In vivo-In vitro Relationship of Methotrexate 7-Hydroxylation by Aldehyde Oxidase in Four Different Strain Rats

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  • MORIYASU Aya
    Division of Medicinal Chemistry, Graduate School of Biomedical Sciences, Hiroshima University
  • SUGIHARA Kazumi
    Division of Medicinal Chemistry, Graduate School of Biomedical Sciences, Hiroshima University
  • NAKATANI Keiko
    Division of Medicinal Chemistry, Graduate School of Biomedical Sciences, Hiroshima University
  • OHTA Shigeru
    Division of Medicinal Chemistry, Graduate School of Biomedical Sciences, Hiroshima University
  • KITAMURA Shigeyuki
    Division of Medicinal Chemistry, Graduate School of Biomedical Sciences, Hiroshima University Nihon Pharmaceutical University

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Abstract

  The in vivo metabolism of methotrexate (MTX) to 7-hydroxymethotrexate (7-OH-MTX) was studied using four strains of rats. When MTX was administered to these rats, 7-OH-MTX was detected as the major in vivo metabolite, mainly in bile and feces, and also slightly in the urine. There were marked strain differences in the amounts of 7-OH-MTX excreted in bile, feces and urine. The highest recovery of 7-OH-MTX in bile, feces and urine was observed in Sea:SD rats (6.2%, 4.2% and 0.8% of dose, respectively), followed by Jcl:SD and Crj:SD rats. The lowest recovery (0.02%, 0.2% and 0.003%, respectively) was observed in WKA/Sea rats. The variations of excreted amount of 7-OH-MTX were closely correlated with the strain differences of cytosolic MTX 7-hydroxylase and benzaldehyde oxidase activities. Our results indicate that variation of formation of 7-OH-MTX from MTX in vivo in rats is due primarily to variation of aldehyde oxidase.<br>

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