Studies on the stereoselective metabolism of citalopram by human liver microsomes and cDNA-expressed cytochrome P450 enzymes.
The involvement of CYP enzymes in the metabolism of citalopram was studied, inclusive the conversion of demethylcitalopram to didemethylcitalopram and the formation of citalopram N-oxide, which both have not been considered previously. Using human mixed liver microsomes and cDNA-expressed CYP enzymes, we confirmed that CYP3A4, 2C19 and 2D6 are involved in the first demethylation step of citalopram, all favouring conversion of the biologically active S-enantiomer. Inhibitor studies indicated that at therapeutic citalopram concentrations CYP3A4 was responsible for 40-50% of demethylcitalopram formation, while the contribution of CYP2C19 increased and that of CYP2D6 tended to decrease with increasing drug concentration. CYP2D6 exclusively mediated the second demethylation step, and citalopram N-oxide was also exclusively formed by CYP2D6. None of the studied CYP enzymes mediated deamination to the propionic acid derivative.
Olesen
O V
OV
Institute for Basic Psychiatric Research, Department of Biological Psychiatry, Psychiatric Hospital in Aarhus, Aarhus University Hospital, Risskov, Denmark. viol1907@post3.tele.dk
Linnet
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K
D015283:Citalopram / Q000737:chemistry / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics; D016666:Fluvoxamine / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D007700:Kinetics; D008745:Methylation / Q000187:drug effects; D008862:Microsomes, Liver / Q000378:metabolism*; D010084:Oxidation-Reduction; D011802:Quinidine / Q000494:pharmacology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013237:Stereoisomerism
D018076:DNA, Complementary; D011994:Recombinant Proteins; D015283:Citalopram; D003577:Cytochrome P-450 Enzyme System; D011802:Quinidine; D016666:Fluvoxamine; D007654:Ketoconazole