of cathinone derivatives in air. Forensic Sci Int 248:48–54CrossRefPubMed
6.
Matsuta S, Katagi M, Nishioka H, Kamata H, Sasaki K, Shima N, Kamata T, Miki A, Tatsuno M, Zaitsu K, Tsuboi K, Tsuchihashi H, Suzuki K (2014) Structural characterization of cathinone-type designer drugs by EI mass spectrometry (in Japanese with English abstract). Jpn J Forensic Sci Technol 19:77–89CrossRef
7.
Matsuta S, Kakehashi H, Nakano S, Shima N, Kamata T, Nishioka H, Miki A, Sakamoto Y, Miyagawa H, Kusano M, Zaitsu K, Tsuchihashi H, Katagi M (2017) Comprehensive analysis and structural estimation of synthetic cathinones using GC–MS/MS (in Japanese with English abstract). Jpn J Forensic Sci Technol 22:109–121CrossRef
8.
Concheiro M, Castaneto M, Kronstrand R, Huestis MA (2015) Simultaneous determination of 40 novel psychoactive stimulants in urine by liquid chromatography-high resolution mass spectrometry and library matching. J Chromatogr A 1397:32–42CrossRefPubMedPubMedCentral
9.
Waters B, Ikematsu N, Hara K, Fujii H, Tokuyasu T, Tanaka M, Matsusue A, Kashiwagi M, Kubo S (2016) GC–PCI–MS/MS and LC–ESI–MS/MS databases for the detection of 104 psychotropic compounds (synthetic cannabinoids, synthetic cathinones, phenethylamine derivatives). Leg Med 20:1–7CrossRef
10.
Sugie K, Akutsu M, Saito K (2016) Quantitative analysis of NPS (new psychoactive substance) containing α-PVP by direct analysis in real time (DART)-TOF-MS with micro syringe injection (in Japanese with English abstract). Bunseki Kagaku 65:439–446CrossRef
11.
Matsuta S, Shima N, Kamata H, Kakehashi H, Nakano S, Sasaki K, Kamata T, Nishioka H, Miki A, Katagi M, Zaitsu K, Sato T, Tsuchihashi H, Suzuki K (2015) Metabolism of the designer drug α-pyrrolidinobutiophenone (α-PBP) in humans: identification and quantification of the phase I metabolites in urine. Forensic Sci Int 249:181–188CrossRefPubMed
12.
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 of urinary metabolites. Forensic Toxicol 32:59–67CrossRef
13.
Shima N, Kakehashi H, Matsuta S, Kamata H, Kamata T, Nishioka H, Zaitsu K, Sato T, Miki A, Katagi M, Tsuchihashi H (2015) Urinary excretion and metabolism of the α-pyrrolidinophenone designer drug 1-phenyl-2-(pyrrolidin-1-yl)octan-1-one (PV9) in humans. Forensic Toxicol 33:279–294CrossRef
14.
Tyrkkö E, Pelander A, Ketola RA, Ojanperä I (2013) In silico and in vitro metabolism studies support identification of designer drugs in human urine by liquid chromatography/quadrupole-time-of-flight mass spectrometry. Anal Bioanal Chem 405:6697–6709CrossRefPubMed
15.
Maurer HH, Kraemer T, Springer D, Staack RF (2004) Chemistry, pharmacology, toxicology, and hepatic metabolism of designer drugs of amphetamine (ecstasy), piperazine, and pyrrolidinophenone types: a synopsis. Ther Drug Monit 26:127–131CrossRefPubMed
16.
Chen X (2015) Simultaneous determination of four designer drugs and their major metabolites by liquid chromatography–mass spectrometry. J Chromatogr B 992:1–7CrossRef
17.
Negreira N, Erratico C, Kosjek T, van Nuijs ALN, Heath E, Neels H, Covaci A (2015) In vitro Phase I and Phase II metabolism of α-pyrrolidinovalerone (α-PVP), methylenedioxypyrovalerone (MDPV) and methedrone by human liver microsomes and human liver cytosol. Anal Bioanal Chem 407:5803–5816CrossRefPubMed
18.
Paul M, Bleicher S, Guber S, Ippisch J, Polettini A, Schultis W (2015) Identification of phase I and II metabolites of new designer drug α-pyrrrolidinohexiophenone (α-PHP) in human urine by liquid chromatography quadrupole time-of-flight mass spectrometry (LC–QTOF-MS). J Mass Spectrom 50:1305–1317CrossRefPubMed
19.
Swortwood MJ, Ellefsen KN, Wohlfarth A, Diao X, Concheiro-Guisan M, Kronstrand R, Huestis MA (2016) First metabolic profile of PV8, a novel synthetic cathinone, in human hepatocytes and urine by high-resolution mass spectrometry. Anal Bioanal Chem 408:4845–4856CrossRefPubMed
Metadata
Title
Metabolism of α-PHP and α-PHPP in humans and the effects of alkyl chain lengths on the metabolism of α-pyrrolidinophenone-type designer drugs
Authors
Shuntaro Matsuta
Noriaki Shima
Hidenao Kakehashi
Hiroe Kamata
Shihoko Nakano
Keiko Sasaki
Tooru Kamata
Hiroshi Nishioka
Akihiro Miki
Kei Zaitsu
Hitoshi Tsuchihashi
Munehiro Katagi
Publication date
01-07-2018
Publisher
Springer Japan
Published in
Forensic Toxicology / Issue 2/2018
Print ISSN: 1860-8965
Electronic ISSN: 1860-8973
DOI
https://doi.org/10.1007/s11419-018-0428-7

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