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MET-A-FOR Report Summary

Project ID: 642380
Funded under: H2020-EU.1.3.1.

Periodic Reporting for period 1 - MET-A-FOR (Metabolomic analysis for the forensic detection of drugs of abuse in performance and food producing animals)

Reporting period: 2015-01-01 to 2016-12-31

Summary of the context and overall objectives of the project

Forensic detection of the illicit use of drugs in performance and food-producing animals is experiencing a growing threat in the form of new compounds emerging from human drug development and clinical applications. One such class of compounds are known as Selective Androgen Receptor Modulators (SARMs) which are therapeutic agents with anabolic activity. From a therapeutic perspective SARM-like compounds hold advantages over existing steroids used for the treatment of human conditions as they demonstrate full anabolic activity in target tissues such as bone and muscle but reduced androgenic activity on other organs such as liver, prostate and cardiovascular tissue, thereby eliminating undesirable effects typically associated with conventional anabolic androgenic compounds. The favourable oral bioavailability and short half-life properties of SARM compounds are attributes which make them suitable for use as anabolic agents in animals, potentially illegally in either performance sports or food producing animals. Oral bioavailability facilitates ease of administration to animals whilst a short half-life and rapid metabolism and elimination from the body makes detection analysis extremely challenging. The MET-A-FOR project is focussed on the development and practical advancement of forensic testing for drugs of abuse based on drug metabolite profiling and metabolomics through the completion of interconnecting research projects. Advanced and novel analytical techniques which can identify the misuse of prohibited drugs in bovine and equine animals will be developed, and skilled researchers trained in these innovative tools which will increase monitoring controls for drug misuse helping maintain animal welfare standards within Europe. The project will seek to develop preliminary high-throughput untargeted sample screening methods to identify biological metabolomic / drug metabolite signature profiles indicative of SARM administration, which can be confirmed by targeted analysis of suspect samples.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Work performed on the project to date has assessed the ability of metabolism studies using in vitro incubation methodologies to rapidly predict in vivo metabolism of SARM compounds. The aim of such in vitro approaches is to accurately reflect the metabolite profile of illegally administered drugs in the absence of extensive elimination and pharmacokinetic animal studies and thereby facilitate rapid development of mass spectrometry based methods to more quickly detect new and emerging designer drug abuse as evidence arises that they are being used. This work has prioritised key classes/types of SARM compounds (both from reputable sources but also unverifiable (e.g. web-based) vendors) based on their current availability and those which potentially pose the greatest risk to being used illegally in sport and food animals - work has also examined new SARM compounds emerging from clinical focused pharmaceutical drug development. Liver/microsomal preparations/fractions from different species have been developed and LC-MS analysis undertaken to profile and identify the phase 1 and 2 metabolites produced through in vitro investigations. The ability of in vitro derived SARM metabolite profiles to accurately reflect in vivo metabolism is currently under investigation. High resolution mass spectrometric methods for the untargeted metabolomic profiling of urine/plasma (and tissues) to detect the biological signatures (metabolites) of SARM compound administration have also been established. This work seeks to profile metabolomic responses in animal tissue samples to SARM administration and develop bioinformatical data analysis and multivariate modelling tools which can identify animals exposed to SARMs based on metabolomics analysis. This development of an untargeted biological screening method is complemented by work validating sample extraction and mass spectrometric (UHPLC-MS/MS) methods enabling the targeted quantification of SARM compounds, residues and degradation products in biological matrices including urine and blood.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Current forensic testing approaches to detect both emerging and existing drug abuse are inadequate in many respects with recent high profile examples in athletics and horse racing a clear indication of testing regime failure. Testing is problematical, costly and inefficient, and whilst mass spectrometry analysis has enabled the targeted analysis of samples for the presence of multiple compounds, effective testing still requires prior knowledge on the types of compounds being used. This thereby limits the range of hazardous and illegal chemicals which can be detected and consequently the MET-A-FOR project aims for a major scientific breakthrough towards applying current and emerging technological developments in the field of mass spectrometry and metabolomic profiling to this issue. Using the combined expertise of academic and industrial beneficiaries a unique advance in drug abuse detection in animals will be developed based based on initial indirect screening to identify biological responses in animals to exogenously administered drugs, followed by targeted confirmatory analysis of drug metabolite presence in suspect samples. This approach will facilitate more a comprehensive screening for the abuse/misuse of a vast array of drugs as it will not be solely reliant on the targeted detection of single or selected compounds of abuse, but on the detection of the metabolic effects of these compounds in their totality on animal biological systems. This will enable detection of the use of illegal and health threatening compounds in food producing and performance sport animals irrespective of whether these chemical agents are of known/unknown structure. Advances in this field will ensure that European animals are thoroughly tested for the presence of harmful/illegal substances and that the integrity of our performance sport and food production animals are of the highest level.

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