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.

A review on the pharmacology, pharmacokinetics and toxicity of sophocarpine

“…Currently, there is limited research on the metabolism and transformation of sophocarpine within the body, and further study is necessary to determine its pharmacokinetic characteristics and design different forms of biological preparations to enhance the activity and protective properties of sophocarpine. Additionally, studies have revealed that sophocarpine can alter the pharmacokinetic properties of the antitumor drug umbralisib in mice ( Weng et al, 2022b ), indicating the need for future research on herb-drug interactions involving sophocarpine to improve the concentration of corresponding drugs in the body or to prevent excessive accumulation.…”

“…However, Weng et al reported that co-administration of umbralisib with sophocarpine led to a significant increase in the metabolism of umbralisib in rats, resulting in alterations to the pharmacokinetic parameters of umbralisib. Specifically, there were significant reductions in the area under the curve for plasma concentration from zero to last measurable plasma sample time (AUC 0-t ) and the area under the curve for plasma concentration from zero to infinity (AUC 0-∞ ), as well as significant decreases in C max and T max ( Weng et al, 2022b ). These alterations cannot be attributed to inhibition of CYP3A4 and 2C9 activity, indicating a potential interaction between sophocarpine and umbralisib that warrants further investigation in future studies.…”

Characterization of Human B Cell Hematological Malignancies Using Protein-Based Approaches

“…Finding differentially expressed proteins between FL and MCL [95] MCL Identification of molecular signatures that differentiate MCL from B cells of the different compartments [96] Identification of proteomic biomarkers to distinguish MCL [97] Searching for specific proteomic biomarkers overexpressed in MCL tumor biopsies [98] Identification of tyrosine-phosphorylated proteins [99] Provision of insights into the dynamics of the disease and response to treatment [99] Evaluation of resistance to antinucleoside drugs [100] Discovery of neo-antigen peptides that mediate the killing of autologous lymphoma cells by circulating CD4 T cells [101] Characterization of the action mechanism of the MDM2-antagonist nutlin-3a [102] Discovery of the mechanisms involved in the pathogenesis of ocular adnexa extranodal MZL [103] Identification of biomarkers for the diagnosis of primary Sjögren's syndrome/MALT and prediction of progression [104] Establishment of the role of ID3 in regulating cell proliferation [105] MZL Study of the pharmacokinetics of umbralisib [106] BL Analysis of differentially expressed proteins between endemic and sporadic BL variants and EBV + and EBV − BL cell lines [107] Prediction of MGUS progression for an early diagnosis of MM [108] Analysis of the tumor microenvironment to identify determinants of durable responses to BCMA CAR T therapy [109] Quantification of surface proteins to identify immunotherapy targets and biomarkers associated with resistance and response to treatment [109] MM Identification of cell surface targets for immune-based therapies [110] Flow Cytometry CLL Design of panels for rapid disease diagnosis and progression assessment [111,112] Comparison of residual normal B cell profiles between CLL and MBL [113] B-ALL Evaluation of neuropilin-1/CD304 as minimal residual disease and prognostic marker [114] DLBCL Assessment of the absolute counts of B cells, T cells, and Treg cells for the prognostication of newly diagnosed DLBCL patients [115] Evaluation of the monocytic population distribution as an independent prognostic factor [116] DLBCL & FL Usage of aneuploidy and cell cycle indexing as tools for differentiating between CD10 + DLBCL and FL [117] DLBCL & BL Identification of cell markers to differentiate between BL and CD10 + DLBCL [118] MZL Distinguishing IgG4-related ophthalmic disease, idiopathic orbital inflammatio...…”