Determination of the chiral isomers of CGS 26214, a synthetic thyromimeticagent, in human plasma using microbore chiral chromatography-tandem mass spectrometry

CGS 26214 is a racemic compound having cholesterol-lowering activity in rat s, dogs, and monkeys. This compound has two equipotent chiral components CG S 28934(-) and CGS 28935(+). An analytical challenge was to develop a sensi tive liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for t he analysis of the chiral components in human plasma following clinical dos es of 1 mg or less. Several issues had to be addressed in order to devise a LC/MS/MS assay for the above compounds. First. the compounds were esters a nd susceptible to hydrolysis under experimental conditions. Second, a lower limit of quantitation (LLOQ) of 0.4 ng/ml was needed. Third, positive elec trospray ionization of CGS 26214 did not yield sufficient sensitivity neede d for the studies in humans. Consequently, LC/MS/MS conditions were optimiz ed for negative ion mode of detection. Fourth, sample preparation steps pro ved to be critical in order to reduce the possibility of microbore chiral-H PLC column (100 x 1.0 mm i.d.) obstruction, chromatographic deterioration, and matrix mediated electrospray ion suppression. Although the present meth od addressed the above challenges, its major drawback was limited sample th roughput capability. Nonetheless, the method was successfully applied to ge nerate plasma concentration-time profiles for human subjects after oral dos es (0.9 mg) of the racemate as well as the optically pure isomers. (C) 2000 Elsevier Science B.V. All rights reserved.