The simultaneous determination of mixtures of drug candidates by liquid chromatography/atmospheric pressure chemical ionization mass spectrometry as an in vivo drug screening procedure.

Liquid chromatography, combined with tandem mass spectrometry (LC/MS/MS) has been rapidly embraced by the pharmaceutical industry as the definitive method for the determination of drug levels in biological fluids obtained from pharmacokinetic and toxicological studies. This technique has proved to be reliable, accurate and precise for the determination of drugs and related substances (e.g. metabolites and isotope-labeled compounds) in support of preclinical and clinical studies. Our group has recently expanded the use of quantitative LC/MS/MS into the area of discovering new substances as potential drug candidates. When used as an accurate mass detector, triple quadrupole instruments have the ability to simultaneously and specifically detect minute quantities of closely-related drug substances in the extracts of biological fluids. Analytical procedures have been developed and validated that simultaneously determine plasma concentrations of up to 12 drug candidates over a concentration range of 1-1000 ng mL-1 in single analytical occasions. This approach is used to support drug discovery by rapidly providing pharmacokinetic data to a wide range of compounds following either the administration of multiple compounds to single animals, or by increasing the speed and efficiency of analyzing samples following the administration of single compounds to multiple animals. Currently, we have screened over 400 compounds in two different target classes in a period of 24 weeks. A standard operating procedure defining the acceptability of quality control data obtained during such screening experiments is described.