Abstract
Objective
Leflunomide is a disease-modifying antirheumatic drug used for treating rheumatoid arthritis (RA). In vitro studies demonstrated that cytochromes P450 (CYPs), mainly CYP1A2 and CYP2C19, might be involved in leflunomide activation. The aim of our study was to investigate whether genetic polymorphisms of CYP1A2, CYP2C19, and CYP2C9 influence leflunomide toxicity.
Methods
A genotyping approach was used to determine CYP1A2*1F, CYP2C19*2, CYP2C19*17, CYP2C9*2, and CYP2C9*3 alleles in 105 RA patients.
Results
Leflunomide treatment was well tolerated by 62 patients, whereas 43 patients discontinued the treatment within the first year due to toxicity. Patients with CYP1A2*1F CC genotype had a 9.7-fold higher risk for overall leflunomide-induced toxicity than did the carriers of CYP1A2*1F A allele [P = 0.002, odds ratio = 9.708, 95% confidence interval = 2.276–41.403]. No significant association between the CYP2C19 and CYP2C9 genotypes and the leflunomide toxicity was observed.
Conclusion
Our results suggest that the CYP1A2*1F allele may be associated with leflunomide toxicity in RA patients.
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Acknowledgements
The authors thank Magnus Ingelman-Sundberg and Sarah Sim from Karolinska Institute, Stockholm, Sweden, for kindly providing control DNA samples with known CYP2C19 *17 genotype.
We acknowledge Mojca Kos-Golja, M.D., Sonja Praprotnik, M.D., Ph.D., Aleš Ambrožič, M.D., Ph.D., Cvetka Kastelic-Klasinc, M.D., and Boris Lestan, M.D., M.Sc. from the Department of Rheumatology, University Medical Centre Ljubljana, Slovenia, for referring the patients. We thank Milena Pavić-Nikolić for her excellent technical support. We are especially grateful to Snežna Sodin-Šemrl, M.S., Ph.D. for language corrections. This work was financially supported by The Slovenian Research Agency, grant no. PO-0503–0381. The authors declare no conflict of interest.
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Bohanec Grabar, P., Rozman, B., Tomšič, M. et al. Genetic polymorphism of CYP1A2 and the toxicity of leflunomide treatment in rheumatoid arthritis patients. Eur J Clin Pharmacol 64, 871–876 (2008). https://doi.org/10.1007/s00228-008-0498-2
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DOI: https://doi.org/10.1007/s00228-008-0498-2