Application of inductively coupled plasma mass spectrometry in drug metabolism studies

Abstract

In the discovery of new drug candidates, profiling and quantification of drug metabolites are of key importance. These tasks are usually performed by radiochemical detection as this detection technique is structure independent. However, this requires the time-consuming and expensive synthesis of radiolabelled drug candidates. ICP-MS has been used as an alternative detector in a variety of drug metabolism studies. The studies are limited to drugs containing metals (Pt, Au, Ru), halogens (I, Br, Cl) and sulfur. Metabolite profiling involves gradient elution HPLC, introducing large amounts of organic solvents to the plasma. Different solutions to this problem have been reviewed, including the use of flow splitting, cooled spray chambers, oxygen addition, small-bore chromatographic columns with low flow nebulisers and desolvation units. The problem of varying sensitivity with increasing amounts of solvent during gradient elution has been addressed as well. So far, ICP-MS detection has been demonstrated to be a valuable alternative to radiochemical detection in metabolite profiling, owing to its higher sensitivity allowing the detection of minor metabolites. Furthermore, the technique has proven to be complementary to radiochemical detection and ESI-MS, as metabolites that have lost the radioactive label or are poorly ionised in ESI-MS can be detected. Considerations regarding endogenous compounds containing the monitored element have only been addressed in a few quantitative studies and mass balance calculations have only been demonstrated to be useful in a single study on an iodine-containing drug. Although ICP-MS is a more selective detector than UV and ESI-MS detectors, and in several studies has proven to be a valuable detector, the technique will probably only be complementary in metabolism studies as only a minority of drugs contain hetero-atoms that are detectable with ICP-MS.