Determination of Penicillium griseofulvum‐oriented pyripyropene A, a selective inhibitor of acyl‐coenzyme A:cholesterol acyltransferase 2, in mouse plasma using liquid chromatography–tandem mass spectrometry and its application to pharmacokinetic studies

Abstract

In this study, we developed a method for the determination of Penicillium griseofulvum-oriented pyripyropene A (PPPA), a selective inhibitor of acyl-coenzyme A:cholesterol acyltransferase 2, in mouse and human plasma and validated it using liquid chromatography-tandem mass spectrometry. Pyripyropene A (PPPA) and an internal standard, carbamazepine, were separated using a Xterra MS C18 column with a mixture of acetonitrile and 0.1% formic acid as the mobile phase. The ion transitions monitored in positive-ion mode [M + H] + of multiple-reaction monitoring (MRM) were m/z 148.0 from m/z 584.0 for PPPA and m/z 194.0 from m/z 237.0 for the internal standard. The detector response was specific and linear for PPPA at concentrationswithin the range from 1 to 5,000 ng/mL. The intra−/inter-day precision and accuracy of the method was acceptable by the criteria for assay validation. The matrix effects of PPPA ranged from 97.6 to 104.2% and from 93.3 to 105.3% in post-preparative mouse and human plasma samples, respectively. PPPA was also stable under various processing and/or handling conditions. Finally, PPPA concentrations in the mouse plasma samples could be measured after intravenous, intraperitoneal, or oral administration of PPPA, suggesting that the assay is useful for pharmacokinetic studies on mice and applicable to human studies.

Development and validation of an LC-MS/MS method for monitoring larotrectinib, a tropomyosin-related kinase inhibitor, in mouse and human plasma and application to pharmacokinetic studies

“…An IS working solution containing carbamazepine (50 ng/mL) was also prepared in acetonitrile. Carbamazepine was used as an IS in this study because there was no IS candidate available with similar structure to larotrectinib, and the analytic method to the compound was well developed to fit various experimental settings (Lee, Chae et al 2018). Calibration standard samples for larotrectinib were prepared by spiking blank mouse and human plasma with the working standard solutions to reach the final concentrations of 5, 10, 50, 100, 500, 1,000, 5,000, and 10,000 ng/ mL.…”