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01-07-2015 | Original Article

Urinary excretion and metabolism of the α-pyrrolidinophenone designer drug 1-phenyl-2-(pyrrolidin-1-yl)octan-1-one (PV9) in humans

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

Published in: Forensic Toxicology | Issue 2/2015

Abstract

1-Phenyl-2-(pyrrolidin-1-yl)octan-1-one (PV9) and 16 metabolites, including diastereomers and conjugates, were identified or tentatively detected in human urine by gas chromatography–mass spectrometry and liquid chromatography–high-resolution tandem mass spectrometry. These urinary metabolites indicated that the metabolic pathways of PV9 include: (1) the reduction of ketone groups to their corresponding alcohols; (2) oxidation of the pyrrolidine ring to the corresponding pyrrolidone; (3) aliphatic oxidation of the terminal carbon atom to the corresponding carboxylate form, possibly through an alcohol intermediate (not detected); and (4) hydroxylation at the penultimate carbon atom to the corresponding alcohols followed by further oxidation to ketones, and combinations of these steps. In addition, results from the quantitative analyses of five phase-I metabolites using newly synthesized authentic standards suggested that the main metabolic pathway includes the aliphatic oxidation of terminal and/or penultimate carbons. Human metabolism of PV9 differed significantly from those of α-pyrrolidinovalerophenone and α-pyrrolidinobutiophenone, suggesting that the main metabolic pathways of α-pyrrolidinophenones significantly change depending on the alkyl chain length of the parent molecule.

Valente MJ, Guedes de Pinho P, de Lourdes Bastos M, Carvalho F, Carvalho M (2014) Khat and synthetic cathinones: a review. Arch Toxicol 88:15–45PubMedCrossRef

Paillet-Loilier M, Cesbron A, Le Boisselier R, Bourgine J, Debruyne D (2014) Emerging drugs of abuse: current perspectives on substituted cathinones. Subst Abuse Rehabil 5:37–52PubMedCentralPubMed

Cottencin O, Rolland B, Karila L (2014) New designer drugs (synthetic cannabinoids and synthetic cathinones): review of literature. Curr Pharm Des 20:4106–4111PubMedCrossRef

Uchiyama N, Shimokawa Y, Kawamura M, Kikura-Hanajiri R, Hakamatsuka T (2014) Chemical analysis of a benzofuran derivative, 2-(2-ethylaminopropyl)benzofuran (2-EAPB), eight synthetic cannabinoids, five cathinone derivatives, and five other designer drugs newly detected in illegal products. Forensic Toxicol 32:266–281CrossRef

Jane MP, Lewis SN (2012) The toxicology of bath salts: a review of synthetic cathinones. J Med Toxicol 8:33–42CrossRef

Wyman JF, Lavins ES, Engelhart D, Armstrong EJ, Snell KD, Boggs PD, Taylor SM, Norris RN, Miller FP (2013) Postmortem tissue distribution of MDPV following lethal intoxication by “bath salts”. J Anal Toxicol 37:182–185PubMedCrossRef

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 45:1426–1442PubMedCrossRef

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 32:59–67CrossRef

Tyrkkö E, Pelander A, Ketola R, 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 405:6697–6709PubMedCrossRef

10.

Hasegawa K, Suzuki O, Wurita A, Minakata K, Yamagishi I, Nozawa H, Gonmori K, Watanabe K (2014) Postmortem 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 32:225–234CrossRef

11.

Sauer S, Peters FT, Haas C, Meyer MR, Fritschi G, Maurer HH (2009) New designer drug α-pyrrolidinovalerophenone (PVP): studies on its metabolism and toxicological detection in rat urine using gas chromatographic/mass spectrometric techniques. J Mass Spectrom 44:952–964PubMedCrossRef

12.

Saito T, Namera A, Osawa M, Aoki H, Inokuchi S (2013) SPME–GC–MS analysis of α-pyrrolidinovalerophenone in blood in a fatal poisoning case. Forensic Toxicol 31:328–332CrossRef

13.

Namera A, Konuma K, Kawamura M, Saito T, Nakamoto A, Yahata M, Ohta S, Miyazaki S, Shiraishi H, Nagao M (2014) Time-course profile of urinary excretion of intravenously administered α-pyrrolidinovalerophenone and α-pyrrolidinobutiophenone in a human. Forensic Toxicol 32:68–74CrossRef

14.

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 249:181–188PubMedCrossRef

15.

Namera A, Urabe S, Saito T, Torikoshi-Hatano A, Shiraishi H, Arima Y, Nagao M (2013) A fatal case of 3,4-methylenedioxypyrovalerone poisoning: coexistence of α-pyrrolidinobutiophenone and α-pyrrolidinovalerophenone in blood and/or hair. Forensic Toxicol 31:338–343CrossRef

16.

Sauer C, Hoffmann K, Schimmel U, Peters FT (2011) Acute poisoning involving the pyrrolidinophenone-type designer drug 4′-methyl-alpha-pyrrolidinohexanophenone (MPHP). Forensic Sci Int 208:20–25CrossRef

17.

Westphal F, Junge T, Rösner P, Fritschi G, Klein B, Girreser U (2007) Mass spectral and NMR spectral data of two new designer drugs with an alpha-aminophenone structure: 4′-methyl-alpha-pyrrolidinohexanophenone and 4′-methyl-alpha-pyrrolidinobutyrophenone. Forensic Sci Int 169:32–42PubMedCrossRef

18.

