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Confirmation that cytochrome P450 2C8 (CYP2C8) plays a minor role in (S)-(+)- and (R)-(-)-ibuprofen hydroxylation in vitro.

Abstract

Various groups have sought to determine the impact of CYP2C8 genotype (and CYP2C8 inhibition) on the pharmacokinetics (PK) of ibuprofen (IBU) enantiomers. However, the contribution of cytochrome P450 2C8 (CYP2C8) in human liver microsomes (HLMs) has not been reported. Therefore, in vitro cytochrome P450 (P450) reaction phenotyping was conducted with selective inhibitors of cytochrome P450 2C9 (CYP2C9) and CYP2C8. In the presence of HLMs, sulfaphenazole (CYP2C9 inhibitor), and anti-CYP2C9 monoclonal antibodies (mAbs) inhibited (73-100%) the 2- and 3-hydroxylation of both IBU enantiomers (1 and 20 microM). At a higher IBU concentration (500 microM), the same inhibitors were less able to inhibit the 2-hydroxylation of (S)-(+)-IBU (32-52%) and (R)-(-)-IBU (30-64%), whereas the 3-hydroxylation of (S)-(+)-IBU and (R)-(-)-IBU was inhibited 66 to 83 and 70 to 89%, respectively. In contrast, less inhibition was observed with montelukast (CYP2C8 inhibitor, < or =35%) and anti-CYP2C8 mAbs (< or =24%) at all concentrations of IBU. When (S)-(+)-IBU and (R)-(-)-IBU (1 microM) were incubated with a panel of recombinant human P450s, only CYP2C9 formed appreciable amounts of the hydroxy metabolites. At a higher IBU enantiomer concentration (500 microM), additional P450s catalyzed 2-hydroxylation (CYP3A4, CYP2C8, CYP2C19, CYP2D6, CYP2E1, and CYP2B6) and 3-hydroxylation (CYP2C19). When the P450 reaction phenotype and additional clearance pathways are considered (e.g., direct glucuronidation and chiral inversion), it is concluded that CYP2C8 plays a minor role in (R)-(-)-IBU (<10%) and (S)-(+)-IBU ( approximately 13%) clearance. By extension, one would not expect CYP2C8 inhibition (and genotype) to greatly affect the pharmacokinetic profile of either enantiomer. On the other hand, CYP2C9 inhibition and genotype are expected to have an impact on the PK of (S)-(+)-IBU.

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  • Authors+Show Affiliations

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    Bristol-Myers Squibb, 311 Pennington-Rocky Hill Rd., Princeton, NJ 08534, USA. shu.chang@bms.com

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    MeSH

    Acetates
    Antibodies, Monoclonal
    Aryl Hydrocarbon Hydroxylases
    Catalysis
    Cytochrome P-450 CYP2C19
    Cytochrome P-450 CYP2C8
    Cytochrome P-450 CYP2C9
    Cytochrome P-450 CYP3A
    Cytochrome P-450 Enzyme Inhibitors
    Cytochrome P-450 Enzyme System
    Diclofenac
    Enzyme Inhibitors
    Genotype
    Humans
    Hydroxylation
    Ibuprofen
    Ketoconazole
    Kinetics
    Mephenytoin
    Microsomes, Liver
    Quinolines
    Recombinant Proteins
    Stereoisomerism
    Sulfaphenazole
    Tandem Mass Spectrometry

