LAUSR

BACKGROUND Aprepitant, an antiemetic selective neurokinin-1 receptor antagonist, is primarily metabolized to the active N-dealkylated (ND-AP) form and then converted to its carbonyl (ND-CAP) form in humans. This study developed simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods using electrospray ionization (ESI) for the quantitation of plasma total and free aprepitant and its N-dealkylated metabolites and used them to analyze patient plasma. METHODS Free aprepitant and ND-AP in plasma were fractionated using centrifugal ultrafiltration. The analytes in plasma or their ultrafiltered specimens treated with triethylamine/acetonitrile were isocratically separated using a 3-μm octadecylsilyl column with a total run time of 10 minutes and scanned using positive ion ESI. RESULTS The calibration curves of total aprepitant, ND-AP, and ND-CAP were prepared at concentration ranges of 50-2500, 20-1000, and 5-250 ng/mL, respectively, while that of free aprepitant and ND-AP was at a concentration range of 2-150 ng/mL. The intra- and inter-assay accuracy and imprecision values were 93.5-107.7% and 94.6-103.3%, and 2.1-7.5% and 1.0-8.9%, respectively. Aprepitant and its metabolites did not exhibit any matrix effects or instabilities in the plasma specimens. In cancer patients receiving oral aprepitant, the plasma concentration ranges of total aprepitant, ND-AP, and ND-CAP, and free aprepitant and ND-AP were 137-2170, 104-928, 22.4-97.6, 8.11-60.0, and 3.53-56.0 ng/mL, respectively. The median plasma free fraction proportion of aprepitant and ND-AP were 4.14% and 4.90%, respectively. CONCLUSIONS The present developed method showed an acceptable analytical performance and can be used to evaluate total and free aprepitant and its N-dealkylated metabolites in patient plasma.