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Vol. 27, Issue 7, 763-766, July 1999

SHORT COMMUNICATION
Sertraline N-Demethylation Is Catalyzed by Multiple Isoforms of Human Cytochrome P-450 In Vitro

Kaoru Kobayashi, Tomoko Ishizuka, Noriaki Shimada, Yoshitaka Yoshimura, Kunitoshi Kamijima, and Kan Chiba

Laboratory of Biochemical
Pharmacology and Toxicology
Faculty of Pharmaceutical Sciences
Chiba University,
Chiba, Japan (K.K., T.I., K.C.)
Materials Technology Research Laboratories
Daiichi Pure Chemicals Co. Ltd.
Ibaraki (N.S.), Japan
Department of Psychiatry
School of Medicine
Showa University
Tokyo, Japan (Y.Y., K.K.)

Sertraline, a new antidepressant of the selective serotonin reuptake inhibitor class, is extensively metabolized to desmethylsertraline in humans. We identified the cytochrome P-450 (CYP) isoforms involved in sertraline N-demethylation using pooled human liver microsomes and cDNA-expressed CYP isoforms. Eadie-Hofstee plots for the sertraline N-demethylation in human liver microsomes were monophasic. The estimated Michaelis-Menten kinetic parameters were: KM = 18.1 ± 2.0 µM, Vmax = 0.45 ± 0.03 nmol/min/mg of protein, and Vmax/KM = 25.2 ± 4.3 µl/min/mg of protein. At the substrate concentration of 20 µM, which approximated the apparent KM value, sulfaphenazole (CYP2C9 inhibitor) and triazolam (CYP3A substrate) reduced the N-demethylation activities by 20 to 35% in human liver microsomes, whereas the inhibition induced by mephenytoin (CYP2C19 substrate) or quinidine (CYP2D6 inhibitor) was marginal. The anti-CYP2B6 antibody inhibited the sertraline N-demethylation activities by 35%. Sertraline N-demethylation activities were detected in all cDNA-expressed CYP isoforms studied. In particular, CYP2C19, CYP2B6, CYP2C9-Arg, CYP2D6-Val, and CYP3A4 all showed relatively high activity. When the contributions of CYP2D6, CYP2C9, CYP2B6, CYP2C19, and CYP3A4 were estimated from the Vmax/KM of cDNA-expressed CYP isoforms and from their contents in pooled human liver microsomes, the values were found to be 35, 29, 14, 13, and 9%, respectively. The results suggest that at least five isoforms of CYP (CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4) are involved in the sertraline N-demethylation in human liver microsomes and that the contribution of any individual isoform does not exceed 40% of overall metabolism. Therefore, concurrent administration of a drug that inhibits a specific CYP isoform is unlikely to cause a marked increase in the plasma concentration of sertraline.

Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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