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/M S) has been rapidly embraced by the pharmaceutical industry as the def initive method for the determination of drug levels in biological flui ds obtained from pharmacokinetic and toxicological studies, This techn ique has proved to be reliable, accurate and precise for the determina tion of drugs and related substances (e.g. metabolites and isotope-lab eled compounds) in support of preclinical and clinical studies, Our gr oup has recently expanded the use of quantitative LC/MS/MS into the ar ea of discovering new substances as potential drug candidates. When us ed as an accurate mass detector, triple qnadrupole instruments have th e ability to simultaneously and specifically detect minute quantities of closely-related drug substances in the extracts of biological fluid s. Analytical procedures have been developed and validated that simult aneously determine plasma concentrations of up to 12 drug candidates o ver a concentration range of 1-1000 ng mL(-1) in single analytical occ asions. This approach is used to support drug discovery by rapidly pro viding pharmacokinetic data to a wide range of compounds following eit her 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 accept ability of quality control data obtained during such screening experim ents is described. (C) 1997 by John Wiley & Sons, Ltd.