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Enantioselective analysis of citalopram and its metabolites in postmortem blood and genotyping for CYD2D6 and CYP2C19
Linköping University, Department of Medical and Health Sciences, Forensic Science and Toxicology . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Forensic Genetics. Linköping University, Faculty of Health Sciences.
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2004 (English)In: Journal of Analytical Toxicology, ISSN 0146-4760, Vol. 28, no 2, 94-104 p.Article in journal (Refereed) Published
Abstract [en]

Citalopram, a selective serotonin reuptake inhibitor, is one of the most commonly found drugs in Swedish forensic autopsy cases. Citalopram is a racemic drug with 50:50 of the S- and R- enantiomers. Enantioselective analysis of citalopram and its metabolites desmethylcitalopram and didesmethylcitalopram were performed in femoral blood from 53 autopsy cases by a chiral high-performance liquid chromatography (HPLC) method. The mean (± standard deviation) S/R ratio for citalopram was 0.67 ± 0.25 and for desmethylcitalopram, 0.68 ± 0.20. We found increasing S/R ratios with increasing concentrations of citalopram. We also found that high citalopram S/R ratios were associated with a high parent drug-to-metabolite ratio and may be an indicator of recent intake. Citalopram is metabolized by cytochrome P450 (CYP) 3A4, 2C19, and 2D6. Genotyping for the polymorphic CYP2C19 and CYP2D6 revealed no poor metabolizers regarding CYP2C19 and only 2 (3.8%) poor metabolizers regarding CYP2D6. The presence of drugs metabolized by and/or inhibiting these enzymes in several of the cases suggests that such pharmacokinetic interactions are a more important (practical) problem than metabolic deficiency. Enantioselective analysis of citalopram and its metabolites can provide additional information when interpreting forensic toxicology results and might be a necessity in the future.

Place, publisher, year, edition, pages
2004. Vol. 28, no 2, 94-104 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-13692DOI: 10.1093/jat/28.2.94OAI: oai:DiVA.org:liu-13692DiVA: diva2:21167
Available from: 2003-06-20 Created: 2003-06-20 Last updated: 2012-11-01
In thesis
1. From achiral to chiral analysis of citalopram
Open this publication in new window or tab >>From achiral to chiral analysis of citalopram
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Within the field of depression the “monoamine hypothesis” has been the leading theory to explain the biological basis of depression. This theory proposes that the biological basis of depression is due to a deficiency in one or more of three key neurotransmitter systems, namely noradrenaline, dopamine and serotonin which are thought to mediate the therapeutic actions of virtually every known antidepressant agent.

Citalopram is a selective serotonin-reuptake inhibitor (SSRI) used for the treatment of depression and anxiety disorders. Citalopram is a racemic compound, in other words composed of a 50:50 mixture of two enantiomers (S-(+)-citalopram and R-(-)-citalopram) and with one of the enantiomers (S-(+)-citalopram) accounting for the inhibitory effect. At the time of introduction of citalopram the physician needed a therapeutic drug monitoring service to identify patients with interactions, compliance problems and for handling questions concerning polymorphic enzymes and drug metabolism. An achiral analytical separation method based on solid-phase extraction followed by high-performance liquid chromatography (HPLC) was developed for routine therapeutic drug monitoring (TDM) of citalopram and its two main demethylated metabolites.

As the data available on citalopram were from achiral concentration determinations and to be able to further investigate citalopram enantiomers effects and distribution, a chiral method for separation of the enantiomers of citalopram and its demethylated metabolites was established. The advances within chiral separation techniques have made measurement of the concentrations of the individual enantiomers in biological fluids possible.

The process behind enantioselective separation is however not fully understood and the mechanism behind the separation can be further scrutinized by the use of multivariate methods. A study of the optimization and characterization of the separation of the enantiomers of citalopram, desmethylcitalopram and didesmethylcitalopram on an acetylated ß-cyclodextrin column, by use of two different chemometric programs - response surface modelling and sequential optimization was performed. Sequential optimization can be a quicker mean of optimizing a chromatographic separation; response surface modelling, in addition to enabling optimization of the chromatographic process, also serves as a tool for learning more about the separation mechanism.

Studies of the antidepressant effect and pharmacokinetics of citalopram have been performed in adults, but the effects on children and adolescents have only been studied to a minor extent, despite the increasing use of citalopram in these age groups.

A study was initiated to investigate adolescents treated for depression, with respect to the steady-state plasma concentrations of the enantiomers of citalopram and its demethylated metabolites. The ratios between the S- and R-enantiomers of citalopram and didesmethylcitalopram were in agreement with studies involving older patients. The concentrations of the S-(+)- and R-(-) enantiomers of citalopram and desmethylcitalopram were also in agreement with values from earlier studies. The results indicate that the use of oral contraceptives may have some influence on the metabolism of citalopram. This might be because of an interaction of the contraceptive hormones with the polymorphic CYP2C19 enzyme.

