Quantification of 16 QT-prolonging Drugs and Metabolites in Human Postmortem Blood and Cardiac Tissue Using UPLC–MS-MS

Abstract

QT-prolonging compounds present a treatment risk in mentally ill patients. Knowledge of the concentration in the heart compared with blood is necessary to assess the cardiac toxicity of QT-prolonging compounds. To address this issue, this article presents a validated analytical method for the quantification of 16 QT-prolonging drugs (QTD) and metabolites in postmortem whole blood and postmortem cardiac tissue. Samples were prepared by protein precipitation and quantified using ultra-performance liquid chromatography coupled with tandem mass spectrometry. Deuterated internal standards were used. Validation results showed that the bias was ±15% and precision was ≤15% for all compounds in both matrices. The recovery ranged from 78.8 to 127.4%, and the matrix effect ranged from 61.0 to 128.7% across both matrices. The limit of detection and the lower limit of quantification were below the therapeutic concentrations of the prescription drugs. No noteworthy degradation during storage of the extracts was detected. The method was applied in five authentic cases of mentally ill patients. In conclusion, an analytical method was successfully developed and validated for the quantification of QTD in postmortem whole blood and cardiac tissue. To the best of the authors' knowledge, this article presents the first fully validated method for quantification of QTD in cardiac tissue.

A four-compartment PBPK heart model accounting for cardiac metabolism - model development and application

“…At that time point, the ratios of the concentrations in the sites in question to the concentration in venous blood are 2.89 for epicardium, 7.13 for midmyocardium, 13.41 for endocardium, 42.65 for pericardial fluid, and 10.47 for the total heart. All of these values (except for pericardial fluid, which is too high according to postmortem findings34 and pericardial fluid composition is similar to plasma55) are within the range of heart Kp values reported in the forensic and animal studies415657, which supports the feasibility of the model and will be further tested to validate effective concentration surrogates. The disposition within the cardiac wall follows the assumed pattern after a postmortem study by Garcia et al 17…”