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

This study aims to investigate the urinary metabolites of two common alpha-pyrrolidinophenones (PPs), alpha-pyrrolidinohexiophenone (alpha-PHP) and alpha-pyrrolidinoheptanophenone (alpha-PHPP). This report also aims to discuss the effects of alkyl chain lengths on the metabolism of PPs. Urinary metabolites of alpha-PHP and alpha-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. For both drugs, metabolites via reduction of the keto moiety (1-OH metabolites) and via oxidation of the pyrrolidine ring (2aEuro(3)-oxo metabolites) were identified, and those via oxidation of the terminal (omega) or penultimate (omega-1) positions of the alkyl chain were tentatively identified. Quantitative analysis indicated oxidation of the pyrrolidine ring to be the major metabolic pathway for alpha-PHP (side chain R: hexyl), but omega or omega-1 oxidation was the major metabolic pathway for alpha-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 alpha-PHP and alpha-PHPP in authentic urine specimens collected from the users using their reference standards synthesized.