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Identification of human liver cytochrome P450 enzymes involved in biotransformation of vicriviroc, a CCR5 receptor antagonist.

Abstract

Vicriviroc (SCH 417690), a CCR5 receptor antagonist, is currently under investigation for the treatment of human immunodeficiency virus infection. The objective of this study was to identify human liver cytochrome P450 enzyme(s) responsible for the metabolism of vicriviroc. Human liver microsomes metabolized vicriviroc via N-oxidation (M2/M3), O-demethylation (M15), N,N-dealkylation (M16), N-dealkylation (M41), and oxidation to a carboxylic acid metabolite (M35b/M37a). Recombinant human CYP3A4 catalyzed the formation of all these metabolites, whereas CYP3A5 catalyzed the formation of M2/M3 and M41. CYP2C9 only catalyzed the formation of M15. There was a high correlation between the rates of formation of M2/M3, M15, and M41, which was determined using 10 human liver microsomal samples and testosterone 6beta-hydroxylation catalyzed by CYP3A4/5 (r > or = 0.91). Ketoconazole and azamulin (inhibitors of CYP3A4) were potent inhibitors of the formation of M2/M3, M15, M41, and M35b/M37a from human liver microsomes. A CYP3A4/5-specific monoclonal antibody (1 microg/microg of protein) inhibited the formation of all metabolites from human liver microsomes by 86 to 100%. The results of this study suggest that formation of the major vicriviroc metabolites in human liver microsomes is primarily mediated via CYP3A4. CYP2C9 and CYP3A5 most likely play a minor role in the biotransformation of this compound. These enzymology data will provide guidance to design clinical studies to address any potential drug-drug interactions.

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

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    MeSH

    Antibodies, Monoclonal
    Aryl Hydrocarbon Hydroxylases
    Biotransformation
    Bridged-Ring Compounds
    CCR5 Receptor Antagonists
    Carboxylic Acids
    Cytochrome P-450 CYP2C9
    Cytochrome P-450 CYP3A
    Cytochrome P-450 Enzyme Inhibitors
    Cytochrome P-450 Enzyme System
    Dealkylation
    Enzyme Inhibitors
    Humans
    Immunologic Factors
    In Vitro Techniques
    Isoenzymes
    Ketoconazole
    Kinetics
    Liver
    Oxidation-Reduction
    Piperazines
    Pyrimidines
    Recombinant Proteins
    Substrate Specificity
    Testosterone
    Triazoles

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    17827338

    Citation

    Ghosal, Anima, et al. "Identification of Human Liver Cytochrome P450 Enzymes Involved in Biotransformation of Vicriviroc, a CCR5 Receptor Antagonist." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 35, no. 12, 2007, pp. 2186-95.
    Ghosal A, Ramanathan R, Yuan Y, et al. Identification of human liver cytochrome P450 enzymes involved in biotransformation of vicriviroc, a CCR5 receptor antagonist. Drug Metab Dispos. 2007;35(12):2186-95.
    Ghosal, A., Ramanathan, R., Yuan, Y., Hapangama, N., Chowdhury, S. K., Kishnani, N. S., & Alton, K. B. (2007). Identification of human liver cytochrome P450 enzymes involved in biotransformation of vicriviroc, a CCR5 receptor antagonist. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 35(12), pp. 2186-95.
    Ghosal A, et al. Identification of Human Liver Cytochrome P450 Enzymes Involved in Biotransformation of Vicriviroc, a CCR5 Receptor Antagonist. Drug Metab Dispos. 2007;35(12):2186-95. PubMed PMID: 17827338.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Identification of human liver cytochrome P450 enzymes involved in biotransformation of vicriviroc, a CCR5 receptor antagonist. AU - Ghosal,Anima, AU - Ramanathan,Ragu, AU - Yuan,Yuan, AU - Hapangama,Neil, AU - Chowdhury,Swapan K, AU - Kishnani,Narendra S, AU - Alton,Kevin B, Y1 - 2007/09/07/ PY - 2007/9/11/pubmed PY - 2008/1/4/medline PY - 2007/9/11/entrez SP - 2186 EP - 95 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab. Dispos. VL - 35 IS - 12 N2 - Vicriviroc (SCH 417690), a CCR5 receptor antagonist, is currently under investigation for the treatment of human immunodeficiency virus infection. The objective of this study was to identify human liver cytochrome P450 enzyme(s) responsible for the metabolism of vicriviroc. Human liver microsomes metabolized vicriviroc via N-oxidation (M2/M3), O-demethylation (M15), N,N-dealkylation (M16), N-dealkylation (M41), and oxidation to a carboxylic acid metabolite (M35b/M37a). Recombinant human CYP3A4 catalyzed the formation of all these metabolites, whereas CYP3A5 catalyzed the formation of M2/M3 and M41. CYP2C9 only catalyzed the formation of M15. There was a high correlation between the rates of formation of M2/M3, M15, and M41, which was determined using 10 human liver microsomal samples and testosterone 6beta-hydroxylation catalyzed by CYP3A4/5 (r > or = 0.91). Ketoconazole and azamulin (inhibitors of CYP3A4) were potent inhibitors of the formation of M2/M3, M15, M41, and M35b/M37a from human liver microsomes. A CYP3A4/5-specific monoclonal antibody (1 microg/microg of protein) inhibited the formation of all metabolites from human liver microsomes by 86 to 100%. The results of this study suggest that formation of the major vicriviroc metabolites in human liver microsomes is primarily mediated via CYP3A4. CYP2C9 and CYP3A5 most likely play a minor role in the biotransformation of this compound. These enzymology data will provide guidance to design clinical studies to address any potential drug-drug interactions. SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/17827338/Identification_of_human_liver_cytochrome_P450_enzymes_involved_in_biotransformation_of_vicriviroc_a_CCR5_receptor_antagonist_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=17827338 DB - PRIME DP - Unbound Medicine ER -