title: Genetic polymorphism of CYP1A2 and the toxicity of leflunomide treatment in rheumatoid arthritis patients.
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.
  
  
  CONCLUSIONS
  Our results suggest that the CYP1A2*1F allele may be associated with leflunomide toxicity in RA patients.
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia. petra.bohanec@mf.uni-lj.si
authors.forename: Petra
authors.initials: P
authors.lastname: Bohanec Grabar
authors.forename: Blaz
authors.initials: B
authors.lastname: Rozman
authors.forename: Matija
authors.initials: M
authors.lastname: Tomsic
authors.forename: Dasa
authors.initials: D
authors.lastname: Suput
authors.forename: Dusan
authors.initials: D
authors.lastname: Logar
authors.forename: Vita
authors.initials: V
authors.lastname: Dolzan
mesh_terms: 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
chemical_list: D018501:Antirheumatic Agents; D007555:Isoxazoles; D019388:Cytochrome P-450 CYP1A2; D000077339:Leflunomide