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Metabolism of a novel phosphodiesterase-IV inhibitor (V11294) by human hepatic cytochrome P450 forms.

Abstract

1. The metabolism of a novel phosphodiesterase-IV inhibitor (V11294) was studied in human liver microsomal and cytosol preparations and in cDNA-expressed human hepatic CYP forms. 2. Human liver microsomes, but not cytosol, catalysed the NADPH-dependent metabolism of V11294 to V10331 (formed by hydroxylation of the cyclopentyl ring), V10332 (N-desethyl V11294) and V11689 (formed by hydroxylation of the isopropyl side chain). In addition, smaller amounts of a secondary metabolite V11690 (which can be formed from either V10332 or V11689) were also produced. 3. Kinetic analysis of V11294 metabolism to V10331, V10332 and V11689 in two preparations of pooled human liver microsomes revealed average K(m) = 2.5, 8.1 and 3.9 micro M, respectively. 4. The metabolism of V11294 was determined with a characterized bank of 16 individual human liver microsomal preparations employing a V11294 substrate concentration of 8 micro M (i.e. approximately the K(m) for V10332 formation and around twice the K(m) for V10331 and V11689 formation). Good correlations (r(2) = 0.570-0.903) were observed between V10331, V10332 and V11689 formation and markers of CYP3A forms. In contrast, poorer correlations (r(2) = 0.0002-0.428) were observed with markers of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP4A9/11. 5. Using human B-lymphoblastoid cell microsomes containing cDNA-expressed CYP forms, V11294 (8 micro M) was metabolized by cDNA-expressed CYP3A4 to V10331, V10332 and V11689, with lower amounts of V11690 also being formed. Lower rates of V11294 metabolism to some V11294 metabolites were also observed with cDNA-expressed CYP2C9, CYP2C19 and CYP2D6, whereas only very low or undetectable rates of V11294 metabolism were observed with cDNA-expressed CYP1A2, CYP2A6, CYP2B6, CYP2C8 and CYP2E1. 6. The metabolism of V11294 (8 micro M) to V10331, V10332 and V11689 was markedly inhibited by the CYP3A mechanism-based inhibitor troleandomycin. In contrast, V11294 metabolism was not significantly affected by inhibitors of CYP1A2, CYP2C9, CYP2D6 and CYP2E1 or by the CYP2C19 substrate S-mephenytoin. 7. In summary, by correlation analysis, chemical inhibition studies and the use of cDNA-expressed CYPs, V11294 metabolism in human liver to V10331, V10332 and V11689 appears to be primarily catalysed by CYP3A forms.

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  • Authors+Show Affiliations

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    Purdue Pharma L.P., 444 Sawmill River Road, Ardsley, NY 10502, USA.

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    MeSH

    3',5'-Cyclic-AMP Phosphodiesterases
    Cyclic Nucleotide Phosphodiesterases, Type 4
    Cytochrome P-450 Enzyme Inhibitors
    Cytochrome P-450 Enzyme System
    DNA, Complementary
    Enzyme Inhibitors
    Humans
    In Vitro Techniques
    Isoenzymes
    Kinetics
    Leukemia, Lymphoid
    Liver
    Microsomes, Liver
    Pharmaceutical Preparations
    Phenotype
    Phosphodiesterase Inhibitors
    Purines
    Tumor Cells, Cultured

