RT Journal Article
SR Electronic
T1 Escitalopram (S-Citalopram) and Its Metabolites in Vitro: Cytochromes Mediating Biotransformation, Inhibitory Effects, and Comparison to R-Citalopram
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1102
OP 1109
VO 29
IS 8
A1 Lisa L. von Moltke
A1 David J. Greenblatt
A1 Gina M. Giancarlo
A1 Brian W. Granda
A1 Jerold S. Harmatz
A1 Richard I. Shader
YR 2001
UL http://dmd.aspetjournals.org/content/29/8/1102.abstract
AB Transformation of escitalopram (S-CT), the pharmacologically active S-enantiometer of citalopram, to S-desmethyl-CT (S-DCT), and ofS-DCT to S-didesmethyl-CT (S-DDCT), was studied in human liver microsomes and in expressed cytochromes (CYPs). Biotransformation of theR-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 fromS-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 andS-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 correspondingS-enantiomers. Thus S-CT, biotransformed by three CYP isoforms in parallel, is unlikely to be affected by drug interactions or genetic polymorphisms. S-CT andS-DCT are also unlikely to cause clinically important drug interactions via CYP inhibition. The American Society for Pharmacology and Experimental Therapeutics