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Sertraline N-demethylation is catalyzed by multiple isoforms of human cytochrome P-450 in vitro.

Abstract

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 microM, Vmax = 0.45 +/- 0.03 nmol/min/mg of protein, and Vmax/KM = 25.2 +/- 4.3 microl/min/mg of protein. At the substrate concentration of 20 microM, 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.

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  • Authors+Show Affiliations

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    Laboratory of Biochemical Pharmacology and Toxicology Faculty of Pharmaceutical Sciences Chiba University, Chiba, Japan.

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    MeSH

    Antidepressive Agents
    Chromatography, High Pressure Liquid
    Cytochrome P-450 Enzyme System
    Humans
    Isoenzymes
    Methylation
    Microsomes, Liver
    Recombinant Proteins
    Serotonin Uptake Inhibitors
    Sertraline

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    10383917

    Citation

    Kobayashi, K, et al. "Sertraline N-demethylation Is Catalyzed By Multiple Isoforms of Human Cytochrome P-450 in Vitro." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 27, no. 7, 1999, pp. 763-6.
    Kobayashi K, Ishizuka T, Shimada N, et al. Sertraline N-demethylation is catalyzed by multiple isoforms of human cytochrome P-450 in vitro. Drug Metab Dispos. 1999;27(7):763-6.
    Kobayashi, K., Ishizuka, T., Shimada, N., Yoshimura, Y., Kamijima, K., & Chiba, K. (1999). Sertraline N-demethylation is catalyzed by multiple isoforms of human cytochrome P-450 in vitro. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 27(7), pp. 763-6.
    Kobayashi K, et al. Sertraline N-demethylation Is Catalyzed By Multiple Isoforms of Human Cytochrome P-450 in Vitro. Drug Metab Dispos. 1999;27(7):763-6. PubMed PMID: 10383917.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Sertraline N-demethylation is catalyzed by multiple isoforms of human cytochrome P-450 in vitro. AU - Kobayashi,K, AU - Ishizuka,T, AU - Shimada,N, AU - Yoshimura,Y, AU - Kamijima,K, AU - Chiba,K, PY - 1999/6/29/pubmed PY - 1999/6/29/medline PY - 1999/6/29/entrez SP - 763 EP - 6 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab. Dispos. VL - 27 IS - 7 N2 - 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 microM, Vmax = 0.45 +/- 0.03 nmol/min/mg of protein, and Vmax/KM = 25.2 +/- 4.3 microl/min/mg of protein. At the substrate concentration of 20 microM, 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. SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/10383917/Sertraline_N_demethylation_is_catalyzed_by_multiple_isoforms_of_human_cytochrome_P_450_in_vitro_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=10383917 DB - PRIME DP - Unbound Medicine ER -