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CYP2C9 genotypes and diclofenac metabolism in Spanish healthy volunteers

  • Phamarcokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Objective

This study analyzed the frequency of CYP2C9 variant alleles and evaluated the impact of CYP2C9 genotype on diclofenac metabolism in a Spanish population.

Methods

Diclofenac hydroxylation capacity was studied in a population of 102 healthy volunteers. After a single oral dose of 50 mg diclofenac the 0- to 8-h urinary concentrations of diclofenac and its main metabolites, 4'-hydroxy (OH), 3′-OH and 5-OH diclofenac were analyzed by high-performance liquid chromatography. CYP2C9 genotyping for the variant alleles CYP2C9*2 and *3 was carried out with PCR-RFLP.

Results

The frequencies of CYP2C9*1, *2, and *3 alleles were 0.74 (95%CI: 0.68–0.80), 0.16 (95%CI: 0.11–0.21) and 0.10 (95%CI: 0.06–0.15), respectively, among the 102 Spaniards studied. The diclofenac/4'-OH diclofenac urinary ratio, but not the diclofenac/3′-OH diclofenac and diclofenac/5-OH diclofenac ratios, was related to CYP2C9 genotype. The diclofenac/4'-OH ratio was significantly higher among subjects with CYP2C9*1/*3 (0.83±0.4, n=14, 95% CI for the difference: 0.02–0.4) and CYP2C9*2/*3 (1.10±0.5, n=4, 95% CI for the difference: 0.16–0.8) genotypes compared to CYP2C9*1/*1 (0.62±0.3, n=59) and approximately threefold higher (1.8) in the only subject homozygous for CYP2C9*3 variant.

Conclusions

The frequencies of CYP2C9*1, *2, and *3 alleles in the Spanish population reported here were similar to those found in the previously studied white European populations, and different of the previously reported in another Spanish population. CYP2C9*3 allele seems to influence the 4'-hydroxylation of diclofenac, although there is a large overlapping in the urinary metabolic ratio between the genotype groups studied

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Acknowledgements

This study was supported by a grant from Ministerio de Sanidad y Consumo, Instituto Carlos III, Spain (FIS 01/0699), and partly by the Swedish Society of Medicine, the European Union INCO-Copernicus Project (ERBIC15CT980340) and the Hungarian-Spanish S&T Cooperation Programme (E-45/2001). The authors thank the volunteers for their participation in the study and A. de la Rubia, O Ledea, I. Almirall, M. Martínez, M. Cáceres, J. Cobaleda, and P. Fernández-Salguero for their contribution in developing methods, samples collection, and analysis.

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Author notes

  1. Roland Berecz

    Present address: Department of Psychiatry, Medical and Health Science Centre, University of Debrecen, Debrecen, Hungary

Authors and Affiliations

  1. Department of Pharmacology and Psychiatry, Faculty of Medicine, University of Extremadura, Av. de Elvas s/n, 06071, Badajoz, Spain

    Pedro Dorado, Roland Berecz, Maria-Jesús Norberto & Adrián LLerena

  2. Department of Clinical Pharmacology, Huddinge University Hospital, Karolinska Institute, Stockholm, Sweden

    Ümit Yasar

  3. Department of Medical Sciences, Clinical Pharmacology, University Hospital, Uppsala, Sweden

    Marja-Liisa Dahl

  4. University of Beira Interior, Covilhã, Portugal

    Adrián LLerena

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  1. Pedro Dorado
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Correspondence to Adrián LLerena.

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Dorado, P., Berecz, R., Norberto, MJ. et al. CYP2C9 genotypes and diclofenac metabolism in Spanish healthy volunteers. Eur J Clin Pharmacol 59, 221–225 (2003). https://doi.org/10.1007/s00228-003-0588-0

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  • DOI: https://doi.org/10.1007/s00228-003-0588-0

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