Abstract
Background: Biotransformation of citalopram (CT), a newly available selective serotonin
reuptake inhibitor antidepressant, to its principal metabolite, desmethycitalopram
(DCT), and the capacity of CT and DCT to inhibit human cytochromes P450, were studied
in vitro.
Methods: Formation of DCT from CT was evaluated using human liver microsomes and microsomes
from cDNA-transfected human lymphoblastoid cells. Cytochrome inhibition by CT and
DCT in liver microsomes was studied using isoform-specific index reactions.
Results: Formation of DCT from CT in liver microsomes had a mean apparent Km of 174 μmol/L. Coincubation with 1 μmol/L ketoconazole reduced reaction velocity
to 46 to 58% of control values, while omeprazole, 10 μmol/L, reduced velocity to 80%
of control. Quinidine produced minimal inhibition. DCT was formed from CT by heterologously
expressed human P450-2D6, -2C19, -3A4. After accounting for the relative abundance
of individual cytochromes, 3A4 and 2C19 were estimated to make major contributions
to net reaction velocity, with a possible contribution of 2D6 at therapeutic CT concentrations.
CT and DCT themselves produced negligible inhibition of 2C9, 2E1, and 3A, and only
weak inhibition of 1A2, 2C19, and 2D6.
Conclusions: Formation of DCT from CT is mediated mainly by P450-3A4 and 2C19, with
an additional contribution of 2D6. CT at therapeutic doses in humans may produce a
small degree of inhibition of P450-1A2, -2C19, and -2D6, but negligible inhibition
of P450-2C9, -2E1, and -3A.
Keywords
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Article info
Publication history
Accepted:
October 28,
1998
Received in revised form:
October 22,
1998
Received:
August 13,
1998
Identification
Copyright
© 1999 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
