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

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.

Chiral Serum Pharmacokinetics of 4-Fluoroamphetamine after Controlled Oral Administration: Can (R)/(S)-Concentration Ratios Help in Interpreting Forensic Cases?

Over the last two decades, misuse of 4-fluoroamphetamine (4-FA) became an emerging issue in many European countries. Stimulating effects last for 4–6 hours and can impact psychomotor performance. The metabolism of amphetamine-type stimulants is stereoselective and quantification of (R)- and (S)-enantiomers has been suggested for assessing time of use. To date, no data on enantioselective pharmacokinetics is available for 4-FA in serum samples. An enantioselective liquid chromatography−tandem mass spectrometry (LC–MS-MS) method was developed using a chiral Phenomenex® Lux 3 μm AMP column. Validation of the method showed satisfactory selectivity, sensitivity, linearity (0.5–250 ng/mL), precision and accuracy. Recreational stimulant users orally ingested two doses (100 mg, n = 12; 150 mg, n = 5) of 4-FA. Blood samples were drawn prior to application and over a period of 12 hours after ingestion and analyzed for 4-FA enantiomers. Peak concentrations and corresponding times did not differ significantly between the enantiomers (mean (R)/(S)-ratio at tmax 1.05, 0.85–1.16). With mean 12.9 (8.3–16.1) hours, apparent elimination half-lives (t1/2) were significantly (P < 0.01) longer for (R)-4-FA than for (S)-4-FA (6.0 hours; range 4.4–10.2 hours) and independent of the dose given. Over time, (R)/(S)-concentration-ratios were linearly increasing in all subjects to maximum ratios of 2.00 (1.08–2.77) in the last samples (after 12 hours). The slopes of the (R)/(S)-ratio exhibited marked interindividual differences (0.023–0.157 h−1, mean 0.095 h−1). Ratios higher than 1.60 only appeared earliest after a minimum of 6 hours and therefore suggest the absence of acute drug effects. Different elimination half-lives of enantiomers lead to constantly increasing (R)/(S)-concentration-ratios. Consequently, ratios of 4-FA enantiomers in serum are a promising indicator for assessment of the time of drug consumption.