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Vol. 29, Issue 8, 1102-1109, August 2001

Escitalopram (S-Citalopram) and Its Metabolites in Vitro: Cytochromes Mediating Biotransformation, Inhibitory Effects, and Comparison to R-Citalopram

Lisa L. von Moltke, David J. Greenblatt, Gina M. Giancarlo, Brian W. Granda, Jerold S. Harmatz, and Richard I. Shader

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.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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Copyright © 2001 by the American Society for Pharmacology and Experimental Therapeutics.