DETERMINATION OF LY355703 IN DOG AND MOUSE PLASMA BY POSITIVE-ION LIQUID-CHROMATOGRAPHY TANDEM MASS-SPECTROMETRY WITH ATMOSPHERIC-PRESSURE CHEMICAL-IONIZATION

A liquid chromatographic/mass spectrometric assay was developed for th e determination of LY355703, a potent anti-tumor drug, in mouse and do g plasma. Empore (3M) C-18 solid-phase extraction cartridges were used for sample preparation in conjunction with a positive pressure manifo ld. Chromatographic separation was obtained with a cyano high-performa nce liquid chromatographic column and detection was conducted using at mospheric pressure chemical ionization tandem mass spectrometry in the selected reaction monitoring mode, A structural analog, compound LY35 4504, was used as the internal standard. The assay was validated for t he determination of LY355703 in mouse (ICR and NuNu) and dog (beagle) plasma. The lower and upper limits of quantitation were 2.1 and 527 ng ml(-1), respectively, using a 0.1 mi plasma aliquot. The signal-to-no ise ratio of a typical 2.1 ng ml(-1) standard was similar to 40:1. The inter-day precision (relative standard deviation) and accuracy (relat ive error) derived from the analysis of validation samples at five con centrations ranged from 2.7 to 7.6% and from 4.8 to 4.5%, respectively . Throughput is approximately one sample every 3 min. This assay is si mple, sensitive, accurate, precise and is being used to support toxico kinetic studies in dog and mouse. (C) 1998 John Wiley & Sons, Ltd.