Microbial degradation products of lurasidone and their significance in postmortem toxicology

Jared W. Castle, Danielle M. Butzbach, G. Stewart Walker, Claire E. Lenehan, Frank Reith, Samuel P. Costello, K. Paul Kirkbride

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Abstract

Recent research reported that lurasidone degrades in unpreserved ante-mortem human whole blood inoculated with microorganisms known to dominate postmortem blood specimens. In vitro degradation occurred at a similar rate to risperidone, known to degrade in authentic postmortem specimens until below analytical detection limits. To identify the lurasidone degradation products formed, an Agilent 6520 liquid chromatograph quadrupole-time-of-flight mass spectrometer (LC-QTOF-MS) operating in auto-MS/MS mode was used. Numerous degradation products not previously reported in prior in vitro or in vivo pharmacokinetic studies or forced degradation studies were detected. Accurate mass data, mass fragmentation data, acetylation experiments, and a proposed mechanism of degradation analogous to risperidone supports initial identification of the major degradation product as N-debenzisothiazole-lurasidone (calculated m/z [M + H]+ = 360.2646). A standard was unavailable to conclusively confirm this identification. Retrospective data analysis of postmortem cases involving lurasidone identified the presence of the major degradation product in four of six cases where lurasidone was also detected. This finding is significant for toxicology laboratories screening for this drug in postmortem casework. The major postmortem lurasidone degradation product has consequently been added to the LC-QTOF-MS drug screen at Forensic Science SA (FSSA) to indicate postmortem lurasidone degradation in authentic postmortem blood specimens and as a marker of lurasidone administration in the event lurasidone is degraded to concentrations below detection limits.

Original languageEnglish
Pages (from-to)551-565
Number of pages15
JournalDrug Testing and Analysis
Volume15
Issue number5
Early online date17 Jan 2023
DOIs
Publication statusPublished - May 2023

Keywords

  • LC-QTOF-MS
  • lurasidone
  • postmortem toxicology
  • stability
  • whole blood

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