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Research ArticleArticle

The 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor Fluvastatin: Effect on Human Cytochrome P-450 and Implications for Metabolic Drug Interactions

Volker Fischer, Laurie Johanson, Francis Heitz, Robert Tullman, Elizabeth Graham, Jean-Pierre Baldeck and William T. Robinson
Drug Metabolism and Disposition March 1999, 27 (3) 410-416;
Volker Fischer
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Laurie Johanson
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Francis Heitz
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Robert Tullman
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Elizabeth Graham
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Jean-Pierre Baldeck
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William T. Robinson
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Abstract

Fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, was metabolized by human liver microsomes to 5-hydroxy-, 6-hydroxy-, and N-deisopropyl-fluvastatin. Total metabolite formation was biphasic with apparentKm values of 0.2 to 0.7 and 7.9 to 50 μM and intrinsic metabolic clearance rates of 1.4 to 4 and 0.3 to 1.5 ml/h/mg microsomal protein for the high and lowKm components, respectively. Several enzymes, but mainly CYP2C9, catalyzed fluvastatin metabolism. Only CYP2C9 inhibitors such as sulfaphenazole inhibited the formation of both 6-hydroxy- and N-deisopropyl-fluvastatin. 5-Hydroxy-fluvastatin formation was reduced by compounds that are inhibitors of CYP2C9, CYP3A, or CYP2C8. Fluvastatin in turn inhibited CYP2C9-catalyzed tolbutamide and diclofenac hydroxylation withKi values of 0.3 and 0.5 μM, respectively. For CYP2C8-catalyzed 6α-hydroxy-paclitaxel formation the IC50 was 20 μM and for CYP1A2, CYP2C19, and CYP3A catalyzed reactions, no IC50 could be determined up to 100 μM fluvastatin. All three fluvastatin metabolites were also formed by recombinant CYP2C9, whereas CYP1A1, CYP2C8, CYP2D6, and CYP3A4 produced only 5-hydroxy-fluvastatin. Km values were ∼1, 2.8, and 7.1 μM for CYP2C9, CYP2C8, and CYP3A, respectively. No difference in fluvastatin metabolism was found between the CYP2C9R144 and CYP2C9C144 alleles, suggesting the absence of polymorphic fluvastatin metabolism by these alleles. CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2E1, and CYP3A5 did not produce detectable amounts of any metabolite. This data indicates that several human cytochrome P-450 enzymes metabolize fluvastatin with CYP2C9 contributing 50–80%. Any coadministered drug would therefore only partially reduce the metabolic clearance of fluvastatin; therefore, the likelihood for serious metabolic drug interactions is expected to be minimal.

Footnotes

  • Send reprint requests to: Dr. Volker Fischer, Novartis Institute for Biomedical Research, 59 Route 10, East Hanover, New Jersey 07936. E-mail: volker.fischer{at}pharma.novartis.com

  • Abbreviations used are::
    HMG-CoA
    3-hydroxy-3-methylglutaryl coenzyme A
    CYP or P-450
    cytochrome P-450
    LC/MS
    liquid chromatography/mass spectrometry
    • Received August 20, 1998.
    • Accepted November 16, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 27 (3)
Drug Metabolism and Disposition
Vol. 27, Issue 3
1 Mar 1999
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Research ArticleArticle

The 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor Fluvastatin: Effect on Human Cytochrome P-450 and Implications for Metabolic Drug Interactions

Volker Fischer, Laurie Johanson, Francis Heitz, Robert Tullman, Elizabeth Graham, Jean-Pierre Baldeck and William T. Robinson
Drug Metabolism and Disposition March 1, 1999, 27 (3) 410-416;

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Research ArticleArticle

The 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor Fluvastatin: Effect on Human Cytochrome P-450 and Implications for Metabolic Drug Interactions

Volker Fischer, Laurie Johanson, Francis Heitz, Robert Tullman, Elizabeth Graham, Jean-Pierre Baldeck and William T. Robinson
Drug Metabolism and Disposition March 1, 1999, 27 (3) 410-416;
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