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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 arthritisBohanec Grabar, Petra ...Leflunomide is a disease-modifying antirheumatic drug used for the treatment of rheumatoid arthritis (RA). Cytochromes P450, mainly CYP1A2 and CYP2C19 might be involved in the transformation of ... leflunomide to leflunomide metabolite (A77 1726). The aim of this study was to investigate if genetic polymorphisms in CYP1A2 and CYP2C19 influence leflunomide pharmacokinetics, treatment response and the occurrence of adverse drug reactions (ADRs). The study included 67 RA patients and 4 patients with polyarthritis resembling RA and psoriasis treated with leflunomide. A77 1726 steady-state plasma concentrations were determined by validated HPLC 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 SNPs that characterize CYP2C19 *2, *3, *4 and *17 alleles. A large inter-individual 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 CYP2C19*2 allele compared to non-carriers. A77 1726 average steady-state plasma concentration was associated with the treatment response. Patients withgreater decrease in C-reactive protein (CRP) had higher average steady-state plasma A77 1726 concentrations, 49.7+/-39.0 mg/L in patients withDeltaCRP of more than 8.5 mg/L compared to 24.8+/-13.7 mg/L in patients with DeltaCRP of less or equal to 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 influence leflunomide metabolite concentrations that are associated with the treatment response, but not with leflunomide-induced toxicity.Source: Drug metabolism and disposition. - ISSN 0090-9556 (Vol. 37, no. 10, 2009, str. 2061-2068)Type of material - article, component part ; adult, seriousPublish date - 2009Language - englishCOBISS.SI-ID - 25801689
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DRS, in which the journal is indexed
Database name | Field | Year |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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Bohanec Grabar, Petra | 25438 |
Grabnar, Iztok | 16107 |
Rozman, Blaž, 1944- | 07180 |
Logar, Dušan, 1951- | 10080 |
Tomšič, Matija, 1959- | 13601 |
Šuput, Daša | 29977 |
Trdan, Tina | 30817 |
Peterlin-Mašič, Lucija | 19317 |
Mrhar, Aleš | 06086 |
Dolžan, Vita | 11711 |
Source: Personal bibliographies
and: SICRIS
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