liu.seSearch for publications in DiVA
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
In vivo steady-state pharmacokinetic outcome following clinical and toxic doses of racemic citalopram to rats
Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Department of Neuroscience and Locomotion, Psychiatry.
Department of Clinical Pharmacology, Institute of Laboratory Medicine, Lund University, Lund, Sweden.
Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
Show others and affiliations
2001 (English)In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 132, no 8, 1683-1690 p.Article in journal (Refereed) Published
Abstract [en]
  • The thymoleptic drug citalopram (CIT) belongs to the selective serotonin reuptake inhibitors (SSRIs) and is today extensively used in psychiatry. Further clarification of the enantiomer-selective distribution of racemic CIT in both clinical and toxic doses is highly warranted.

  • By a steady-state in vivo paradigm, rats underwent chronic systemic exposure for 10 days by using osmotic pumps and the total as well as the individual distributions of the S- and R-enantiomers of CIT, and its metabolites in serum and two different brain regions, were analysed.

  • In serum, the S/R ratios in the groups treated with 10, 20, or 100 mg kg−1 day−1 were 0.94, 0.83, and 0.34, respectively. The ratios were almost the same in the brain regions.

  • In the group treated with 100 mg kg−1 day−1, the serum and brain total CIT levels were found to be 20 times and 6 – 8 times higher than in the rats treated with 10 or 20 mg kg−1 day−1, respectively. In all groups, the CIT levels were higher in brain tissue as compared to serum.

  • In a spontaneous open-field behavioural test, a correlation between clinical and toxic drug concentrations was observed.

  • In conclusion, the R-enantiomer was present in an increased proportion compared with the S-enantiomer when higher steady-state CIT concentration was prevailing. This is of particular interest, since the S-enantiomer is responsible for the inhibition of serotonin reuptake in vitro. The present data may be of importance, as full understanding on where different racemic or enantiomeric drug effects of CIT and its main metabolites are unravelled.

Place, publisher, year, edition, pages
2001. Vol. 132, no 8, 1683-1690 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-26749DOI: 10.1038/sj.bjp.0704015Local ID: 11344OAI: oai:DiVA.org:liu-26749DiVA: diva2:247299
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Chiral and toxicological aspects of citalopram: an experimental study in rats
Open this publication in new window or tab >>Chiral and toxicological aspects of citalopram: an experimental study in rats
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Citalopram (CIT) is a selective serotonin reuptake inhibitor (SSRI), which is used for the treatment of different psychiatric disorders. The indications for prescription of OT are linked to high risks for intentional intoxications. CIT is one of the most commonly found drugs in Swedish forensic autopsy cases. CIT is a chiral compound, which exists as a racemic mixture (50:50) of the S-(+)-enantiomer (S-CIT) and the R-(-)-enantiomer (R-CIT). The main metabolites, demethylcitalopram (DCIT) and didemethylcitalopram (DCIT), are also chiral compounds. The SSRI effect of CIT is mediated by S-CIT. The routine toxicological screening is an achiral analysis, in which the total amount of the two enantiomers of CIT and metabolites are measured. An extended analysis of the disposition of the Sand R-enantiomers may provide additional information in interpreting forensic toxicological results. Hence, the blood and brain dispositions of the enantiomers of CIT, DCIT and DDCIT in vivo as well as postmortem were studied in an animal model, which also included studies of the behavioural activity.

Rats underwent systemic CIT exposure of clinically relevant and high/toxic doses, which were administered acute, chronic or acute-on-chronic. Samples from serum/blood and two brain regions (cortex and mesencephalon-pons) were collected for analysis of the concentrations of the enantiomers of CIT and metabolites using a chiral high performance liquid chromatography (HPLC) method. The open-field locomotor and rearing activities were examined after the chronic CIT exposure.

Following chronic CIT administration, R-CIT was present in an increased proportion compared with S-CIT when higher CIT concentration prevailed. Higher drug levels were observed in brain than in serum, and the drug levels between the two compartments correlated well. The rats treated with the high/toxic dose displayed lower behavioural activity during the first test hour as compared to controls and rats given clinically relevant doses. No major effects of CIT on the behavioural rhythm were observed. Shortly after the acute CIT administration, the ratio between S- and R-CIT was close to unity, whereas R-OT was found in higher amount than S-CIT at the end of the study period. The heart blood levels of CIT and metabolites increased postmortem in comparison with the levels observed antemortem after acute, chronic and acute-on-chronic administration. Irrespective of administered dose, the ratios between the S- and R-enantiomers of CIT and DCIT, as well as the CIT/DCIT ratios, were similar antemortem and postmortem.

Chiral analysis provided additional information regarding the different administration procedures as compared to achiral analysis. The stereoselective in vivo disposition of the enantiomers of CIT and metabolites was found similar in blood and brain. An equal degree of postmortem redistribution was also seen regarding the enantiomers of CIT and metabolites. These findings may facilitate and improve the interpretation of forensic toxicological results in humans.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2003. 83 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 826
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-27508 (URN)12164 (Local ID)91-7373-512-4 (ISBN)12164 (Archive number)12164 (OAI)
Public defence
2003-07-01, Patologsalen, Hälsouniversitetet, Linköping, 13:00 (Swedish)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-10-17Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full text

Authority records BETA

Kugelberg, FredrikCarlsson, BjörnAhlner, JohanBengtsson, Finn

Search in DiVA

By author/editor
Kugelberg, FredrikCarlsson, BjörnAhlner, JohanBengtsson, Finn
By organisation
Clinical PharmacologyPsychiatryFaculty of Health SciencesClinical Chemistry
In the same journal
British Journal of Pharmacology
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 62 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf