Abstract
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. TheN-demethylation activities showed significant correlations with the α- and 4-hydroxylation activities of triazolam (r s = 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 CITN-demethylation and (S)-mephenytoin 4′-hydroxylation (r s = 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.
Footnotes
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Send reprint requests to: Yukio Kuroiwa, Ph.D., Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Showa University, Hatanodai 1–5-8, Shinagawa-ku, Tokyo 142, Japan.
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↵1 This work was supported by a Grant-in-aid for Encouragement of Young Scientists from the Ministry of Education and Science (06772215), the Japan Health Science Foundation (1–7-1-C) and the Drug Innovation Science Project (1–2-10), Tokyo, Japan.
- Abbreviations:
- CIT
- citalopram
- CYP or P450
- cytochrome P450
- DCIT
- desmethylcitalopram
- EM
- extensive metabolizer
- HPLC
- high-performance liquid chromatography
- PM
- poor metabolizer
- RAF
- relative activity factor
- Received April 15, 1996.
- Accepted October 15, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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