Investigation of the influence of CYP1A2 and CYP2C19 genetic polymorphism on 2-Cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide (A77 1726) pharmacokinetics in leflunomide-treated patients with rheumatoid arthritis.

Abstract

Leflunomide is a disease-modifying antirheumatic drug used for the treatment of rheumatoid arthritis (RA). Cytochromes P450, mainly CYP1A2 and CYP2C19, may be involved in the transformation of leflunomide to leflunomide metabolite (A77 1726, 2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide). The aim of this study was to investigate whether genetic polymorphisms in CYP1A2 and CYP2C19 influence leflunomide pharmacokinetics, treatment response, and the occurrence of adverse drug reactions (ADRs). The study included 67 patients with RA and 4 patients with polyarthritis resembling RA and psoriasis treated with leflunomide. A77 1726 steady-state plasma concentrations were determined by validated high-performance liquid chromatography with UV detection. A population pharmacokinetic model was developed to estimate the oral clearance (CL/F) and volume of distribution (V/F). A genotyping approach was used to determine C-163A, C-729T, and T-739G in the CYP1A2 gene as well as single nucleotide polymorphisms that characterize CYP2C19*2, *3, *4, and *17 alleles. A large interindividual variability in trough A77 1726 steady-state plasma concentrations was observed (from 1.9 to 156.9 mg/l). A77 1726 CL/F was 71% higher in carriers of the CYP2C19*2 allele compared with noncarriers. The A77 1726 average steady-state plasma concentration was associated with the treatment response. Patients with a greater decrease in C-reactive protein (CRP) had higher average steady-state plasma A77 1726 concentrations: 49.7 +/- 39.0 mg/l in patients with DeltaCRP of more than 8.5 mg/l compared with 24.8 +/- 13.7 mg/l in patients with DeltaCRP of <or=8.5 mg/l (p = 0.015). No association of A77 1726 steady-state plasma concentrations with the occurrence of ADRs was observed. Our results suggest that genetic variability in leflunomide-metabolizing enzymes influences leflunomide metabolite concentrations that are associated with the treatment response but not with leflunomide-induced toxicity.

• Authors: Petra Bohanec Grabar, Iztok Grabnar, Blaz Rozman, Dusan Logar, Matija Tomsic, Dasa Suput, Tina Trdan, Lucija Peterlin Masic, Ales Mrhar, Vita Dolzan
• Journal: Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 37 Issue 10 Pg. 2061-8 (Oct 2009) ISSN: 1521-009X [Electronic] United States
• PMID: 19581389 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aniline Compounds
• Antirheumatic Agents
• Crotonates
• Hydroxybutyrates
• Isoxazoles
• Nitriles
• Toluidines
• teriflunomide
• Aryl Hydrocarbon Hydroxylases
• CYP2C19 protein, human
• Cytochrome P-450 CYP1A2
• Cytochrome P-450 CYP2C19
• Leflunomide

Topics

• Adult
• Aged
• Aged, 80 and over
• Aniline Compounds (pharmacokinetics, therapeutic use)
• Antirheumatic Agents (pharmacokinetics, therapeutic use)
• Arthritis, Rheumatoid (blood, drug therapy, metabolism)
• Aryl Hydrocarbon Hydroxylases (genetics, physiology)
• Crotonates
• Cytochrome P-450 CYP1A2 (genetics, physiology)
• Cytochrome P-450 CYP2C19
• Female
• Humans
• Hydroxybutyrates (pharmacokinetics, therapeutic use)
• Isoxazoles (pharmacokinetics, therapeutic use)
• Leflunomide
• Male
• Middle Aged
• Nitriles
• Polymorphism, Genetic
• Synovial Membrane
• Toluidines