Abstract
A method for analysis of the four stereoisomers of 1045U85 in rat plasma was developed and validated. The method involved liquid extraction of 1045U85 and an internal standard (propranolol) from plasma, followed by reaction with a chiral derivatizing reagent, GITC. The diastereoisomeric products were then separated by reversed-phase LC. The range of quantitation was 9.828-0.121 μg ml−1 for total 1045U85 (3.440-0.042 μg ml−1 for the RR and SS isomers, and 1.474-0.018 μg ml−1 for the RS and SR isomers). Specificity of the method for 1045U85 was demonstrated using spiked plasma samples as well as plasma samples from dosed animals. Extraction recovery of 1045U85 and propranolol was greater than 95%, and the derivatization reaction was shown to be complete. Accuracy (% bias) ranged from −2.6 to 3.9% for total 1045U85 and from −4.7 to 14.1% for the individual stereoisomers. Precision (% RSD) was 3.8–8.7% for total 1045U85 and 2.9–16.5% for the individual isomers. Plasma samples stored at −70°C were stable for 19 weeks. The method has been used to determine plasma 1045U85 concentrations in nonclinical studies with this compound.
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