2,4-diamino-7-hydroxy-pteridines, a new class of catabolites of methotrexate.
Methotrexate remains a commonly used drug in the chemotherapy of various malignancies. The known catabolites are 7-hydroxy-methotrexate, formed in the liver, and diamino-methyl-pteroic acid formed in the gut. We report for the first time evidence that 2,4-diamino-7-hydroxy-pteridine derivatives are present in the biological fluids of patients on high-dose methotrexate protocols. So far, two major derivatives have been identified as 2,4-diamino-6-hydroxymethyl-7-hydroxy-pteridine and 2,4-diamino-6-methyl-7-hydroxy-pteridine. In regard to the actual knowledge of the catabolism of pteridines, these compounds are presumably formed by intestinal bacteria during enterohepatic circulation of the drug. Their slow clearance from the body raises the question of possible interference of these compounds on pteridine-dependent enzymes, which might explain in part some of the toxic effects of methotrexate.
Dhondt
J L
JL
Laboratoire de Biochimie, Faculté Libre de Médecine, Lille, France.
Hayte
J M
JM
Millot
F
F
Klein
R
R
Blais
J C
JC
Pfleiderer
W
W
D000293:Adolescent; D000328:Adult; D000818:Animals; D001711:Biotransformation; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D008401:Gas Chromatography-Mass Spectrometry; D006689:Hodgkin Disease / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D008727:Methotrexate / Q000378:metabolism* / Q000627:therapeutic use; D012516:Osteosarcoma / Q000188:drug therapy / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism; D011621:Pteridines / Q000097:blood* / Q000652:urine; D011817:Rabbits; D051381:Rats
D011621:Pteridines; C070627:2,4-diamino-6-methyl-7-hydroxypteridine; C070628:2,4-diamino-6-hydroxymethyl-7-hydroxypteridine; D008727:Methotrexate