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    12160484

    Citation

    Subrahmanyam, V, et al. "Metabolism of a Novel phosphodiesterase-IV Inhibitor (V11294) By Human Hepatic Cytochrome P450 Forms." Xenobiotica; the Fate of Foreign Compounds in Biological Systems, vol. 32, no. 6, 2002, pp. 521-34.
    Subrahmanyam V, Renwick AB, Walters DG, et al. Metabolism of a novel phosphodiesterase-IV inhibitor (V11294) by human hepatic cytochrome P450 forms. Xenobiotica. 2002;32(6):521-34.
    Subrahmanyam, V., Renwick, A. B., Walters, D. G., Price, R. J., Tonelli, A. P., & Lake, B. G. (2002). Metabolism of a novel phosphodiesterase-IV inhibitor (V11294) by human hepatic cytochrome P450 forms. Xenobiotica; the Fate of Foreign Compounds in Biological Systems, 32(6), pp. 521-34.
    Subrahmanyam V, et al. Metabolism of a Novel phosphodiesterase-IV Inhibitor (V11294) By Human Hepatic Cytochrome P450 Forms. Xenobiotica. 2002;32(6):521-34. PubMed PMID: 12160484.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Metabolism of a novel phosphodiesterase-IV inhibitor (V11294) by human hepatic cytochrome P450 forms. AU - Subrahmanyam,V, AU - Renwick,A B, AU - Walters,D G, AU - Price,R J, AU - Tonelli,A P, AU - Lake,B G, PY - 2002/8/6/pubmed PY - 2002/9/19/medline PY - 2002/8/6/entrez SP - 521 EP - 34 JF - Xenobiotica; the fate of foreign compounds in biological systems JO - Xenobiotica VL - 32 IS - 6 N2 - 1. The metabolism of a novel phosphodiesterase-IV inhibitor (V11294) was studied in human liver microsomal and cytosol preparations and in cDNA-expressed human hepatic CYP forms. 2. Human liver microsomes, but not cytosol, catalysed the NADPH-dependent metabolism of V11294 to V10331 (formed by hydroxylation of the cyclopentyl ring), V10332 (N-desethyl V11294) and V11689 (formed by hydroxylation of the isopropyl side chain). In addition, smaller amounts of a secondary metabolite V11690 (which can be formed from either V10332 or V11689) were also produced. 3. Kinetic analysis of V11294 metabolism to V10331, V10332 and V11689 in two preparations of pooled human liver microsomes revealed average K(m) = 2.5, 8.1 and 3.9 micro M, respectively. 4. The metabolism of V11294 was determined with a characterized bank of 16 individual human liver microsomal preparations employing a V11294 substrate concentration of 8 micro M (i.e. approximately the K(m) for V10332 formation and around twice the K(m) for V10331 and V11689 formation). Good correlations (r(2) = 0.570-0.903) were observed between V10331, V10332 and V11689 formation and markers of CYP3A forms. In contrast, poorer correlations (r(2) = 0.0002-0.428) were observed with markers of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP4A9/11. 5. Using human B-lymphoblastoid cell microsomes containing cDNA-expressed CYP forms, V11294 (8 micro M) was metabolized by cDNA-expressed CYP3A4 to V10331, V10332 and V11689, with lower amounts of V11690 also being formed. Lower rates of V11294 metabolism to some V11294 metabolites were also observed with cDNA-expressed CYP2C9, CYP2C19 and CYP2D6, whereas only very low or undetectable rates of V11294 metabolism were observed with cDNA-expressed CYP1A2, CYP2A6, CYP2B6, CYP2C8 and CYP2E1. 6. The metabolism of V11294 (8 micro M) to V10331, V10332 and V11689 was markedly inhibited by the CYP3A mechanism-based inhibitor troleandomycin. In contrast, V11294 metabolism was not significantly affected by inhibitors of CYP1A2, CYP2C9, CYP2D6 and CYP2E1 or by the CYP2C19 substrate S-mephenytoin. 7. In summary, by correlation analysis, chemical inhibition studies and the use of cDNA-expressed CYPs, V11294 metabolism in human liver to V10331, V10332 and V11689 appears to be primarily catalysed by CYP3A forms. SN - 0049-8254 UR - https://www.unboundmedicine.com/medline/citation/12160484/Metabolism_of_a_novel_phosphodiesterase_IV_inhibitor__V11294__by_human_hepatic_cytochrome_P450_forms_ L2 - http://www.tandfonline.com/doi/full/10.1080/00498250210128684 DB - PRIME DP - Unbound Medicine ER -