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Sertraline N-demethylation is catalyzed by multiple isoforms of human cytochrome P-450 in vitro.
Drug Metab Dispos 1999; 27(7):763-6DM

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.

Authors+Show Affiliations

Laboratory of Biochemical Pharmacology and Toxicology Faculty of Pharmaceutical Sciences Chiba University, Chiba, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

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 -