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Research ArticleArticle

Metabolism of Cerivastatin by Human Liver Microsomes In Vitro

Characterization of Primary Metabolic Pathways and of Cytochrome P450 Isozymes involved

Michael Boberg, Rolf Angerbauer, Peter Fey, Wolfgang K. Kanhai, Wolfgang Karl, Armin Kern, Jürgen Ploschke and Martin Radtke
Drug Metabolism and Disposition March 1997, 25 (3) 321-331;
Michael Boberg
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Rolf Angerbauer
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Peter Fey
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Wolfgang K. Kanhai
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Wolfgang Karl
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Armin Kern
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Jürgen Ploschke
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Martin Radtke
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Characterization of Primary Metabolic Pathways and of Cytochrome P450 Isozymes involved

Abstract

Biotransformation of cerivastatin, a new cholesterol-lowering drug, by human liver microsomes was investigated using the14C-labeled drug. Metabolite profiles were established by HPLC and structures of metabolites were elucidated. Two metabolic pathways were equally important, demethylation of the benzylic methyl ether and hydroxylation at one methyl group of the 6-isopropyl substituent. The product of combined hydroxylation and demethylation was observed as a minor metabolite. During sample preparation the lactone forms of both primary metabolites were isolated in small amounts. Detailed structural analysis by NMR and LC-ESI-MS showed that hydroxylation occurred with high regio- and stereoselectivity. The proposed structures were confirmed by chemical synthesis of enantiomerically pure reference compounds. Microsomes from a human lymphoblastoid AHH-1 cell line, stably expressing CYP 3A4, catalyzed the demethylation reaction. Upon incubation of cerivastatin with human liver microsomes in the presence of the specific CYP 3A inhibitor TAO, both hydroxylation and demethylation were considerably reduced. This indicates that CYP 3A enzymes play a major role in cerivastatin metabolism.

Footnotes

  • Send reprint requests to: Dr. M. Boberg, Bayer AG, PH-PD P Drug Metabolism and Isotope Chemistry, D-42096 Wuppertal, Germany.

  • ↵2 M. Radtke and R. Angerbauer, manuscript in preparation

  • Abbreviations used are::
    HMG-CoA
    3-hydroxy-3-methylglutaryl-coenzyme A
    CYP
    cytochrome P450
    TBAII
    tetrabutylammonium hydrogensulfate
    TAO
    triacetylolcandomycin
    TBDMS
    tert. butyldimethylsilyl
    TBDS
    tert. butyldiphenylsilyl
    BuLi
    butylithium
    DMF
    dimethylformamide
    EtOAc
    ethyl acetate
    THF
    tetrahydrofuran
    Et3N
    triethylamine
    PE
    petroleum ether
    DIBAL
    diisobutylaluminiumhydride
    PCC
    pyridinium chlorochromate
    Et3B
    triethylborane
    ESI
    electrospray ionization
    HEPES
    N-2-hydroxyethpiperazine-N′-2-ethanesulfonic acid
    • Received July 24, 1996.
    • Accepted October 29, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 25, Issue 3
1 Mar 1997
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Research ArticleArticle

Metabolism of Cerivastatin by Human Liver Microsomes In Vitro

Michael Boberg, Rolf Angerbauer, Peter Fey, Wolfgang K. Kanhai, Wolfgang Karl, Armin Kern, Jürgen Ploschke and Martin Radtke
Drug Metabolism and Disposition March 1, 1997, 25 (3) 321-331;

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Research ArticleArticle

Metabolism of Cerivastatin by Human Liver Microsomes In Vitro

Michael Boberg, Rolf Angerbauer, Peter Fey, Wolfgang K. Kanhai, Wolfgang Karl, Armin Kern, Jürgen Ploschke and Martin Radtke
Drug Metabolism and Disposition March 1, 1997, 25 (3) 321-331;
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