Aberrant biochemical and metabolite signaling plays an important role in the development and progression of diseased tissue. This concept has been studied by the science community for decades. However, with relatively recent advances in analytical technology and bioinformatics as well as the development of the Human Metabolome Database (HMDB), metabolomics has become an invaluable field of research.
At the “International Conference and Exhibition on Metabolomics & Systems Biology” held recently in San Francisco, researchers and industry leaders discussed how the underlying cellular biochemical/metabolite fingerprint in response to a specific disease state, toxin exposure, or pharmaceutical compound is useful in clinical diagnosis and biomarker discovery and in understanding disease development and progression.
Developed by BASF, MetaMap® Tox is a database that helps identify in vivo systemic effects of a tested compound, including targeted organs, mechanism of action, and adverse events. Based on 28-day systemic rat toxicity studies, MetaMap Tox is composed of differential plasma metabolite profiles of rats after exposure to a large variety of chemical toxins and pharmaceutical compounds.
“Using the reference data, we have developed more than 110 patterns of metabolite changes, which are specific and predictive for certain toxicological modes of action,” said Hennicke Kamp, Ph.D., group leader, department of experimental toxicology and ecology at BASF.
With MetaMap Tox, a potential drug candidate can be compared to a similar reference compound using statistical correlation algorithms, which allow for the creation of a toxicity and mechanism of action profile.
“MetaMap Tox, in the context of early pre-clinical safety enablement in pharmaceutical development,” continued Dr. Kamp, has been independently validated “by an industry consortium (Drug Safety Executive Council) of 12 leading biopharmaceutical companies.”
By allowing for quick and accurate decisions on the safety and efficacy of compounds during early and preclinical toxicological studies, this technology may prove invaluable for high-throughput drug candidate screening, added Dr. Kamp. Furthermore, by comparing a lead compound to a variety of molecular derivatives, the rapid identification of the most optimal molecular structure with the best efficacy and safety profiles might be streamlined.
Targeted Tandem Mass Spectrometry
Biocrates Life Sciences focuses on targeted metabolomics, an important approach for the accurate quantification of known metabolites within a biological sample. Originally used for the clinical screening of inherent metabolic disorders from dried blood-spots of newborn children, Biocrates has developed a tandem mass spectrometry (MS/MS) platform, which allows for the identification, quantification, and mapping of more than 800 metabolites to specific cellular pathways.
Based on “flow injection analysis and high-performance liquid chromatography MS/MS,” according to Guido Dallmann, Ph.D., director, customer method development, biomarker and funding, at Biocrates, the MetaDisIDQ® Kit is a new generation “multiparamatic” diagnostic assay designed for the “comprehensive assessment of a person’s metabolic state” and the early determination of pathophysiological events with regards to a specific disease.
With the use of isotopically labeled internal standards, MetaDisIDQ is designed to quantify a diverse range of 181 metabolites involved in major metabolic pathways, from a small amount of human serum (10 µL).
In animal and clinical studies, the value of this kit has been demonstrated with its ability to detect changes in metabolites that are commonly associated with the development of metabolic syndrome, type 2 diabetes, and diabetic nephropathy, according to Dr. Dallmann. Data generated with the MetaDisIDQ kit correlates strongly with routine chemical analyses of common metabolites including glucose and creatinine, he added.
Biocrates has also developed the MS/MS-based AbsoluteIDQ® kits, which are an “easy-to-use” biomarker analysis tool for laboratory research. The kit, which functions on MS machines from a variety of vendors, allows for the quantification of 150-180 metabolites.
The SteroIDQ® kit is a high-throughput standardized MS/MS diagnostic assay, validated in human serum, for the rapid and accurate clinical determination of 16 known steroids. Initially focusing on the analysis of steroid ranges in premenopausal women, for the potential development of optimized hormone replacement therapy, the SteroIDQ Kit is expected to have a wide clinical application, according to the company.