Abstract
Mephedrone is a synthetic cathinone known for its psychostimulant properties. Despite its ban in the United Kingdom in 2010, mephedrone use in London remains popular and there are reports describing an increasing problem of the drug being injected. Nevertheless, there is little known about the distribution of mephedrone and its metabolites in humans as only two controlled mephedrone administration studies and one dose-finding pilot study have been previously reported. In recent years, there has been a growing interest in the use of alternative biological matrices for determining drug abuse. The collection of these samples is usually non-invasive, fast and cost effective which allows for drug testing in the workplace, by the roadside and in addiction treatment centres.A single dose administration study of 100 mg mephedrone hydrochloride via nasal insufflation to six healthy male volunteers was performed to determine the distribution and pharmacokinetics of mephedrone and its metabolites in conventional (whole blood, plasma, urine) and alternative (oral fluid, fingerprint sweat, dried blood spots, head hair) biological matrices. Samples were collected at different timepoints after mephedrone administration and were analysed for the presence of mephedrone, 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, where 4-CARBOXY reached the highest concentration. The mean Tmax for mephedrone (55.0 ± 18.2 min in whole blood and 52.5 ± 20.7 min in plasma) correlated well between both matrices, indicating rapid absorption of the drug after nasal insufflation. Other analytes had a more delayed Tmax but were all detected up to 6 h in both matrices, with mephedrone also being detectable on Day 2 in one participant in whole blood. Mephedrone had a mean half-life of 2.12 ± 0.33 h and 1.98 ± 0.30 h in whole blood and plasma, respectively. 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). Chiral analysis revealed that R-mephedrone reached higher concentrations than S-mephedrone in whole blood and had comparable pharmacokinetic parameters to total mephedrone. It has been shown that the two enantiomers of mephedrone exhibit different pharmacokinetic profiles in humans, but the clinical significance of this finding is not yet fully understood. In urine, 4-CARBOXY and DHNM were the only metabolites detectable on Day 3, making them promising markers of mephedrone use.
In the alternative biological matrices, mephedrone metabolites were detected for the first-time in head hair one month after mephedrone administration. Calculated NOR:mephedrone and DHNM:mephedrone ratios were 0.19 (n=1) and 0.21 (n=1), respectively. However, sample size was too small to suggest robust metabolite to mephedrone ratios that would differentiate external drug contamination from drug consumption. In fingerprint sweat, mephedrone and NOR were detected above the limit of detection in 62% and 3.8% of all post administration samples, respectively. Inter- and intra-subject variability was observed which can be attributed to the differences in pressure applied during fingerprint deposition, the angle and duration of contact with the deposition surface coupled with an inability to control the ‘amount’ of collected sweat. Given these limitations fingerprint sweat may not be ideal for use in quantitative analysis until practical solutions to these problems are found. In dried blood spots, mephedrone, NOR and 4-CARBOXY were the only analytes detected in the majority of samples. In oral fluid, mephedrone and NOR were detected but their concentrations peaked earlier than in whole blood and plasma which may be due to the contamination of the oral cavity with mephedrone after nasal insufflation.
It is hoped that this work will help with interpreting results and reporting findings from the analysis of conventional and alternative biological matrices following mephedrone use in forensic (drug-related deaths and crime) and clinical (acute drug toxicity and drug dependence) toxicology as well as in the workplace and roadside drug testing.
| Date of Award | 1 Sept 2020 |
|---|---|
| Original language | English |
| Awarding Institution |
|
| Supervisor | Vincenzo Abbate (Supervisor) & Paul I. Dargan (Supervisor) |