Stereoselective biotransformation of the selective serotonin reuptake inhibitor citalopram and its demethylated metabolites by monoamine oxidases in human liver

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Serval ID
serval:BIB_D1985D3E5E7E
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Stereoselective biotransformation of the selective serotonin reuptake inhibitor citalopram and its demethylated metabolites by monoamine oxidases in human liver
Journal
Biochemical Pharmacology
Author(s)
Rochat  B., Kosel  M., Boss  G., Testa  B., Gillet  M., Baumann  P.
ISSN
0006-2952 (Print)
Publication state
Published
Issued date
07/1998
Volume
56
Number
1
Pages
15-23
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Jul 1
Abstract
Citalopram (CIT) is an antidepressive drug of the group of selective serotonin reuptake inhibitors (SSRIs). The tertiary amine CIT is given as a racemic drug, but its pharmacological activity resides mainly in S-CIT. CIT is metabolised by cytochrome P450 (CYP) to N-demethylcitalopram (DCIT) and N-didemethylcitalopram (DDCIT). The citalopram propionic acid derivative (CIT-PROP) is another, but pharmacologically inactive, metabolite, the formation of which has been poorly characterised but is postulated to occur by deamination of CIT, DCIT and/or DDCIT. The aim of the present investigation was to study the formation of the enantiomers of CIT-PROP from CIT and its two N-demethylated metabolites, DCIT and DDCIT, in an in vitro incubation system (microsomal and cytosolic fractions) obtained from human livers. The production of CIT-PROP was measured by a stereospecific HPLC method. Incubation of rac-CIT, rac-DCIT and rac-DDCIT (500 microM each, separately) in the presence (or absence) of NADP showed that CIT-PROP formation was substrate-dependent and essentially NADP-independent. Monoamine oxidases (MAO) type A and B and aldehyde oxidase were identified as the probable enzymes involved in the formation of CIT-PROP from CIT, DCIT and DDCIT. Indeed, the irreversible monoamine oxidase type A inhibitor clorgyline and the irreversible monoamine oxidase type B inhibitor selegiline (both at 0.5 microM in the incubation mixture) inhibited CIT-PROP formation, depending on the substrate, up to 70% and 88%, respectively. The participation of aldehyde oxidase in the subsequent step is suggested by the inhibition caused by menadione (50 microM) in CIT-PROP formation. Preliminary experiments suggest the presence of four unknown metabolites, probably products of deamination, which were detected in plasma and urine samples of patients treated with CIT as well as in in vitro biotransformations. Their presence confirms the importance of deamination in the biotransformation of CIT and its demethylated metabolites, especially in the brain where, in contrast to the liver, the role of cytochrome P450 appears to be low.
Keywords
Adult Animals Biotransformation Citalopram/*pharmacokinetics Female Humans Liver/*enzymology Male Methylation Middle Aged Monoamine Oxidase/*metabolism Monoamine Oxidase Inhibitors/pharmacology NADP/metabolism Rats Serotonin Uptake Inhibitors/*pharmacokinetics
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25/01/2008 8:47
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20/08/2019 15:51
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