| SUBJECT |
"The idea is to assess metabonomics in toxicology at the stage when compounds are being tested in vivo prior to the discovery-development interface. "People are looking for adverse effects to try to minimize attrition in the drug discovery program later on. Once you get a drug into humans, it's very expensive if it fails." The COMET team is performing metabonomic experiments on a range of model compounds with well-known toxic effects. The NMR spectra are being collected in a database that can be interrogated using multivariate statistical models. All animal handling and dosing is done at the pharmaceutical companies, which send samples to the group. "We've spent a long time making sure that the protocols we operate to are uniform across all the companies. "We hammered out all the NMR and data-processing protocols that we do at Imperial College so that they can be transferred back to the companies." That work appears to have paid off. Lindon presented data at the San Francisco meeting showing that COMET has gotten good analytical reproducibility, for instance, when a company prepares a split sample that is analyzed at both Imperial College and the company. In addition, biological variations were small compared with the effects of the toxins. "We could still look at dose response and time responses of toxins, despite the natural biological variation," Lindon said. Over the three-year period, COMET will collect tens of thousands of NMR spectra. "We can have a very good definition of what normality is for rat or mouse urine and blood serum," Lindon said. He told C&EN that there have been some "interesting subtleties" with distinctly nonnormal and bimodal concentration distributions for some metabolites. They are investigating the significance of these findings prior to publication. |
| UPDATE | 12.02 |
| AUTHOR | Imperial College's COMET's Lindon John |
| LITERATURE REF. | This data is not available for free |
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