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Stereoselective single-dose kinetics of citalopram and its metabolites in rats
Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
2003 (English)In: Chirality, ISSN 0899-0042, E-ISSN 1520-636X, Vol. 15, no 7, 622-629 p.Article in journal (Refereed) Published
Abstract [en]

The single-dose kinetics of the enantiomers of citalopram (CIT) and its metabolites, demethylcitalopram (DCIT) and didemethylcitalopram (DDCIT), were investigated after administration of 10, 20, or 100 mg/kg (s.c.) rac-CIT to rats. Samples from serum and two brain regions were collected 1, 3, 10, or 20 h postdose for HPLC analysis. In the 100 mg/kg rats, the enantiomeric (S/R) serum concentration ratios of CIT decreased during the study period (0.93 at 1 h vs. 0.59 at 20 h; P < 0.001). In the 10 and 20 mg/kg rats, the decrease in serum S/R CIT ratios was not so evident as in the 100 mg/kg rats. In all three groups the S/R CIT ratio was almost the same in the brain as in serum, although both CIT enantiomer levels in the brain were found to be 5–10 times higher than the levels in serum. The serum and brain metabolite levels were low in the 10 and 20 mg/kg rats, whereas the levels increased during the study period in the 100 mg/kg rats. In conclusion, the CIT enantiomers were shown for the first time to be stereoselectively metabolized after single-dose administration to rats, as previously shown in steady-state dosing studies in humans and rats. Chirality 15:622–629, 2003. © 2003 Wiley-Liss, Inc.

Place, publisher, year, edition, pages
2003. Vol. 15, no 7, 622-629 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-26746DOI: 10.1002/chir.10266Local ID: 11341OAI: oai:DiVA.org:liu-26746DiVA: diva2:247296
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

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Kugelberg, FredrikCarlsson, BjörnAhlner, JohanBengtsson, Finn

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