Abstract
A sensitive and selective LC–MS–MS method for the determination of DPC 423 ( I), an antithrombotic agent, is described. This method used a solid-phase extraction from 0.1 ml plasma with an Isolute C 2 cartridge. HPLC separation was carried out on a YMC ODS-AQ C 18 column (50×2 mm) at a flow-rate of 300 μl/min with an analysis time of 5 min. Compounds were eluted using a mobile phase of H 2O/CH 3CN/HCOOH: 66:34:0.1 (v/v/v), pH 4.0. A structural analogue of I was used as the internal standard to account for variations in recovery and instrument response. Mass spectrometric detection was carried out with a PE Sciex API III + triple quadrupole mass spectrometer equipped with a Turbo IonSpray™ source as the LC–MS interface. Good intra-day and inter-day assay precision (<10% CV) and accuracy (<10% difference) were observed over a concentration range of 0.005–2.5 μ M in plasma. The extraction recoveries were approximately 90% and the method was found to be linear for the assay ( r 2>0.999). The method has been successfully applied to discovery and preclinical pharmacokinetic studies, including a dose range-finding study and toxicokinetic exposure studies in rat and dog.
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