In vivo-in vitro relationship of methotrexate 7-hydroxylation by aldehyde oxidase in four different strain rats.
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.
Moriyasu
Aya
A
Division of Medicinal Chemistry, Graduate School of Biomedical Sciences, Hiroshima University.
Sugihara
Kazumi
K
Nakatani
Keiko
K
Ohta
Shigeru
S
Kitamura
Shigeyuki
S
D042931:Aldehyde Oxidase / Q000378:metabolism*; D000818:Animals; D001646:Bile / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D005493:Folic Acid Antagonists / Q000378:metabolism / Q000493:pharmacokinetics / Q000652:urine; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D011919:Rats, Inbred Strains; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013045:Species Specificity
D005493:Folic Acid Antagonists; D042931:Aldehyde Oxidase; C011864:7-hydroxymethotrexate; D008727:Methotrexate