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. 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…
Contents
Introduction
Chirality
Drugs and Stereochemistry
Chirality and Psychopharmacology
Chirality and Pharmacodynamics
Chirality and Pharmacokinetics
Selective serotonin reuptake inhibitors
Cytochrome P450 enzyme system
Citalopram a selective serotonin reuptake inhibitor
Chemical and physical properties
Citalopram and cytochrome P450 superfamily
Pharmacokinetics
Pharmacodynamics
Adverse drug reaction – Toxicology
Chiral bioanalysis
Indirect methods
Direct methods
Mechanistic aspects of enantioseparation
Chiral stationary phases
Cyclodextrins
Fluorescence detection
Chemometrics
Systematic optimization
Experimental design
Design of experiments
Screening designs
Full factorial and fractional factorial design
Optimization design
Central composite designs
Modified sequential simplex approach
Aims of the present study
Methods, results and discussion
Paper I
Achiral determination of citalopram
Citalopram extraction version I
Solid-phase extraction
Internal standard
Achiral chromatography
Summary of paper I
Paper II
Optimization of the chiral separation of citalopram and
its demethylated metabolites
Chiral separation of citalopram
Optimization with Modde
Optimization with Multisimplex
Separation mechanism
Summary of paper II
Paper III
Citalopram and adolescents
Citalopram extraction version II
Results, citalopram and adolescents
Other examples where chiral analysis has been of value
Animal studies
Summary of paper III
Paper IV
Enantioselective analysis of citalopram in postmortem blood and genotyping
Citalopram extraction version III
Drug levels in post mortem whole blood versus plasma concentrations
from patients with toxicological symptoms Genotyping
Summary of paper IV
Conclusions
Chemometrics-Experimental design
Therapeutic drug monitoring: Achiral or chiral analysis of citalopram
Forensic chemistry: Achiral or chiral analysis of citalopram
Future studies
LCMS
On-line extraction and chiral analysis
Free fraction
Chiral switches
Acknowledgements
References
Appendix
Author: Carlsson, Björn
Source: Linköping University
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