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Research ArticleArticle

Evaluation of the Relationship between Sex, Polymorphisms in CYP2C8 and CYP2C9, and Pharmacokinetics of Angiotensin Receptor Blockers

Teresa Cabaleiro, Manuel Román, Dolores Ochoa, María Talegón, Rocío Prieto-Pérez, Aneta Wojnicz, Rosario López-Rodríguez, Jesús Novalbos and Francisco Abad-Santos
Drug Metabolism and Disposition January 2013, 41 (1) 224-229; DOI: https://doi.org/10.1124/dmd.112.046292
Teresa Cabaleiro
Service of Clinical Pharmacology, Hospital Universitario de la Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria Princesa, Madrid, Spain (T.C., M.R., D.O., M.T., R.P.-P., A.W., J.N., F.A.-S.); Liver Unit, Gastroenterology Service, Hospital Universitario de La Princesa, Instituto de Investigación Sanitario Princesa, Madrid, Spain (R.L.-R.); and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain (R.L.-R., F.A.-S.)
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Manuel Román
Service of Clinical Pharmacology, Hospital Universitario de la Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria Princesa, Madrid, Spain (T.C., M.R., D.O., M.T., R.P.-P., A.W., J.N., F.A.-S.); Liver Unit, Gastroenterology Service, Hospital Universitario de La Princesa, Instituto de Investigación Sanitario Princesa, Madrid, Spain (R.L.-R.); and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain (R.L.-R., F.A.-S.)
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Dolores Ochoa
Service of Clinical Pharmacology, Hospital Universitario de la Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria Princesa, Madrid, Spain (T.C., M.R., D.O., M.T., R.P.-P., A.W., J.N., F.A.-S.); Liver Unit, Gastroenterology Service, Hospital Universitario de La Princesa, Instituto de Investigación Sanitario Princesa, Madrid, Spain (R.L.-R.); and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain (R.L.-R., F.A.-S.)
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María Talegón
Service of Clinical Pharmacology, Hospital Universitario de la Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria Princesa, Madrid, Spain (T.C., M.R., D.O., M.T., R.P.-P., A.W., J.N., F.A.-S.); Liver Unit, Gastroenterology Service, Hospital Universitario de La Princesa, Instituto de Investigación Sanitario Princesa, Madrid, Spain (R.L.-R.); and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain (R.L.-R., F.A.-S.)
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Rocío Prieto-Pérez
Service of Clinical Pharmacology, Hospital Universitario de la Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria Princesa, Madrid, Spain (T.C., M.R., D.O., M.T., R.P.-P., A.W., J.N., F.A.-S.); Liver Unit, Gastroenterology Service, Hospital Universitario de La Princesa, Instituto de Investigación Sanitario Princesa, Madrid, Spain (R.L.-R.); and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain (R.L.-R., F.A.-S.)
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Aneta Wojnicz
Service of Clinical Pharmacology, Hospital Universitario de la Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria Princesa, Madrid, Spain (T.C., M.R., D.O., M.T., R.P.-P., A.W., J.N., F.A.-S.); Liver Unit, Gastroenterology Service, Hospital Universitario de La Princesa, Instituto de Investigación Sanitario Princesa, Madrid, Spain (R.L.-R.); and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain (R.L.-R., F.A.-S.)
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Rosario López-Rodríguez
Service of Clinical Pharmacology, Hospital Universitario de la Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria Princesa, Madrid, Spain (T.C., M.R., D.O., M.T., R.P.-P., A.W., J.N., F.A.-S.); Liver Unit, Gastroenterology Service, Hospital Universitario de La Princesa, Instituto de Investigación Sanitario Princesa, Madrid, Spain (R.L.-R.); and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain (R.L.-R., F.A.-S.)
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Jesús Novalbos
Service of Clinical Pharmacology, Hospital Universitario de la Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria Princesa, Madrid, Spain (T.C., M.R., D.O., M.T., R.P.-P., A.W., J.N., F.A.-S.); Liver Unit, Gastroenterology Service, Hospital Universitario de La Princesa, Instituto de Investigación Sanitario Princesa, Madrid, Spain (R.L.-R.); and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain (R.L.-R., F.A.-S.)
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Francisco Abad-Santos
Service of Clinical Pharmacology, Hospital Universitario de la Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria Princesa, Madrid, Spain (T.C., M.R., D.O., M.T., R.P.-P., A.W., J.N., F.A.-S.); Liver Unit, Gastroenterology Service, Hospital Universitario de La Princesa, Instituto de Investigación Sanitario Princesa, Madrid, Spain (R.L.-R.); and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain (R.L.-R., F.A.-S.)
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Abstract

