A key assumption in pharmaceutical bioanalysis is that spiked standards mimic incurred samples in every analytical aspect. Although deviations from this assumption have been reported in terms of the difference in ion suppression or metabolite interference, the difference of extraction recovery and its impact has been rarely reported and is often characterized as unlikely. In this work, we demonstrated the presence and significance of differential recovery using a real-world example: the assay of bortezomib in whole blood. Recovery differences of up to 10-fold were observed between the spiked standards and the incurred samples when different extraction methods were used. Because of its high impact, it is important that the potential of differential recovery between standards and incurred samples be evaluated during method validation. A simple time course incubation experiment was proposed to screen compounds for potential differential recovery during method validation in heterogeneous matrixes, such as whole blood and tissue. The use of this approach and the interpretation of the results from this experiment were demonstrated using bortezomib in whole blood as an example. The differential recovery of bortezomib is likely to be driven by slow binding to the proteosome present in red blood cells. Spiked samples, however, do not have sufficient time for binding to occur.
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