Even though the SSRIs are considered less toxic compared with older monoamine-active drugs like the tricyclic/tetracyclic antidepressants, the risk of developing serious side effects such as ECG abnormalities and convulsions has been seen for citalopram, when larger doses have been ingested. Furthermore, fatal overdoses have been reported where citalopram alone was the cause of death. Data on the toxicity of each of the enantiomers in humans have not been reported and no data on blood levels of the enantiomers in cases of intoxication have been presented.

An investigation was initiated on forensic autopsy cases where citalopram had been found at the routine screening and these cases were further analysed with enantioselective analysis to determine the blood concentrations of the enantiomers of citalopram and metabolites. Furthermore the genotyping regarding the polymorphic enzymes CYP2D6 and CYP2C19 were performed.

In 53 autopsy cases, we found increasing S/R ratios with increasing concentrations of citalopram. We found also that high citalopram S/R ratio were associated with high parent drug to metabolite ratio and may be an indicator of recent intake. Only 3.8 % were found to be poor metabolizers regarding CYP2D6 and for CYP2C19 no poor metabolizer was found.

Enantioselective analysis of citalopram and its metabolites can provide valuable information about the time that has elapsed between intake and death. Genotyping can be of help in specific cases but the possibility of pharmacokinetic interactions is apparently a far greater problem than genetic enzyme deficiency.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2003. 91 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 793
Keyword
depression, noradrenaline, dopamine, serotonin, citalopram, selective serotonin-reuptake inhibitor (SSRI), high-performance liquid chromatography (HPLC), therapeutic drug monitoring (TDM), enantioselective separation
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-5217 (URN)91-7373-550-7 (ISBN)
Public defence
2003-05-28, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 13:00 (English)
Opponent
Note
On the day of the public defence the status of article IV was: Submitted.Available from: 2003-06-20 Created: 2003-06-20 Last updated: 2012-01-25Bibliographically approved
2. Postmortem toxicology: aspects on interpretation
Open this publication in new window or tab >>Postmortem toxicology: aspects on interpretation
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Postmortem toxicology is a matter of analytical chemistry and the consequent interpretation of the results. Thus, both parts are of great importance to come to the right conclusion or the most probable explanation of the analytical results. When interpreting toxicological results there are a lot of different aspects to consider, such as: were the analytical methods used appropriate and with acceptable accuracy, what specimen was analyzed and how was it collected and stored before the analysis, what concentration of a drug can be considered normal or "therapeutic" and which concentration is fatal. Other circumstance to consider is the stability of the drug substances, the pharmacokinetics and pharmacodynamics of the drugs, possible drug interactions, pharmacogenetics and postmortem redistribution.

One crucial question in interpretation of postmortem toxicology results is to find reliable data on the significance of different drug concentrations. Instead of comparing concentrations found in postmortem blood with so called therapeutic concentrations in serum or plasma from the clinical setting, an inappropriate way that will lead to erroneous results, a new approach was used. Data was collected on drug concentrations in femoral blood from autopsy cases where the cause of death by certain not was intoxication and where the diseased was not incapacitated. These concentrations does not reflect any "therapeutic" concentration, which seldom is the key issue in postmortem toxicology, but represents concentrations which could be regarded as normally found and not associated with a fatal outcome. Applying this way to get reference concentrations, errors can be reduced and the problem associated with drug redistribution can be diminished.

Normally samples are stored for one year or more and for a variety of drugs no concentration changes in femoral blood were noted when stored at -20° C with the exception of e.g. ethanol, tetrahydrocannabinol (THC) and zopiclone. Vitreous humor (VH) can be used as an alternative specimen to blood and there exists a correlation between the concentration in VH compared to the blood concentration and the degree of protein binding of the substances. VH can also be used to estimate the corresponding blood concentration under certain circumstances.

Several drugs exist as racemate, containing two or several enantiomers. Chiral analysis can provide additional information about the time that has passed between intake of a drug and the time of death, thus improving the possibilities to predict whether an acute or chronic intake is at hand.

Pharmacokinetic and pharmacodynamic interactions are issues of great importance and have a great impact on interpretation in postmortem toxicology. Pharmacogenetics is another issue that attracts more and more attention in forensic toxicology. Awareness and knowledge of these factors are of utmost importance in order to produce accurate interpretations of postmortem toxicology results.

Place, publisher, year, edition, pages
Linköping: Linköping Universitet, 2004. 61 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 862
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24323 (URN)3946 (Local ID)91-7373-834-4 (ISBN)3946 (Archive number)3946 (OAI)
Public defence
2004-10-15, Berzeliussalen, Hälsouniversitetet, Linköping, 13:00 (Swedish)
Opponent
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-11-01Bibliographically approved

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Holmgren, PerCarlsson, BjörnZackrisson, Anna-LenaLindblom, BertilAhlner, Johan

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