Pharmacokinetics of Mephedrone Enantiomers in Whole Blood after a Controlled Intranasal Administration to Healthy Human Volunteers

Abstract

Mephedrone, which is one of the most popular synthetic cathinones, has one chiral centre and thus exists as two enantiomers: R-(+)-mephedrone and S-(−)-mephedrone. There are some preliminary data suggesting that the enantiomers of mephedrone may display enantioselective pharmacokinetics and exhibit different neurological effects. In this study, enantiomers of mephedrone were resolved via chromatographic chiral recognition and the absolute configuration was unambiguously determined by a combination of elution order and chiroptical analysis (i.e., circular dichroism). A chiral liquid chromatography tandem mass spectrometry method was fully validated and was applied to the analysis of whole blood samples collected from a controlled intranasal administration of racemic mephedrone hydrochloride to healthy male volunteers. Both enantiomers showed similar kinetics, however, R-(+)-mephedrone had a greater mean Cmax of 48.5 ± 11.9 ng/mL and a longer mean half-life of 1.92 ± 0.27 h compared with 44.6 ± 11.8 ng/mL and 1.63 ± 0.23 h for S-(−)-mephedrone, respectively. Moreover, R-(+)-mephedrone had a lower mean clearance and roughly 1.3 times greater mean area under the curve than S-(−)-mephedrone. Significant changes in the enantiomeric ratio over time were observed, which suggest that the analytes exhibit enantioselective pharmacokinetics. Even though the clinical significance of this finding is not yet fully understood, the study confirms that the chiral nature, and consequently the enantiomeric purity of mephedrone, can be a crucial consideration when interpreting toxicological results.

Abuse Potential of Cathinones in Humans: A Systematic Review

“…According to the figure showing the time-course of cathinone concentrations in blood, the maximum value of the time-course was approximately 105 ng/mL, and the Tmax was at 1.2 h post-administration. From the accessible full-text articles about experimental studies that were screened four were excluded for only including the pharmacokinetic data regarding the pharma cological effects of cathinone [46], diethylpropion [47], and mephedrone [48,49] withou providing results. Another six studies were excluded since they evaluated pharmaco logical effects that were not related to the abuse potential of cathinone [9,50] or dieth ylpropion [51][52][53][54].…”

“…The most popular mephedrone administration route is insufflation, and few studies have analyzed the pharmacokinetics of mephedrone and its metabolites in human plasma and oral fluid after intranasal administration [48,49,62]. As expected, mephedrone concentrations reached its maximum levels in the blood earlier after the intranasal administration of 100 mg (Tmax of 0.88 ± 0.35 h) [49] compared to the oral administration of the same dose (Tmax of 1 h ranging from 1 to 2 h) in laboratory conditions [60].…”

Excretion of mephedrone and its phase I metabolites in urine after a controlled intranasal administration to healthy human volunteers

“…Ethical approval for the study was obtained from the Riverside National Research Ethics Service (16/LO/1342). Details of the controlled mephedrone administration have been published elsewhere 11,12,14 . In short, occasional users of mephedrone or other stimulant drugs were enrolled into the study.…”

“…Pharmacokinetic (PK) data gained from analysis of whole blood and plasma collected in the same study have been presented previously. 11,12 2 | MATERIALS AND METHODS…”

“…Herein, we report for the first time the results of a study where urine samples were quantitatively analysed for mephedrone and five of its phase I metabolites (Figure 1) after nasal insufflation of 100 mg of pure mephedrone hydrochloride by six volunteers under controlled conditions. Pharmacokinetic (PK) data gained from analysis of whole blood and plasma collected in the same study have been presented previously 11,12 …”