Angiotensin II receptor blockers (ARBs) are used to treat hypertension. Most ARBs are metabolized by CYP2C9. The aim of this study is to evaluate the possible association between sex, polymorphisms in the CYP2C8 and CYP2C9 genes, and the pharmacokinetics of losartan, valsartan, candesartan, and telmisartan. The study population comprised 246 healthy volunteers from seven single-dose clinical trials: 64 from two candesartan studies, 43 from a telmisartan study, 36 from a losartan study, and 103 from three valsartan studies. DNA was extracted from blood samples and single-nucleotide polymorphisms in the CYP2C8 (CYP2C8*2, CYP2C8*3, CYP2C8*4, CYP2C8*5) and CYP2C9 (CYP2C9*2, CYP2C9*3) genes were evaluated using real-time polymerase chain reaction. Sex only affected telmisartan pharmacokinetics, since women showed a higher telmisartan Cmax than men (590.5 ± 75.8 ng/ml versus 282.1 ± 30.8 ng/ml; P ≤ 0.01). CYP2C9 variants were associated only with losartan pharmacokinetics: the half-life of losartan was higher in CYP2C9*3 allele carriers (3.1 ± 0.4 hours) than in volunteers with the wild-type genotype (2.3 ± 0.1 hours) (P ≤ 0.05). CYP2C8 polymorphisms were associated only with valsartan pharmacokinetics, since *2 allele carriers showed faster clearance (1.07 ± 0.57 l/h·kg) than those with the wild-type genotype (0.48 ± 0.72 l/h·kg; P ≤ 0.01) and carriers of the *3 allele (0.35 ± 0.49 l/h·kg; P ≤ 0.001). These results suggest that genotypes for CYP2C9 and CYP2C8 are relevant to the pharmacokinetics of losartan and valsartan, respectively, but not the pharmacokinetics of candesartan or telmisartan.

Footnotes

  • This work was partially funded by Fundación Teófilo Hernando, a nonprofit foundation linked to Universidad Autónoma de Madrid, and the Fundación de Investigación Biomédica del Hospital Universitario de la Princesa.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • dx.doi.org/10.1124/dmd.112.046292.

  • Received April 17, 2012.
  • Accepted November 1, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (1)
Drug Metabolism and Disposition
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1 Jan 2013
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Research ArticleArticle

Pharmacogenetics and Pharmacokinetics of ARBs

Teresa Cabaleiro, Manuel Román, Dolores Ochoa, María Talegón, Rocío Prieto-Pérez, Aneta Wojnicz, Rosario López-Rodríguez, Jesús Novalbos and Francisco Abad-Santos
Drug Metabolism and Disposition January 1, 2013, 41 (1) 224-229; DOI: https://doi.org/10.1124/dmd.112.046292

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Research ArticleArticle

Pharmacogenetics and Pharmacokinetics of ARBs

Teresa Cabaleiro, Manuel Román, Dolores Ochoa, María Talegón, Rocío Prieto-Pérez, Aneta Wojnicz, Rosario López-Rodríguez, Jesús Novalbos and Francisco Abad-Santos
Drug Metabolism and Disposition January 1, 2013, 41 (1) 224-229; DOI: https://doi.org/10.1124/dmd.112.046292
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