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Identification of human liver cytochrome P450 enzymes involved in the metabolism of SCH 351125, a CCR5 antagonist.

Abstract

The identification and relative contribution of human cytochrome P450 enzyme(s) involved in the metabolism of SCH 351125 were investigated. In human liver microsomes, O-deethylation was the major metabolic pathway, whereas aromatization of a piperidine ring to pyridine and the reduction of the N-oxide moiety were minor routes. Recombinant human CYP3A4 and CYP2C9 both exhibited catalytic activity with respect to the formation of rotameric O-deethylated metabolites (M12, M13), the metabolites resulting from aromatization (M22/M24) and N-oxide reduction (M31). Using the relative activity factor (RAF) approach, the relative contributions of CYP3A4 and CYP2C9 to M13 formation were estimated to be 76 and 24%, respectively. There was a high correlation (r>0.96) between the rate of formation of M12 and M13 and 6 beta-hydroxylation of testosterone catalysed by CYP3A4/5. Ketoconazole (2microM) and CYP3A4/5-specific inhibitory monoclonal antibody inhibited the formation of M12 and M13 from human liver microsomes by approximately 60 and 71%, respectively. The results demonstrate that the in vitro metabolism of SCH 351125 is mediated primarily via CYP3A4 and that CYP2C9 plays a minor role. Clinical study designs should encompass these enzymology data to address any potential drug interactions.

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  • Authors+Show Affiliations

    ,

    Drug, Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. anima.ghosal@spcorp.com

    , , , , , , ,

    Source

    MeSH

    Biotransformation
    CCR5 Receptor Antagonists
    Cyclic N-Oxides
    Cytochrome P-450 CYP3A
    Cytochrome P-450 Enzyme System
    Humans
    Kinetics
    Microsomes, Liver
    Piperidines
    Pyridines
    Recombinant Proteins

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    16012074

    Citation

    Ghosal, A, et al. "Identification of Human Liver Cytochrome P450 Enzymes Involved in the Metabolism of SCH 351125, a CCR5 Antagonist." Xenobiotica; the Fate of Foreign Compounds in Biological Systems, vol. 35, no. 5, 2005, pp. 405-17.
    Ghosal A, Chowdhury SK, Gupta S, et al. Identification of human liver cytochrome P450 enzymes involved in the metabolism of SCH 351125, a CCR5 antagonist. Xenobiotica. 2005;35(5):405-17.
    Ghosal, A., Chowdhury, S. K., Gupta, S., Yuan, Y., Iannucci, R., Zhang, H., ... Alton, K. B. (2005). Identification of human liver cytochrome P450 enzymes involved in the metabolism of SCH 351125, a CCR5 antagonist. Xenobiotica; the Fate of Foreign Compounds in Biological Systems, 35(5), pp. 405-17.
    Ghosal A, et al. Identification of Human Liver Cytochrome P450 Enzymes Involved in the Metabolism of SCH 351125, a CCR5 Antagonist. Xenobiotica. 2005;35(5):405-17. PubMed PMID: 16012074.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Identification of human liver cytochrome P450 enzymes involved in the metabolism of SCH 351125, a CCR5 antagonist. AU - Ghosal,A, AU - Chowdhury,S K, AU - Gupta,S, AU - Yuan,Y, AU - Iannucci,R, AU - Zhang,H, AU - Zbaida,S, AU - Patrick,J E, AU - Alton,K B, PY - 2005/7/14/pubmed PY - 2005/9/22/medline PY - 2005/7/14/entrez SP - 405 EP - 17 JF - Xenobiotica; the fate of foreign compounds in biological systems JO - Xenobiotica VL - 35 IS - 5 N2 - The identification and relative contribution of human cytochrome P450 enzyme(s) involved in the metabolism of SCH 351125 were investigated. In human liver microsomes, O-deethylation was the major metabolic pathway, whereas aromatization of a piperidine ring to pyridine and the reduction of the N-oxide moiety were minor routes. Recombinant human CYP3A4 and CYP2C9 both exhibited catalytic activity with respect to the formation of rotameric O-deethylated metabolites (M12, M13), the metabolites resulting from aromatization (M22/M24) and N-oxide reduction (M31). Using the relative activity factor (RAF) approach, the relative contributions of CYP3A4 and CYP2C9 to M13 formation were estimated to be 76 and 24%, respectively. There was a high correlation (r>0.96) between the rate of formation of M12 and M13 and 6 beta-hydroxylation of testosterone catalysed by CYP3A4/5. Ketoconazole (2microM) and CYP3A4/5-specific inhibitory monoclonal antibody inhibited the formation of M12 and M13 from human liver microsomes by approximately 60 and 71%, respectively. The results demonstrate that the in vitro metabolism of SCH 351125 is mediated primarily via CYP3A4 and that CYP2C9 plays a minor role. Clinical study designs should encompass these enzymology data to address any potential drug interactions. SN - 0049-8254 UR - https://www.unboundmedicine.com/medline/citation/16012074/Identification_of_human_liver_cytochrome_P450_enzymes_involved_in_the_metabolism_of_SCH_351125_a_CCR5_antagonist_ L2 - http://www.tandfonline.com/doi/full/10.1080/00498250500136569 DB - PRIME DP - Unbound Medicine ER -