Metabolomics for Drug Discovery

Application of metabolomics in the exploratory stages of drug discovery, particularly in combination with high throughput screening, improves compound/target selection and reduces costs. Lipomic profiling (see Chap. 2) is a particularly powerful tool for drug discovery and target validation because many common disorders such cardiovascular disease, obesity, and diabetes produce changes in lipid metabolism. Throughout the development process, lipomic profiling can be used to evaluate a drug’s effect on metabolic pathways and to quickly identify good drug candidates. A lipomic profile can also eliminate seemingly effective drugs that disturb metabolic pathways to cause adverse effects. Lipomic profiling has the potential to identify toxic effects of drug compounds. Because toxins can alter lipid levels in serum or tissues, assaying for these changes could point out potential pitfalls early in the discovery process.

Biomarkers and Drug Safety Biomarkers of Adverse Drug Reactions

Susceptibility to ADRs varies with genetic make up, age, sex, physiology, exogenous factors, and disease state. The clinical consequences of ADRs range from patient discomfort through serious clinical illness to the occasional fatality. Some facts about ADRs are:

  • • There are 2.2 million hospitalizations due to ADRs per year in the US.
  • • Fatal ADRs are the fourth leading cause of death in the US.
  • • ADRs are a serious problem in infants and children.
  • • ADRs are more frequent in the elderly - the fastest growing segment of the population in the US.
  • • Ethnic group may act as a marker for underlying genetic or environmental differences in the susceptibility to ADRs, e.g., during treatment with angiotensin converting enzymes and thrombolytic drugs.

The problems of ADRs in children is being increasingly recognized, and they differ from adult reactions in frequency, nature, and severity. Infants and young children, when exposed to some drugs such as anticholinergic agents, are more likely than adults to develop ADRs, but may also be less susceptible to toxic reactions to other drugs. ADRs in children caused by drugs of abuse are a major problem in the US. Children may be exposed to these drugs through in utero exposure during pregnancy, through breast feeding, and through exposure during adolescence. These ADRs can include effects on the nervous system, cognitive problems, cardiovascular anomalies, and, in the case of second-hand tobacco smoke, an increased risk for sudden infant death syndrome, acute respiratory infections, asthma, middle-ear disease, and multiple sclerosis in children.

In 2008, the US NIH announced funding to support research that includes use of genomics, proteomics, and transcriptomics technologies in the discovery and identification of toxicity biomarkers; use of metabolomics alone or in combination with other technology to identify and characterize novel toxicity-associated drug metabolites and unraveling of novel ADR mechanisms; genomic studies that may identify animals that develop idiosyncratic reactions similar to humans; using genomics to define patterns of genes association with pediatric ADRs; placental genomics, pro- teomics, and biomarker identification to understand ADRs; the role of epigenetic factors to explain or predict developmental differences in the expression of ADRs; and other studies.

 
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