GC–MS Quantification Method for Mephedrone in Plasma and Urine: Application to Human Pharmacokinetics

Abstract

Increasing consumption has been observed among young people of new psychoactive substances, including synthetic cathinone derivatives. The most well known of these is mephedrone whose use has been related to acute intoxication and fatality. Several methods able to detect mephedrone have been reported, although to date, none have been applied to human pharmacokinetic studies in a controlled setting. We developed a gas chromatography-mass spectrometry technique for mephedrone quantification in human plasma and urine. Plasma after deproteinization and urine were submitted to a liquid-liquid extraction and derivatization of the extract with MSTFA prior to analysis. Calibration curves covered concentration ranges in plasma between 5 and 300 ng/mL and in urine between 20 and 1,500 ng/mL. The method has been successfully applied to biological samples obtained from a pilot clinical trial intended to evaluate the human pharmacology of mephedrone and its relative bioavailability and pharmacokinetics. Six healthy males were administered 150 mg of mephedrone by the oral route in a randomized, double-blind, cross-over controlled trial. Peak plasma concentration (Cmax = 122.6 ± 32.9 ng/mL) was reached at 1 hour (0.5-2 h) post-drug administration. Mephedrone showed a rapid elimination half-life (t1/2 = 2.2 h) compared to other psychostimulants. Less than 15% of the dose was excreted in urine as a free-form. Mephedrone concentrations displayed a relevant inter-subject variability.

Dose‐Response Pharmacological Study of Mephedrone and Its Metabolites: Pharmacokinetics, Serotoninergic Effects, and Impact of CYP2D6 Genetic Variation

“…The pharmacokinetics of MEPH and its metabolites was investigated after the administration of four different doses (50, 100, 150, and 200 mg). MEPH was rapidly absorbed at all doses, plasma concentrations peaked at around 1 hour post–drug administration, and the elimination process was rapid, in accordance with previous studies . The profile of metabolites recovered in urine was similar for all doses tested.…”

“…MEPH was rapidly absorbed at all doses, plasma concentrations peaked at around 1 hour post-drug administration, and the elimination process was rapid, in accordance with previous studies. 7,17,25 The profile of metabolites recovered in urine was similar for all doses tested. The poor and variable bioavailability of MEPH by the oral route in rats, 9 about six times lower than for MDMA, 9,25 and its normal metabolism 13 partially mediated by CYP2D6 12 are likely contributing to a high inter individual variability in its recovery.…”

HPLC‐MS/MS combined with membrane‐protected molecularly imprinted polymer micro‐solid‐phase extraction for synthetic cathinones monitoring in urine

“…Described sample pre‐treatments for urine consist of conventional liquid–liquid extraction (LLE), dispersive liquid–liquid microextraction (DLLME) and SPE, with and without enzymatic hydrolysis (use of β‐glucuronidase) for total cathinones and free cathinones, respectively; although direct determination after protein precipitation and QuEChERS have also been proposed . Recent proposals also perform direct determination (chromatographic injection) after protein separation by centrifugation, enzymatic hydrolysis and centrifugation, conventional (available commercial cartridges) SPE, and LLE . Finally, solid‐phase microextraction (SPME), and volumetric absorptive microsampling (VAMS) have been also used for cathinones assessment in urine.…”

“…24 Recent proposals also perform direct determination (chromatographic injection) after protein separation by centrifugation, 26-28 enzymatic hydrolysis and centrifugation, 29,30 conventional (available commercial cartridges) SPE, [31][32][33][34][35] and LLE. [36][37][38][39][40][41][42] Finally, solid-phase microextraction (SPME), 43 and volumetric absorptive microsampling (VAMS) 44 have been also used for cathinones assessment in urine. Some of these developments deal with the assessment of a specific synthetic cathinone, such as 3,4-dimethylmethcathinone (3,4-DMMC), 29 4′-methyl-α-pyrrolidinohexanophenone (MPHP), 27 3,4methylenedioxypyrovalerone (MDPV), 41 mephedrone, 42 and metabolic profiles regarding pyrrolidinohexiophenone (α-PHP), 39 1-phenyl-2-(1-pyrrolidinyl)-1-heptanone (PV8), 34 and 1-phenyl-2-(pyrrolidin-1-yl)pentan-1-one (α-PVP).…”

“…[36][37][38][39][40][41][42] Finally, solid-phase microextraction (SPME), 43 and volumetric absorptive microsampling (VAMS) 44 have been also used for cathinones assessment in urine. Some of these developments deal with the assessment of a specific synthetic cathinone, such as 3,4-dimethylmethcathinone (3,4-DMMC), 29 4′-methyl-α-pyrrolidinohexanophenone (MPHP), 27 3,4methylenedioxypyrovalerone (MDPV), 41 mephedrone, 42 and metabolic profiles regarding pyrrolidinohexiophenone (α-PHP), 39 1-phenyl-2-(1-pyrrolidinyl)-1-heptanone (PV8), 34 and 1-phenyl-2-(pyrrolidin-1-yl)pentan-1-one (α-PVP). 40 However, appealing methodologies should be applicable to the simultaneous extraction of synthetic cathinones.…”