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Chiral and toxicological aspects of citalopram: an experimental study in rats
Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
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: urn:nbn:se:liu:diva-27508Local ID: 12164ISBN: 91-7373-512-4 (print)OAI: oai:DiVA.org:liu-27508DiVA: diva2:248060
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
List of papers
1. In vivo steady-state pharmacokinetic outcome following clinical and toxic doses of racemic citalopram to rats
Open this publication in new window or tab >>In vivo steady-state pharmacokinetic outcome following clinical and toxic doses of racemic citalopram to rats
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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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26749 (URN)10.1038/sj.bjp.0704015 (DOI)11344 (Local ID)11344 (Archive number)11344 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
2. Effects of chronic citalopram treatment on central and peripheral spontaneous open-field behaviours in rats
Open this publication in new window or tab >>Effects of chronic citalopram treatment on central and peripheral spontaneous open-field behaviours in rats
2002 (English)In: Pharmacology and Toxicology, ISSN 0901-9928, E-ISSN 1600-0773, Vol. 90, no 6, 303-310 p.Article in journal (Refereed) Published
Abstract [en]

The spontaneous open-field behavioural effects of 10 days of chronic treatment with two clinical doses (10 and 20 mg/kg daily) and one high/toxic dose (100 mg/kg daily) of the selective serotonin reuptake inhibitor citalopram (delivered subcutaneously by implanted osmotic pumps) were examined in rats. Central and peripheral arena locomotor and rearing activities were recorded simultaneously, and the data were assessed during the first hour as well as during the following 24 hr (the latter for effects on the diurnal rhythm). Rats treated with 100 mg/kg daily exhibited lower peripheral locomotor and rearing activities than the other groups during the first test hour. The ratio between central and peripheral activity increased in a dose-dependent non-proportional manner during the first test hour, indicating a general increase in the central arena activity exerted by the rats when treated with citalopram. No major differences were observed between any of the four groups in overall behavioural activities over the 24-hr period. This study indicated that the open-field locomotor and rearing behaviours in normal rats were affected by increasing doses of racemic citalopram, particularly during the first hour of adaptation.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-27659 (URN)10.1034/j.1600-0773.2002.900603.x (DOI)12397 (Local ID)12397 (Archive number)12397 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
3. Stereoselective single-dose kinetics of citalopram and its metabolites in rats
Open this publication in new window or tab >>Stereoselective single-dose kinetics of citalopram and its metabolites in rats
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26746 (URN)10.1002/chir.10266 (DOI)11341 (Local ID)11341 (Archive number)11341 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
4. Postmortem redistribution of the enantiomers of citalopram and its metabolites: an experimental study in rats
Open this publication in new window or tab >>Postmortem redistribution of the enantiomers of citalopram and its metabolites: an experimental study in rats
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2004 (English)In: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 28, no 8, 631-637 p.Article in journal (Refereed) Published
Abstract [en]

A rat model was used to study if postmortem redistribution of the S- and R-enantiomers of citalopram (CIT) and its metabolites demethylcitalopram (DCIT) and didemethylcitalopram (DDCIT) occurs after three different subcutaneous dosing procedures with racemic CIT. Two groups underwent chronic administration (20 mg/kg daily) using osmotic pumps. After 10 days, 1 of these groups received an acute-on-chronic drug challenge with a single 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 for enantioselective HPLC analysis. Increased postmortem blood drug and metabolite concentrations compared with corresponding antemortem concentrations were observed in all groups (p < 0.05 to p < 0.001). At 24 h after death, the ratios between postmortem and antemortem blood concentrations were around 3–4 for CIT as well as for the metabolites. In the brain, no major differences between antemortem and postmortem drug and metabolite concentrations were observed. The enantiomeric (S/R) concentrations ratios of CIT and metabolites in blood and brain were of similar magnitude before and after death. No differences between antemortem and postmortem parent drug-to-metabolite (P/M) ratios for CIT/DCIT in blood were observed. Finally, this animal model demonstrates that the S- and R-enantiomers of CIT and its metabolites were redistributed to the same extent postmortem.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24023 (URN)10.1093/jat/28.8.631 (DOI)3578 (Local ID)3578 (Archive number)3578 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved

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