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Vol. 29, Issue 8, 1102-1109, August 2001
Department of Pharmacology and Experimental Therapeutics, Tufts
University School of Medicine; and the Division of Clinical
Pharmacology, New England Medical Center Hospital, Boston,
Massachusetts
Transformation of escitalopram (S-CT), the
pharmacologically active S-enantiometer of citalopram,
to S-desmethyl-CT (S-DCT), and of
S-DCT to S-didesmethyl-CT
(S-DDCT), was studied in human liver microsomes and in
expressed cytochromes (CYPs). Biotransformation of the
R-enantiomer (R-CT) was studied in
parallel. S-CT was transformed to S-DCT
by CYP2C19 (Km = 69 µM), CYP2D6
(Km = 29 µM), and CYP3A4 (Km = 588 µM). After normalization
for hepatic abundance, relative contributions to net intrinsic
clearance were 37% for CYP2C19, 28% for CYP2D6, and 35% for CYP3A4.
At 10 µM S-CT in liver microsomes, S-DCT formation was reduced to 60% of control by 1 µM
ketoconazole, and to 80 to 85% of control by 5 µM quinidine or 25 µM omeprazole. S-DDCT was formed from
S-DCT only by CYP2D6; incomplete inhibition by quinidine
in liver microsomes indicated participation of a non-CYP pathway. Based
on established index reactions, S-CT and S-DCT were negligible inhibitors (IC50 > 100 µM) of CYP1A2, -2C9, -2C19, -2E1, and -3A, and weakly
inhibited CYP2D6 (IC50 = 70-80 µM).
R-CT and its metabolites, studied using the same
procedures, had properties very similar to those of the corresponding
S-enantiomers. Thus S-CT, biotransformed
by three CYP isoforms in parallel, is unlikely to be affected by drug
interactions or genetic polymorphisms. S-CT and
S-DCT are also unlikely to cause clinically important drug interactions via CYP inhibition.
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