Enantiospecific Pharmacogenomics of Fluvastatin.

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  • Additional Information
    • Source:
      Publisher: Wiley Country of Publication: United States NLM ID: 0372741 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1532-6535 (Electronic) Linking ISSN: 00099236 NLM ISO Abbreviation: Clin Pharmacol Ther Subsets: MEDLINE
    • Publication Information:
      Publication: 2015- : Hoboken, NJ : Wiley
      Original Publication: St. Louis : C.V. Mosby
    • Subject Terms:
      Anticholesteremic Agents/*chemistry ; Anticholesteremic Agents/*pharmacokinetics ; Cytochrome P-450 CYP2C9/*genetics ; Fluvastatin/*chemistry ; Fluvastatin/*pharmacokinetics ; Liver-Specific Organic Anion Transporter 1/*genetics; Area Under Curve ; Half-Life ; Humans ; Pharmacogenetics ; Polymorphism, Single Nucleotide
    • Abstract:
      The aim of this study was to investigate how variability in multiple genes related to pharmacokinetics affects fluvastatin exposure. We determined fluvastatin enantiomer pharmacokinetics and sequenced 379 pharmacokinetic genes in 200 healthy volunteers. CYP2C9*3 associated with significantly increased area under the plasma concentration-time curve (AUC) of both 3R,5S-fluvastatin and 3S,5R-fluvastatin (by 67% and 94% per variant allele copy, P = 3.77 × 10 -9 and P = 3.19 × 10 -12 ). In contrast, SLCO1B1 c.521T>C associated with increased AUC of active 3R,5S-fluvastatin only (by 34% per variant allele copy; P = 8.15 × 10 -8 ). A candidate gene analysis suggested that CYP2C9*2 also affects the AUC of both fluvastatin enantiomers and that SLCO2B1 single-nucleotide variations may affect the AUC of 3S,5R-fluvastatin. Thus, SLCO transporters have enantiospecific effects on fluvastatin pharmacokinetics in humans. Genotyping of both CYP2C9 and SLCO1B1 may be useful in predicting fluvastatin efficacy and myotoxicity.
      (© 2019 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)
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    • Accession Number:
      0 (Anticholesteremic Agents)
      0 (Liver-Specific Organic Anion Transporter 1)
      0 (SLCO1B1 protein, human)
      4L066368AS (Fluvastatin)
      EC 1.14.13.- (Cytochrome P-450 CYP2C9)
    • Publication Date:
      Date Created: 20190417 Date Completed: 20200511 Latest Revision: 20200511
    • Publication Date:
      20221213
    • Accession Number:
      PMC6767327
    • Accession Number:
      10.1002/cpt.1463
    • Accession Number:
      30989645