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Vol. 280, Issue 2, 927-933, 1997

Identification of Cytochrome P450 Isoforms Involved in Citalopram N-Demethylation by Human Liver Microsomes1

Kaoru Kobayashi, Kan Chiba, Tomomi Yagi, Noriaki Shimada, Tomoyoshi Taniguchi, Toru Horie, Masayoshi Tani, Toshinori Yamamoto, Takashi Ishizaki and Yukio Kuroiwa

Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan (K.K., Tom.Y., Tos.Y., Y.K.); Division of Drug Metabolism and Disposition, Department of Clinical Pharmacology, Research Institute (K.C., T.I.), and Department of General Surgery (M.T.), International Medical Center of Japan, Tokyo, Japan; Tokai Research Laboratories, Daiichi Pure Chemicals Co., Osaka, Japan (N.S.); and Tsukuba Research Laboratories, Eisai Co., Ibaragi, Japan (T.T., T.H.)

Studies to assess the enzyme kinetic behavior and to identify the cytochrome P450 (CYP) isoform(s) involved in the major metabolic pathway (N-demethylation) for citalopram (CIT), a selective serotonin reuptake inhibitor, were performed using human liver microsomes and cDNA-expressed human cytochrome P450 isoforms. The N-demethylation activities showed significant correlations with the alpha - and 4-hydroxylation activities of triazolam (rs = 0.818 and 0.851, respectively; P < .01) in 10 different human liver microsomes. Anti-CYP3A antibodies and ketoconazole strongly inhibited CIT N-demethylation. In addition, there was a significant correlation between CIT N-demethylation and (S)-mephenytoin 4'-hydroxylation (rs = 0.773, P < .05), although little inhibition was observed in the presence of anti-CYP2C antibodies or (S)-mephenytoin. cDNA-expressed CYP3A4 and CYP2C19 catalyzed CIT N-demethylation, whereas no appreciable activities were observed for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6 and CYP2E1. The percentage contributions of CYP3A4 and CYP2C19 to the overall N-demethylation of CIT in human liver microsomes were estimated using a relative activity factor; respective values of 70% and 7% were calculated for microsomes obtained from livers from putative extensive metabolizers for (S)-mephenytoin 4'-hydroxylation. These results suggest that CYP3A4 is the major isoenzyme and CYP2C19 is the minor form involved in the major metabolic pathway for CIT in human liver microsomes.

Copyright © by The American Society for Pharmacology and Experimental Therapeutics


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