SOFT 2004 Meeting Abstracts - Society of Forensic Toxicologists

P3
POSTMORTEM REDISTRIBUTION OF THE ENANTIOMERS OF CITALOPRAM AND ITS
METABOLITES IN A RAT MODEL
Kugelberg FC i ', Kingback M i , Carlsson B i , Druid H2
iDepartment of Clinical Pharmacology, Linkoping University, SE-581 85 Linkoping, Sweden
2Department of Forensic Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden
Enantioselective drug analysis is used to study the variation in the disposition of the enantiomers of
racemic drugs. This type of analysis may give additional information in interpreting forensic toxicological
results, provided that the postmortem redistribution is of the same magnitude for the enantiomers. One
example of a racemic drug is the widely used antidepressant citalopram (CIT) that belongs to the selective
serotonin reuptake inhibitors (SSRIs). Different therapeutic properties have been shown for the CIT
enantiomers, and the S-(+)-enantiomer is responsible for the clinically relevant effects. Recent data indicate
that the R-(-)-enantiomer instead counteracts the SSRI effect that is produced by the S-(+)-enantiomer. The
major CIT metabolites, demethylcitalopram (DCIT) and didemethylcitalopram (DDCIT), are less potent
than the parent compound with regard to SSRI properties. In recent years, several reports on CIT
concentrations in human postmortem cases have become available. However, only limited data are
available describing postmortem concentrations of the separate enantiomers of CIT and metabolites. There
is a general awareness that the concentration of a drug in an autopsy blood sample may not necessarily
reflect the in vivo concentration just before death, and this difference is explained by postmortem drug
redistribution. Thus, in order to accurlltely interpret the postmortem concentrations of CIT a general
understanding of the changes in the enantiomer concentrations after death is required. Hence, the aim of the
present study was to investigate if postmortem redistribution of the enantiomers of CIT, DCIT .and DDCIT
occurs in an experimental rat model after three different dosing procedures with racemic CIT. Two rat
groups underwent chronic administration (20 mglkg daily) using subcutaneously (s.c.) implanted osmotic
pumps. After 10 days, one of these groups received an acute-on-chronic drug challenge by a single s.c.
injection of 100 mg/kg. The third group received the single 100 mg/kg dose only. Heart blood and brain
samples were collected antemortem and 1,3 or 24 h postmortem after storage in room temperature. In an
additional experiment, we examined the role of the lungs as a reservoir of postmortem drug release and if
the early-phase postmortem redistribution was different in room temperature (21°C) as compared with a
cold environment (4°C). The samples were analyzed with an enantioselective HPLC method with
fluorescence detection. Increased postmortem blood drug and metabolite concentrations compared to
corresponding antemortem concentrations were observed in all groups (p