Pharmacokinetics of Mephedrone and Its Metabolites in Whole Blood and Plasma after Controlled Intranasal Administration to Healthy Human Volunteers

Abstract

Mephedrone is a popular synthetic cathinone, known for its psychostimulant effects. At present, there is no data available on the pharmacokinetics of mephedrone and its metabolites in concurrently collected whole blood and plasma samples after a controlled intranasal administration to healthy volunteers. In this study, six healthy male volunteers nasally insufflated 100 mg of pure mephedrone hydrochloride (Day 1). Whole blood and plasma samples were collected at different timepoints after the administration and were analysed for the presence of mephedrone and its metabolites, dihydro-mephedrone (DHM), nor-mephedrone (NOR), hydroxytolyl-mephedrone (HYDROXY), 4-carboxy-mephedrone (4-CARBOXY) and dihydro-nor-mephedrone (DHNM), by validated liquid chromatography–tandem mass spectrometry methods. All analytes were detected in whole blood and plasma for 6 h post administration, with mephedrone and NOR also being detectable on Day 2 in some participants. 4-CARBOXY, followed by NOR, were the most abundant metabolites in both matrices. Compared to other psychostimulants, mephedrone showed rapid absorption (mean Tmax of 52.5 ± 20.7 min in plasma and 55.0 ± 18.2 min in whole blood) and elimination (mean t1/2 of 1.98 ± 0.30 h in plasma and 2.12 ± 0.33 h in whole blood). In addition, statistical analysis showed that median whole blood to plasma distribution ratios, reported here for the first time, were statistically different from 1 (unity) for mephedrone (median: 1.11), DHM (median: 1.30) and NOR (median: 0.765). It is hoped that the study will aid forensic and clinical toxicologists in detection, identification and interpretation of cases associated with mephedrone use.

Investigation of Biotransformation Products of p-Methoxymethylamphetamine and Dihydromephedrone in Wastewater by High-Resolution Mass Spectrometry

“…Therefore, mephedrone consumption is possibly overestimated if the in-sewer dynamics and transformation processes are not taken into consideration. TP-164 could be identified as nor-mephedrone, since its characteristics matched in vitro, in vivo [ 15 , 16 , 41 , 50 , 51 ], and in-sewer [ 5 ] studies. However, it could not be confirmed without a commercial reference standard ( Figure 5 ).…”

“…Detection and identification of PMMA and DHM TPs was performed by a post-acquisition approach [ 36 ]. A suspect database of potential TPs was built using two in silico prediction tools, the Eawag-Biocatalysis/Biodegradation Database Pathway Prediction System and the MetabolitePredict software, and a list of reported metabolites and TPs from the literature [ 5 , 15 , 16 , 40 , 41 , 51 , 53 ]. Samples were screened using specific criteria [ 52 ] and an in-house retention time prediction model [ 37 ].…”

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

“…Recently published [11] mean racemic mephedrone concentrations in whole blood were approximately two times higher than the mean concentrations of each individual enantiomer. R-MEPH had more comparable pharmacokinetic parameters to those obtained for racemic mephedrone in whole blood.…”

“…The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Riverside National Research Ethics Service (16/LO/1342). Details of the administration study have been recently published [11]. Briefly, participants enrolled into the study were occasional users of mephedrone or other stimulant drugs, but were drug-free 1 week before the mephedrone administration, which was verified by urine analysis (performed using a validated ultra-high-performance liquid chromatographyhigh-resolution mass spectrometry method).…”

“…In a recently published study describing detection of racemic mephedrone in human whole blood and plasma, mephedrone was detected for 6 h post administration and showed rapid absorption and elimination [11]. Herein, we report the first in-depth investigation of pharmacokinetic profiles of mephedrone enantiomers derived from whole blood analysis following a controlled intranasal administration of 100 mg of pure racemic mephedrone hydrochloride to healthy human volunteers.…”