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Identification of human liver cytochrome P450 enzymes responsible for the metabolism of lonafarnib (Sarasar).

Abstract

Lonafarnib (Sarasar), a farnesyl transferase inhibitor, is currently under development for the treatment of solid tumors. Incubation of lonafarnib with human liver microsomes resulted in the formation of four oxidative metabolites (M1, M2, M3, and M4). Minor to trace levels of these metabolites were detected in humans after multiple-dose administration of lonafarnib. Liquid chromatography-mass spectrometry analyses exhibited a mass to charge ratio (m/z) for the (M+H)(+) ion of M1, M2, M3, and M4 at 653, 635, 669, and 653 Th, respectively. These metabolites, respectively, resulted from changes of +O, -2H, +2O, and +O relative to lonafarnib. Recombinant human CYP3A4 and CYP3A5 exhibited catalytic activity with respect to the formation of M1, M2, and M3, whereas CYP2C8 exhibited catalytic activity with respect to the formation of M4. There was a high correlation between the formation of M1, determined in 10 human liver microsomal samples, and 6beta-hydroxylation of testosterone catalyzed by CYP3A4/5 (r = 0.93). The IC(50) values of ketoconazole for inhibition of M1 and M2 were 0.61 and 0.92 microM, respectively. The formation of M4 by human liver microsomes was inhibited 72% by 50 microM quercetin, suggesting that the formation of M4 was mediated via CYP2C8. A CYP3A4/5-specific inhibitory monoclonal antibody inhibited the formation of M1, M2, and M3 by 85, 75, and 100%, respectively. In conclusion, the formation of metabolites M1, M2, and M3 from lonafarnib was mediated via CYP3A4 and CYP3A5.

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  • Authors+Show Affiliations

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    Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, 2015 Galloping Hill Rd., K-15-1945, Kenilworth, NJ 07033, USA. anima.ghosal@spcorp.com

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    MeSH

    Antineoplastic Agents
    Cytochrome P-450 CYP3A
    Cytochrome P-450 Enzyme Inhibitors
    Cytochrome P-450 Enzyme System
    Enzyme Inhibitors
    Humans
    Ketoconazole
    Microsomes, Liver
    Oxidation-Reduction
    Piperidines
    Pyridines
    Recombinant Proteins

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    16443667

    Citation

    Ghosal, Anima, et al. "Identification of Human Liver Cytochrome P450 Enzymes Responsible for the Metabolism of Lonafarnib (Sarasar)." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 34, no. 4, 2006, pp. 628-35.
    Ghosal A, Chowdhury SK, Tong W, et al. Identification of human liver cytochrome P450 enzymes responsible for the metabolism of lonafarnib (Sarasar). Drug Metab Dispos. 2006;34(4):628-35.
    Ghosal, A., Chowdhury, S. K., Tong, W., Hapangama, N., Yuan, Y., Su, A. D., & Zbaida, S. (2006). Identification of human liver cytochrome P450 enzymes responsible for the metabolism of lonafarnib (Sarasar). Drug Metabolism and Disposition: the Biological Fate of Chemicals, 34(4), pp. 628-35.
    Ghosal A, et al. Identification of Human Liver Cytochrome P450 Enzymes Responsible for the Metabolism of Lonafarnib (Sarasar). Drug Metab Dispos. 2006;34(4):628-35. PubMed PMID: 16443667.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Identification of human liver cytochrome P450 enzymes responsible for the metabolism of lonafarnib (Sarasar). AU - Ghosal,Anima, AU - Chowdhury,Swapan K, AU - Tong,Wei, AU - Hapangama,Neil, AU - Yuan,Yuan, AU - Su,Ai-Duen, AU - Zbaida,Shmuel, Y1 - 2006/01/27/ PY - 2006/1/31/pubmed PY - 2006/9/26/medline PY - 2006/1/31/entrez SP - 628 EP - 35 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab. Dispos. VL - 34 IS - 4 N2 - Lonafarnib (Sarasar), a farnesyl transferase inhibitor, is currently under development for the treatment of solid tumors. Incubation of lonafarnib with human liver microsomes resulted in the formation of four oxidative metabolites (M1, M2, M3, and M4). Minor to trace levels of these metabolites were detected in humans after multiple-dose administration of lonafarnib. Liquid chromatography-mass spectrometry analyses exhibited a mass to charge ratio (m/z) for the (M+H)(+) ion of M1, M2, M3, and M4 at 653, 635, 669, and 653 Th, respectively. These metabolites, respectively, resulted from changes of +O, -2H, +2O, and +O relative to lonafarnib. Recombinant human CYP3A4 and CYP3A5 exhibited catalytic activity with respect to the formation of M1, M2, and M3, whereas CYP2C8 exhibited catalytic activity with respect to the formation of M4. There was a high correlation between the formation of M1, determined in 10 human liver microsomal samples, and 6beta-hydroxylation of testosterone catalyzed by CYP3A4/5 (r = 0.93). The IC(50) values of ketoconazole for inhibition of M1 and M2 were 0.61 and 0.92 microM, respectively. The formation of M4 by human liver microsomes was inhibited 72% by 50 microM quercetin, suggesting that the formation of M4 was mediated via CYP2C8. A CYP3A4/5-specific inhibitory monoclonal antibody inhibited the formation of M1, M2, and M3 by 85, 75, and 100%, respectively. In conclusion, the formation of metabolites M1, M2, and M3 from lonafarnib was mediated via CYP3A4 and CYP3A5. SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/16443667/Identification_of_human_liver_cytochrome_P450_enzymes_responsible_for_the_metabolism_of_lonafarnib__Sarasar__ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=16443667 DB - PRIME DP - Unbound Medicine ER -