Meyer MR, Mauer S, Meyer GM, Dinger J, Klein B, Westphal F, Maurer HH (2014) The in vivo and in vitro metabolism and the detectability in urine of 3′,4′-methylenedioxy-alpha-pyrrolidinobutyrophenone (MDPBP), a new pyrrolidinophenone-type designer drug, studied by GC–MS and LC–MS(n.). Drug Test Anal 6:746–756PubMedCrossRef

19.

Hasegawa K, Wurita A, Minakata K, Gonmori K, Nozawa H, Yamagishi I, Suzuki O, Watanabe K (2014) Identification and quantitation of a new cathinone designer drug PV9 in an “aroma liquid” product, antemortem whole blood and urine specimens, and a postmortem whole blood specimen in a fatal poisoning case. Forensic Toxicol 32:243–250CrossRef

20.

Hasegawa K, Wurita A, Minakata K, Gonmori K, Nozawa H, Yamagishi I, Watanabe K, Suzuki O (2015) Postmortem distribution of PV9, a new cathinone derivative, in human solid tissues in a fatal poisoning case. Forensic Toxicol 33:141–147CrossRef

21.

Iversen L, White M, Treble R (2014) Designer psychostimulants: pharmacology and differences. Neuropharmacology 87:59–65PubMedCrossRef

22.

Zaitsu K, Katagi M, Tsuchihashi H, Ishii A (2014) Recently abused synthetic cathinones, α-pyrrolidinophenone derivatives: a review of their pharmacology, acute toxicity, and metabolism. Forensic Toxicol 32:1–8CrossRef

23.

Marusich JA, Antonazzo KR, Wiley JL, Blough BE, Partilla JS, Baumann MH (2014) Pharmacology of novel synthetic stimulants structurally related to the “bath salts” constituent 3,4-methylenedioxypyrovalerone (MDPV). Neuropharmacology 87:206–213PubMedCrossRef

24.

Kaizaki A, Tanaka S, Numazawa S (2014) New recreational drug 1-phenyl-2-(1-pyrrolidinyl)-1-pentanone (alpha-PVP) activates central nervous system via dopaminergic neuron. J Toxicol Sci 39:1–6PubMedCrossRef

25.

Simmler LD, Buser TA, Donzelli M, Schramm Y, Dieu LH, Huwyler J, Chaboz S, Hoener MC, Liechti ME (2013) Pharmacological characterization of designer cathinones in vitro. Br J Pharmacol 168:458–470PubMedCentralPubMedCrossRef

26.

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 38:552–562PubMedCentralPubMedCrossRef

27.

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 24:2706–2714PubMedCrossRef

28.

Springer D, Fritschi G, Maurer HH (2003) Metabolism of the new designer drug α-pyrrolidinopropiophenone (PPP) and the toxicological detection of PPP and 4-methyl-α-pyrrolidinopropiophenone (MPPP) studied in rat urine using gas chromatography mass spectrometry. J Chromatogr B 796:253–266CrossRef

29.

Shin H-S, Shin Y-SO, Lee S, Park B-B (1996) Detection and identification of pyrovalerone and its hydroxylated metabolite in the rat. J Anal Toxicol 20:568–572PubMedCrossRef

30.

Minakata K, Yamagishi I, Nozawa H, Hasegawa K, Wurita A, Gonmori K, Suzuki M, Watanabe K, Suzuki O (2015) Determination of new pyrrolidino cathinone derivatives, PVT, F-PVP, MPHP, PV8, PV9 and F-PV9, in human blood by MALDI-Q-TOF mass spectrometry. Forensic Toxicol 33:148–154CrossRef

31.

Shima N, Katagi M, Kamata H, Matsuta S, Nakanishi K, Zaitsu K, Kamata T, Nishioka H, Miki A, Tatsuno M, Sato T, Tsuchihashi H, Suzuki K (2013) Urinary excretion and metabolism of the newly encountered designer drug 3,4-dimethylmethcathinone in humans. Forensic Toxicol 31:101–112CrossRef

32.

Zaitsu K, Katagi M, Kamata HT, Kamata T, Shima N, Miki A, Tsuchihashi H, Mori Y (2009) Determination of the metabolites of the new designer drugs bk-MBDB and bk-MDEA in human urine. Forensic Sci Int 188:131–139PubMedCrossRef

33.

Kamata HT, Shima N, Zaitsu K, Kamata T, Miki A, Nishikawa M, Katagi M, Tsuchihashi H (2006) Metabolism of the recently encountered designer drug, methylone, in humans and rats. Xenobiotica 36:709–723PubMedCrossRef

34.

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 397:1225–1233PubMedCrossRef

Title: Urinary excretion and metabolism of the α-pyrrolidinophenone designer drug 1-phenyl-2-(pyrrolidin-1-yl)octan-1-one (PV9) in humans
Authors: Noriaki Shima
Hidenao Kakehashi
Shuntaro Matsuta
Hiroe Kamata
Shihoko Nakano
Keiko Sasaki
Tooru Kamata
Hiroshi Nishioka
Kei Zaitsu
Takako Sato
Akihiro Miki
Munehiro Katagi
Hitoshi Tsuchihashi
Publication date: 01-07-2015
Publisher: Springer Japan
Published in: Forensic Toxicology / Issue 2/2015
Print ISSN: 1860-8965
Electronic ISSN: 1860-8973
DOI: https://doi.org/10.1007/s11419-015-0274-9

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Urinary excretion and metabolism of the α-pyrrolidinophenone designer drug 1-phenyl-2-(pyrrolidin-1-yl)octan-1-one (PV9) in humans

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