Mephedrone: a single-dose administration study to determine human pharmacokinetics after nasal insufflation and to detect mephedrone and its metabolit
Lead Research Organisation:
King's College London
Department Name: Analytical & Environmental Sciences
Abstract
Mephedrone is the most widely used new psychoactive substance ("legal high") in the UK. It is a synthetic cathinone that was classified in the UK as a Class B drug in 2010.
Despite its popularity there is very little human data on the pharmacokinetics of mephedrone. Most of the available data comes from animal models and biological sample analysis from individuals presenting to hospital with acute mephedrone toxicity.
We plan to conduct a human administration study involving nasal insufflation of 100 mg of pure mephedrone by healthy male volunteers. Conventional samples (blood, urine, hair) as well as alternative biological matrices (oral fluid, breath, dried blood spots, head sweat, fingermark deposit) will be collected at specific time points and analysed for mephedrone and its metabolites. The alternative biological matrices are of interest as they require less stringent storage than blood/urine and can be easier to collect in non-specialist settings like drug treatment centres and in roadside drug testing. Sample preparation and extraction methods will be developed and validated. LC MS/MS will be used to quantify the presence of target analytes.
There has only been one human volunteer study (Papaseit et al.) involving oral mephedrone administration. This study has several limitations: mephedrone was obtained from police seizures and sample purity was not assessed; only blood and urine samples were collected and mephedrone metabolites were not determined; and mephedrone was given orally rather than by nasal insufflation.
The project will benefit our Industrial CASE Partner, Alere Toxicology, as it will enable them to incorporate validated assays into their business. At the same time, the study will better inform doctors in treating patients with mephedrone related problems and will also be of value in evidential analysis. Potential applications include testing of those in custody/prisons, testing related to crime and in workplace/roadside drug testing.
Despite its popularity there is very little human data on the pharmacokinetics of mephedrone. Most of the available data comes from animal models and biological sample analysis from individuals presenting to hospital with acute mephedrone toxicity.
We plan to conduct a human administration study involving nasal insufflation of 100 mg of pure mephedrone by healthy male volunteers. Conventional samples (blood, urine, hair) as well as alternative biological matrices (oral fluid, breath, dried blood spots, head sweat, fingermark deposit) will be collected at specific time points and analysed for mephedrone and its metabolites. The alternative biological matrices are of interest as they require less stringent storage than blood/urine and can be easier to collect in non-specialist settings like drug treatment centres and in roadside drug testing. Sample preparation and extraction methods will be developed and validated. LC MS/MS will be used to quantify the presence of target analytes.
There has only been one human volunteer study (Papaseit et al.) involving oral mephedrone administration. This study has several limitations: mephedrone was obtained from police seizures and sample purity was not assessed; only blood and urine samples were collected and mephedrone metabolites were not determined; and mephedrone was given orally rather than by nasal insufflation.
The project will benefit our Industrial CASE Partner, Alere Toxicology, as it will enable them to incorporate validated assays into their business. At the same time, the study will better inform doctors in treating patients with mephedrone related problems and will also be of value in evidential analysis. Potential applications include testing of those in custody/prisons, testing related to crime and in workplace/roadside drug testing.
People |
ORCID iD |
| Mark Parkin (Primary Supervisor) | |
| Joanna Czerwinska (Student) |
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/M014940/1 | 01/10/2015 | 30/09/2019 | |||
| 1721833 | Studentship | BB/M014940/1 | 01/10/2015 | 30/09/2019 | Joanna Czerwinska |
| Description | All analytes were detected in whole blood and plasma, where 4-CARBOXY reached the highest concentration. The mean Tmax of approximately 55 min for mephedrone corresponded well between whole blood and plasma, 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. Moreover, 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 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. Interestingly, capillary NOR concentrations were 2.42-fold and 1.58-fold higher than the concentrations measured in whole blood and plasma, respectively. 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. |
| Exploitation Route | Low detectability of mephedrone and its metabolites in several biological matrices, such as fingerprint sweat and oral fluid, has been partially attributed to a single and relatively low dose of administered mephedrone. Future research would benefit from conducting a controlled mephedrone administration study with higher and/or repeated doses and larger sample size. The latter would also help minimise inter subject variability which was observed in the study. It has been shown that mephedrone enantiomers exhibit different pharmacokinetic profiles in humans which might be a result of pharmacokinetic processes occurring at different rates during drug absorption, distribution, metabolism or excretion. The mechanism responsible for the difference in concentrations has not been explored and warrants further work. In addition, clinical significance of this finding is not yet fully understood. The next useful step would be to conduct receptor binding assays. Even though mephedrone and its metabolites have been detected and quantified in samples collected from controlled administration studies, more translational research involving the analysis of clinical and forensic samples is needed. To my knowledge only one other study has reported the presence of mephedrone metabolites (DHM, NOR, HYDROXY and 4-CARBOXY) in urine and blood samples collected from road traffic cases. It is especially important to target NOR which has been shown to be an active metabolite able to cross the blood-brain barrier and contribute to the psychostimulant effects of mephedrone. Lastly, metabolites which have demonstrated longer windows of detection should be targeted in clinical and forensic studies where they could be used as markers of mephedrone use. |
| Sectors | Pharmaceuticals and Medical Biotechnology |
| Description | Fingerprint sweat analysis by paper spray |
| Organisation | University of Surrey |
| Department | Department of Chemistry |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Fingerprint sweat samples were collected on triangular pieces of paper during this study. |
| Collaborator Contribution | Fingerprint sweat samples were sent to the University of Surrey for analysis. |
| Impact | Mephedrone and some of its metabolites were detected in some samples. |
| Start Year | 2018 |