Genetic Polymorphisms in Metabolic and Cellular Transport Pathway of Methotrexate Impact Clinical Outcome of Methotrexate Monotherapy in Japanese Patients with Rheumatoid Arthritis

Access this Article

Author(s)

    • KATO Tomomi
    • Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University
    • HAMADA Akinobu
    • Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University|Department of Pharmacy, Kumamoto University Hospital
    • MORI Shunsuke
    • Department of Rheumatology, Clinical Research Center for Rheumatic Disease, Kumamoto Saishunso National Hospital
    • SAITO Hideyuki
    • Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University|Department of Pharmacy, Kumamoto University Hospital

Abstract

  The aim of this study was to investigate the impact of genetic polymorphisms in the metabolic and cellular transport pathway of methotrexate (MTX) on the clinical outcome of MTX monotherapy in Japanese rheumatoid arthritis (RA) patients. Fifty-five patients were treated with MTX monotherapy at a dose of 4–10 mg/week. The total concentration of MTX-polyglutamates (MTX-PGs) was measured at steady-state in red blood cells (RBCs) by high performance liquid chromatography. The genotype at 16 polymorphic sites in 11 genes (<i>ABCB1</i>, <i>ABCG2</i>, <i>ABCC2</i>, <i>RFC1</i>, <i>PCFT</i>, <i>SLCO1B1</i>, <i>MTHFR</i>, <i>GGH</i>, <i>ATIC</i>, <i>MTR</i>, and <i>MTRR</i>) was analyzed. No significant association between the total concentration of MTX-PGs in RBCs and clinical outcome was found. However, patients with the <i>ABCB1</i> 3435TT genotype had a significantly lower mean disease activity score (DAS) 28 than did patients with the <i>ABCB1</i> 3435CC genotype (p = 0.02). Similarly, patients with the <i>ABCB1</i> 2677AA/AT/TT genotypes had a significantly lower mean DAS28 than did patients with the <i>ABCB1</i> 2677GG/GA/GT genotypes (p = 0.04). The patients with the <i>MTHFR</i> 1298AA genotype had a significantly lower mean DAS28 than those with the <i>MTHFR</i> 1298AC/CC genotypes (p = 0.04). In conclusion, the <i>ABCB1</i> 3435C>T, <i>ABCB1</i> 2677G>A/T, and <i>MTHFR</i> 1298A>C polymorphisms influenced the efficacy of MTX monotherapy.<br>

Journal

  • Drug Metabolism and Pharmacokinetics

    Drug Metabolism and Pharmacokinetics 27(2), 192-199, 2012

    The Japanese Society for the Study of Xenobiotics

Codes

Page Top