Stereoselective Biotransformation of the Selective Serotonin Reuptake Inhibitor Citalopram and Its Demethylated Metabolites by Monoamine Oxidases in Human Liver

摘要: Citalopram (CIT) is an antidepressive drug of the group selective serotonin reuptake inhibitors (SSRIs). The tertiary amine CIT given as a racemic drug, but its pharmacological activity resides mainly in S-CIT. metabolised by cytochrome P450 (CYP) to N-demethylcitalopram (DCIT) and N-didemethylcitalopram (DDCIT). citalopram propionic acid derivative (CIT-PROP) another, pharmacologically inactive, metabolite, formation which has been poorly characterised postulated occur deamination CIT, DCIT and/or DDCIT. aim present investigation was study enantiomers CIT-PROP from two N-demethylated metabolites, DDCIT, vitro incubation system (microsomal cytosolic fractions) obtained human livers. production measured stereospecific HPLC method. Incubation rac-CIT, rac-DCIT rac-DDCIT (500 microM each, separately) presence (or absence) NADP showed that substrate-dependent essentially NADP-independent. Monoamine oxidases (MAO) type A B aldehyde oxidase were identified probable enzymes involved Indeed, irreversible monoamine inhibitor clorgyline selegiline (both at 0.5 mixture) inhibited formation, depending on substrate, up 70% 88%, respectively. participation subsequent step suggested inhibition caused menadione (50 microM) formation. Preliminary experiments suggest four unknown probably products deamination, detected plasma urine samples patients treated with well biotransformations. Their confirms importance biotransformation demethylated especially brain where, contrast liver, role appears be low.