Genetic polymorphism of CYP1A2 and the toxicity of leflunomide treatment in rheumatoid arthritis patients.
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.


CONCLUSIONS
Our results suggest that the CYP1A2*1F allele may be associated with leflunomide toxicity in RA patients.
Bohanec Grabar
Petra
P
Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia. petra.bohanec@mf.uni-lj.si
Rozman
Blaz
B
Tomsic
Matija
M
Suput
Dasa
D
Logar
Dusan
D
Dolzan
Vita
V
D000368:Aged; D018501:Antirheumatic Agents / Q000633:toxicity*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics*; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000633:toxicity*; D000077339:Leflunomide; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D010597:Pharmacogenetics; D010865:Pilot Projects; D011110:Polymorphism, Genetic; D011537:Pruritus / Q000139:chemically induced; D014839:Vomiting / Q000139:chemically induced
D018501:Antirheumatic Agents; D007555:Isoxazoles; D019388:Cytochrome P-450 CYP1A2; D000077339:Leflunomide