Applications of new liquid chromatography-tandem mass spectrometry technologies for drug development support

We have evaluated (i) a multiplexed electrospray interface, (ii) serial sample introduction, and (iii) a quadrupole time-of-flight mass spectrometer for quantitative bioanalysis in compliance with good laboratory practice. These evaluations were done using a 96-well plate liquid chromatography-tandem mass spectrometry method for the quantitation of loratadine and its metabolite, descarboethoxyloratadine. The assay has a dynamic range of 1-1000 ng/ml with 5.56 pg of each analyte being injected on-column at the limit of quantitation. For the four-channel multiplexed electrospray experiments, one-run validations were performed simultaneously in rat, rabbit, mouse and dog plasma. In the four-stream serial experiments, the total run time of the assay was reduced from 3.5 to 0.35 min, resulting in a net acquisition time of 11 s. Four simulated validation runs with standard and quality control solutions were analyzed. Precision and accuracy for standards and quality control samples met US Food and Drug Administration recommended criteria for both the drug and the metabolite using those two approaches. In addition, a quadrupole time-of-flight mass spectrometer was used as a detector in the tandem mass spectrometry mode for the loratadine assay. Our results demonstrated that a dynamic range of three orders of magnitude could be achieved using the quadrupole time-of-flight mass spectrometer, making it useful for quantitation in preclinical toxicology studies.