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

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 a-pyrrolidinovalerophenone and a-pyrrolidinobutiophenone, suggesting that the main metabolic pathways of a-pyrrolidinophenones significantly change depending on the alkyl chain length of the parent molecule.

Identification of phase I and II metabolites of the new designer drug α‐pyrrolidinohexiophenone (α‐PHP) in human urine by liquid chromatography quadrupole time‐of‐flight mass spectrometry (LC‐QTOF‐MS)

“…These two specific mass fragments of dihydro‐ α ‐PHP have already been observed for other dihydro metabolites from pyrrolidinophenones (e.g. α ‐PVP, α ‐PBP and PV‐9) in papers published recently . In all of these publications, the similar specific fragmentation pattern, as observed here for M1, can be deduced for the dihydro metabolites from pyrrolidinophenones.…”

“…Additionally, some of the structures presented here were derived from metabolic profiles of similar pyrrolidinophenones [e.g. α ‐pyrrolidinovalerophenone ( α ‐PVP), α ‐pyrrolidinobutiophenone ( α ‐PBP), MDPV and 1‐phenyl‐2‐(pyrrolidin‐1‐yl)octan‐1‐one (PV9)] already reported in the literature . The extracted ion chromatograms (EICs) with a mass accuracy of +/−10 ppm, MS/MS spectra and the proposed MS/MS fragmentation pathways are given in Figures SI1–59 and Tables SI1 and SI2 in the electronically available Supporting Information.…”

“…Shima et al . monitored it for the dihydro metabolites of α ‐PVP (transitions: [M + H] + at 234 > 216, loss of H 2 O; and [M − H 2 O] + at 216 > 173, loss of a propyl radical) and PV9 (transitions: [M + H] + at 276 > 258, loss of H 2 O; and [M − H 2 O] + at 258 > 173, loss of a hexyl radical), respectively . Matsuta et al .…”

“…Shima et al . published data on urinary metabolites from abusers of pyrrolidinophenones with chemically synthesised standards thereof . Important data on specific fragments and fragmentation reactions of cathinones, including pyrrolidinophenones, by nominal and high‐resolution mass spectrometry (HR‐MS) [i.e.…”

Different in vitro and in vivo tools for elucidating the human metabolism of alpha‐cathinone‐derived drugs of abuse

“…11,[15][16][17][18][19] In addition, the kinetic parameters of CYP isoforms involved in the metabolism were determined for assessing hepatic clearances and to predict possible individual variations in drug elimination or the risk of drug-drug or drug-food interactions. The results were then compared with published results obtained from pHLM, PHH, and authentic human urine samples.…”