|Quantitative drug metabolite profiling without authentic standards or radiolabels using LC-ICP-MS
|Dr Filip Cuyckens
Abstract Information :
Radiotracer technology (14C or 3H) still is the method of choice to study the in vivo disposition of a new drug. Due to its structure independent response and selectivity it enables the quantitative detection of the parent drug and all of its metabolites in verbonden metcomplex matrices and in the absence of authentic standards. There can, however, be ethical reasons or cost concerns that hinder the use of radiotracers, e.g., no radiolabels are usually available in discovery or used in first-in-human studies.
Inductively coupled plasma - mass spectrometry (ICP-MS) allows the detection of elements that are often encountered in drug molecules. Since the intensity of the signal obtained with ICP-MS is also independent of the chemical structure analysed it can be a valuable alternative for radioactive detection.
LC-ICP-MS methods were developed for the accurate quantification of bromine, chlorine and sulphur containing drug molecules and their metabolites. Online isotope dilution, reverse online isotope dilution or a mathematical correction5 were applied to correct for the change in instrumental response inherent to the changing eluent composition during the LC gradient.
The quantitative results obtained by LC-ICP-MS and radio-LC analysis on the same in vivo samples were in very good accordance. The sensitivity of the LC-ICP-MS detection showed to be comparable or better than with radioactive detection. Bromine quantification with LC-ICP-MS on patient samples was used, for the first time ever, as an alternative for a traditional radioactive human ADME study.
Finally, simple derivatization strategies were developed introducing ICP-MS detectable hetero-elements in compounds containing an amine, phenol and/or carboxylic acid moiety, making the analysis and quantification possible of compounds normally not detectable with ICP-MS.