title: 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.
authors.affiliation: Section of Forensic Chemistry, Department of Forensic Medicine, Aarhus University, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus, Denmark crmi@forens.au.dk.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Mikkelsen
authors.affiliation: Section of Forensic Chemistry, Department of Forensic Medicine, Aarhus University, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus, Denmark.
authors.forename: Jakob R
authors.initials: JR
authors.lastname: Jornil
authors.affiliation: Section of Forensic Chemistry, Department of Forensic Medicine, Aarhus University, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus, Denmark Department of Clinical Pharmacology, Aarhus University, Wilhelm Meyers Allé 4, DK-8000 Aarhus C, Denmark.
authors.forename: Ljubica V
authors.initials: LV
authors.lastname: Andersen
authors.affiliation: Section of Forensic Pathology, Department of Forensic Medicine, University of Copenhagen, Frederik V's Vej 11, DK-2100 Copenhagen, Denmark.
authors.forename: Jytte
authors.initials: J
authors.lastname: Banner
authors.affiliation: Section of Forensic Chemistry, Department of Forensic Medicine, Aarhus University, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus, Denmark.
authors.forename: Jørgen B
authors.initials: JB
authors.lastname: Hasselstrøm
mesh_terms: D001344:Autopsy; D002138:Calibration; D002851:Chromatography, High Pressure Liquid; D003903:Deuterium; D006801:Humans; D057230:Limit of Detection; D008133:Long QT Syndrome / Q000139:chemically induced*; D009206:Myocardium / Q000737:chemistry*; D011180:Postmortem Changes; D055553:Prescription Drugs / Q000009:adverse effects / Q000032:analysis*; D011786:Quality Control; D012015:Reference Standards; D015203:Reproducibility of Results; D053719:Tandem Mass Spectrometry
chemical_list: D055553:Prescription Drugs; D003903:Deuterium