Molecular and Cellular PharmacologyStereoselective Biotransformation of the Selective Serotonin Reuptake Inhibitor Citalopram and Its Demethylated Metabolites by Monoamine Oxidases in Human Liver
Section snippets
Chemicals
The following drugs were gifts: The racemates and enantiomers (purity >99%) of CIT hydrobromide or oxalate, DCIT hydrochloride or fumarate, DDCIT L-tartrate or fumarate, citalopram N-oxide (CIT-N-oxide) and CIT-PROP (Lundbeck AS, Copenhagen, Denmark), the IS S-Flurbi (Boots Limited, Nottingham, U.K.), ketoconazole (Prof. P. Dayer, Geneva, Switzerland), and omeprazole (Astra, Dietikon, Switzerland).
CIT, its metabolites and S-Flurbi were dissolved in methanol at a concentration of 1 mg/mL of base
Production of CIT-PROP from CIT, DCIT and DDCIT
In preliminary experiments, S-enantiomers of CIT, DCIT and DDCIT were incubated for 120 min in the presence of an NADPH-regenerating system (NADP). CIT-PROP formation by the human liver microsomal fraction was observed for all substrates. S-CIT-PROP production was linear at least until 60 min and with microsomal protein concentrations ranging from 50 to 200 μg with or without cytosolic proteins (100 μg) in the incubation mixture (data not shown). The cytosolic fraction alone was unable to
Discussion
Several clinical pharmacokinetic studies showed the presence of CIT-PROP in the blood of patients treated with CIT (for a review, cf. 8, 27). This study demonstrates the stereoselective in vitro formation of CIT-PROP from the three racemic amines CIT, DCIT and DDCIT in human liver extracts (Table 1). CIT-PROP production was highest using a mixture of microsomal and cytosolic fractions. In the presence of NADP, deamination was observed with substrate selectivity and stereoselectivity, the S/R
Overview and Perspectives
Taking into account that CYP content in human brain is very low 33, 34, 35, in situ deamination of CIT and its demethylated metabolites by MAO should be the main biotransformation in this target organ. It could be very interesting to investigate more intensively this biochemical pathway from a pharmacokinetic as well as pharmacodynamic point of view.
No data are available concerning CIT brain concentrations under therapeutic conditions. It is, however, of interest that chronic oral
Acknowledgements
This study was financed by the Fonds national suisse de la recherche scientifique, FNSRS (32-27579.89, 32-42-42076.94), by the OFES (COST B1), the Lundbeck Foundation, and the Société Académique Vaudoise. We are grateful to Drs. Claus Selch Larsen and Nils Mørk (Lundbeck, Copenhagen, Denmark) and to Dr. Marianne Reymond, CHUV, Lausanne, Switzerland, for providing us with the enantiomers of CIT and of its metabolites, and for rat brain tissues, respectively. We thank Christine Beedham for her
References (37)
- et al.
High-performance liquid chromatographic determination of CIT and four of its metabolites in plasma and urine samples from psychiatric patients
J Chromatogr Biomed Appl
(1984) - et al.
High-performance liquid chromatographic determination of citalopram and of four of its metabolites in plasma and urine samples from psychiatric patients
J Chromatogr Biomed Appl
(1984) - et al.
Neuroendocrine effects of a 20-mg citalopram infusion in healthy males—A placebo-controlled evaluation of citalopram as 5-HT function probe
Neuropsychopharmacology
(1996) - et al.
Hepatic microsomal oxygenation of aldehydes to carboxylic acids
Biochem Biophys Res Commun
(1990) - et al.
Characterization of the enzyme responsible for the metabolism of sumatriptan in human liver
Biochem Pharmacol
(1994) - et al.
Enzymatic basis of the debrisoquine/sparteine-type genetic polymorphism of drug oxidation—Characterization of bufuralol 1′-hydroxylation in liver microsomes of in vivo phenotyped carriers of the genetic deficiency
Biochem Pharmacol
(1987) - et al.
Screening of unsubstituted cyclic compounds as inhibitors of monoamine oxidases
Biochem Pharmacol
(1994) - et al.
Protein measurement with the folin phenol reagent
J Biol Chem
(1951) - et al.
GC and GC-MS procedures for simultaneous phenotyping with dextromethorphan and mephenytoin
Clin Chim Acta
(1988) - et al.
Determination of plasma levels of citalopram and its demethylated and deaminated metabolites by gas chromatography and gas chromatography-mass spectrometry
J Chromatogr Biomed Appl
(1993)