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Evaluation of the relationship between polymorphisms in CYP2C8 and CYP2C9 and the pharmacokinetics of celecoxib

Authors

  • Rocío Prieto-Pérez PhD,

    1. Service of Clinical Pharmacology, Hospital Universitario de la Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain
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  • Dolores Ochoa MD,

    1. Service of Clinical Pharmacology, Hospital Universitario de la Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain
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  • Teresa Cabaleiro PhD,

    1. Service of Clinical Pharmacology, Hospital Universitario de la Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain
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  • Manuel Román,

    1. Service of Clinical Pharmacology, Hospital Universitario de la Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain
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  • Sergio Daniel Sánchez-Rojas MD,

    1. Service of Clinical Pharmacology, Hospital Universitario de la Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain
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  • María Talegón,

    1. Service of Clinical Pharmacology, Hospital Universitario de la Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain
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  • Francisco Abad-Santos MD, PhD

    Corresponding author
    1. Service of Clinical Pharmacology, Hospital Universitario de la Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain
    2. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
    • Corresponding Author:

      Francisco Abad-Santos, Service of Clinical Pharmacology, Hospital Universitario de la Princesa, Diego de León, 62, Madrid 28006, Spain.

      Email: francisco.abad@salud.madrid.org

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  • Rocío Prieto-Pérez and Dolores Ochoa contributed equally to the manuscript.

Abstract

Celecoxib is metabolized by enzymes of the cytochrome P450 (CYP450) superfamily, mainly CYP2C9 and CYP3A4. Polymorphisms in the CYP2C9 gene have been associated with decreased enzyme activity and alteration of celecoxib pharmacokinetic parameters. However, literature reports are limited, and some results are contradictory. We enrolled 24 healthy volunteers in a single-dose replicated crossover trial with celecoxib 200 mg. We evaluated the association between single-nucleotide polymorphisms in the CYP2C8 and CYP2C9 genes (CYP2C8*2, CYP2C8*3, CYP2C8*4, CYP2C9*2, and CYP2C9*3) of these individuals and the pharmacokinetic parameters of celecoxib. Subjects carrying CYP2C9*1/*3 and CYP2C9*3/*3 had a higher AUC (2- and 7.7-fold, respectively) and Cmax (1.5- and 1.8-fold, respectively) and lower clearance (2.3- and 10-fold, respectively) than those carrying CYP2C9*1/*1. Half-life was 2.7-fold higher in subjects with CYP2C9*3/*3 than in those with the wild type but not in those with CYP2C9*1/*3. We did not find any significant effect of gender or CYP2C8 polymorphisms on the pharmacokinetics of celecoxib. In conclusion, the recommended dose of celecoxib should be decreased in CYP2C9*3 carriers, especially in homozygous subjects.

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