A population pharmacokinetic model developed in this study implies only a limited influence of genetic factors on the systemic disposition of MTX. Clearance is moderately reduced in patients with the MTHFR 677TT genotype. Genetic polymorphisms in the folate metabolic pathway and SLC19A1 were associated with HD-MTX toxicity.

Our results suggest that genetic polymorphisms in the folate metabolic pathway and MTX transporters modify the toxicity but not the efficacy of MTX treatment.

Our results suggest that the CYP1A2*1F allele may be associated with leflunomide toxicity in RA patients.

Abstract.Reactive oxygen and nitrogen species are involved in the pathology of rheumatoid arthritis (RA). Polymorphisms in genes coding for superoxide dismutases (SOD2 and SOD3), catalase (CAT), tumor necrosis factor-alpha (TNFA) and inducible NO synthase (NOS2A) may influence RA activity. We determined SOD2 Ala-9Val, SOD3 Arg213Gly, CAT C-262T, TNFA G-308A, TNFA C-857T and NOS2A (CCTTT)n polymorphisms in 327 RA patients. Carriers of CAT -262T and TNFA -308A allele had lower mean disease activity score of 28 joint count (DAS28) values than patients with CAT -262CC and TNFA -308GG genotypes (p = 0.014 and p = 0.046, respectively). Patients with the combination of CAT -262T and TNFA -308A allele had lower mean DAS28 values and a higher probability for low disease activity than non-carriers (p = 0.003, OR = 3.585, 95% CI = 1.538-8.357). Our results suggest that CAT and TNFA polymorphisms alone and in combination influence the activity of RA.

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- (Fig. 1) that inhibits dihydroorotate dehydrogenase, a rate-limiting enzyme in de novo synthesis of pyrimidine (Mladenovic et al., 1995). Clinical trials, reviewed by Kunkel and Cannon (2006), have shown that efficacy of leflunomide is comparable to those of methotrexate (MTX) and sulfasalazine. However, the rate of withdrawal from leflunomide therapy was found to range between 40 and 70% in the 1st year because of the development of adverse drug reactions (ADRs) and lack of efficacy. 3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide). The aim of this study was to investigate whether genetic polymorphisms in Leflunomide (5-methyl-N-[4-(trifluoromethyl)phenyl]-4-isoxazolecarboxamide) is a disease-modifying antirheumatic drug of the isoxazole class used for the treatment of rheumatoid arthritis (RA). In vivo it is converted to its active metabolite A77 1726 (2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide)Leflunomide acts as a prodrug. After oral administration it is rapidly and almost completely absorbed and predominantly presystemically metabolized to A77 1726. Plasma levels of leflunomide are observed only occasionally at very low concentrations. Peak concentrations of the active metabolite occur 6 to 12 h after dosing. The metabolite is 99% bound to plasma albumin, resulting in a relatively low apparent volume of distribution (V/F) ranging between 6 and 30.8 liters, with an average of 12.7 liters (Rozman, 2002). The active metabolite of leflunomide is eliminated by further metabolism to glucuronides of methyl-hydroxy A77 1726 and trifluoromethylanine- P.B.G. and I.G. equally contributed to this work. Article, publication date, and citation information can be found at