Journal
EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY
Volume 64, Issue 9, Pages 871-876Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s00228-008-0498-2
Keywords
rheumatoid arthritis; leflunomide toxicity; cytochromes P450; polymorphism
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Funding
- The Slovenian Research Agency [PO-0503-0381]
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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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