Effect of Sophocarpine on the Pharmacokinetics of Umbralisib in Rat Plasma Using a Novel UPLC-MS/MS Method

Abstract

Umbralisib is a dual inhibitor of phosphatidylinositol 3-kinase delta (PI3Kδ) and casein kinase 1 epsilon (CK1ε) for treating marginal zone lymphoma (MZL) and follicular lymphoma (FL). This study aimed to develop a fast and stable ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for quantitative analysis of umbralisib in rat plasma and its application for evaluating the effect of sophocarpine on the pharmacokinetics of umbralisib. A direct protein preparation with acetonitrile was used to deal with rat plasma. Umbralisib and duvelisib (internal standard, IS) were isolated on a Waters Acquity UPLC BEH C18 column with mobile phase consisted of acetonitrile and 0.1% formic acid in water. The linear range was from 0.5 to 1,000 ng/ml. Both of the precision (RSD%) and accuracy (RE%) were less than 15% in a permissible range. The mean recovery and matrix effect of umbralisib were 86.3–96.2% and 97.8–112.0%, respectively. When umbralisib was combined with sophocarpine, AUC0→∞ of umbralisib was significantly reduced to 2462.799 ± 535.736 ng/ml•h from 5416.665 ± 1,451.846 ng/ml•h, and Cmax also was markedly diminished. Moreover, CLz/F was increased more than two times. This developed, optimized and technical UPLC-MS/MS method was extremely suitable for detecting the concentrations of umbralisib in rat plasma after an oral administration, and sophocarpine significantly changed the pharmacokinetics of umbralisib in rats. This obvious pharmacokinetic changes indicates that there seems to exist herb-drug interaction between sophocarpine and umbralisib.