Czerwinska Joanna, Parkin Mark C, Cilibrizzi Agostino, George Claire, Kicman Andrew T, Dargan Paul I, Abbate Vincenzo
King's Forensics, Department of Analytical, Environmental and Forensic Sciences, King's College London, London SE1 9NH, UK.
Toxicology Department, Eurofins Forensic Services, Teddington TW11 0LY, UK.
Pharmaceuticals (Basel). 2020 Dec 23;14(1):5. doi: 10.3390/ph14010005.
Mephedrone, which is one of the most popular synthetic cathinones, has one chiral centre and thus exists as two enantiomers: -(+)-mephedrone and -(-)-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, -(+)-mephedrone had a greater mean C 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 -(-)-mephedrone, respectively. Moreover, -(+)-mephedrone had a lower mean clearance and roughly 1.3 times greater mean area under the curve than -(-)-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.
4-甲基甲卡西酮是最受欢迎的合成卡西酮之一，它有一个手性中心，因此以两种对映体形式存在：(+)-4-甲基甲卡西酮和(-)-4-甲基甲卡西酮。有一些初步数据表明，4-甲基甲卡西酮的对映体可能表现出对映选择性药代动力学，并产生不同的神经学效应。在本研究中，通过色谱手性识别拆分了4-甲基甲卡西酮的对映体，并结合洗脱顺序和旋光分析（即圆二色性）明确确定了其绝对构型。一种手性液相色谱串联质谱方法得到了充分验证，并应用于分析从健康男性志愿者鼻腔内控制性给予外消旋盐酸4-甲基甲卡西酮后采集的全血样本。两种对映体显示出相似的动力学，然而，(+)-4-甲基甲卡西酮的平均血药浓度更高，为48.5±11.9 ng/mL，平均半衰期更长，为1.92±0.27 h，而(-)-4-甲基甲卡西酮的平均血药浓度分别为44.6±11.8 ng/mL和1.63±0.23 h。此外，(+)-4-甲基甲卡西酮的平均清除率较低，曲线下平均面积比(-)-4-甲基甲卡西酮大约高1.3倍。观察到对映体比例随时间有显著变化，这表明分析物表现出对映选择性药代动力学。尽管这一发现的临床意义尚未完全明确，但该研究证实，在解释毒理学结果时，4-甲基甲卡西酮的手性性质以及因此其对映体纯度可能是一个关键考虑因素。