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    18787056

    Citation

    Chang, Shu-Ying, et al. "Confirmation That Cytochrome P450 2C8 (CYP2C8) Plays a Minor Role in (S)-(+)- and (R)-(-)-ibuprofen Hydroxylation in Vitro." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 36, no. 12, 2008, pp. 2513-22.
    Chang SY, Li W, Traeger SC, et al. Confirmation that cytochrome P450 2C8 (CYP2C8) plays a minor role in (S)-(+)- and (R)-(-)-ibuprofen hydroxylation in vitro. Drug Metab Dispos. 2008;36(12):2513-22.
    Chang, S. Y., Li, W., Traeger, S. C., Wang, B., Cui, D., Zhang, H., ... Rodrigues, A. D. (2008). Confirmation that cytochrome P450 2C8 (CYP2C8) plays a minor role in (S)-(+)- and (R)-(-)-ibuprofen hydroxylation in vitro. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 36(12), pp. 2513-22. doi:10.1124/dmd.108.022970.
    Chang SY, et al. Confirmation That Cytochrome P450 2C8 (CYP2C8) Plays a Minor Role in (S)-(+)- and (R)-(-)-ibuprofen Hydroxylation in Vitro. Drug Metab Dispos. 2008;36(12):2513-22. PubMed PMID: 18787056.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Confirmation that cytochrome P450 2C8 (CYP2C8) plays a minor role in (S)-(+)- and (R)-(-)-ibuprofen hydroxylation in vitro. AU - Chang,Shu-Ying, AU - Li,Wenying, AU - Traeger,Sarah C, AU - Wang,Bei, AU - Cui,Donghui, AU - Zhang,Hongjian, AU - Wen,Bo, AU - Rodrigues,A David, Y1 - 2008/09/11/ PY - 2008/9/13/pubmed PY - 2009/6/6/medline PY - 2008/9/13/entrez SP - 2513 EP - 22 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab. Dispos. VL - 36 IS - 12 N2 - Various groups have sought to determine the impact of CYP2C8 genotype (and CYP2C8 inhibition) on the pharmacokinetics (PK) of ibuprofen (IBU) enantiomers. However, the contribution of cytochrome P450 2C8 (CYP2C8) in human liver microsomes (HLMs) has not been reported. Therefore, in vitro cytochrome P450 (P450) reaction phenotyping was conducted with selective inhibitors of cytochrome P450 2C9 (CYP2C9) and CYP2C8. In the presence of HLMs, sulfaphenazole (CYP2C9 inhibitor), and anti-CYP2C9 monoclonal antibodies (mAbs) inhibited (73-100%) the 2- and 3-hydroxylation of both IBU enantiomers (1 and 20 microM). At a higher IBU concentration (500 microM), the same inhibitors were less able to inhibit the 2-hydroxylation of (S)-(+)-IBU (32-52%) and (R)-(-)-IBU (30-64%), whereas the 3-hydroxylation of (S)-(+)-IBU and (R)-(-)-IBU was inhibited 66 to 83 and 70 to 89%, respectively. In contrast, less inhibition was observed with montelukast (CYP2C8 inhibitor, < or =35%) and anti-CYP2C8 mAbs (< or =24%) at all concentrations of IBU. When (S)-(+)-IBU and (R)-(-)-IBU (1 microM) were incubated with a panel of recombinant human P450s, only CYP2C9 formed appreciable amounts of the hydroxy metabolites. At a higher IBU enantiomer concentration (500 microM), additional P450s catalyzed 2-hydroxylation (CYP3A4, CYP2C8, CYP2C19, CYP2D6, CYP2E1, and CYP2B6) and 3-hydroxylation (CYP2C19). When the P450 reaction phenotype and additional clearance pathways are considered (e.g., direct glucuronidation and chiral inversion), it is concluded that CYP2C8 plays a minor role in (R)-(-)-IBU (<10%) and (S)-(+)-IBU ( approximately 13%) clearance. By extension, one would not expect CYP2C8 inhibition (and genotype) to greatly affect the pharmacokinetic profile of either enantiomer. On the other hand, CYP2C9 inhibition and genotype are expected to have an impact on the PK of (S)-(+)-IBU. SN - 1521-009X UR - https://www.unboundmedicine.com/medline/citation/18787056/Confirmation_that_cytochrome_P450_2C8__CYP2C8__plays_a_minor_role_in__S___+___and__R______ibuprofen_hydroxylation_in_vitro_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&amp;pmid=18787056 DB - PRIME DP - Unbound Medicine ER -