Detection and identification of 6-methylmercapto-8-hydoxypurine, a major metabolite of 6-mercaptopurine, in plasma during intravenous administration.
6-Mercaptopurine, a hypoxanthine antimetabolite, is used in the treatment of acute lymphoblastic leukemia (ALL) in children. Extensively metabolized before it exerts cytotoxic action, it is catabolized into 6-mercapto-2,8-dihydroxypurine (thiouric acid), which is excreted by the kidneys. We describe a metabolite of 6-mercaptopurine, 6-methylmercapto-8-hydroxypurine, whose presence has not been previously reported in plasma. This compound was found in high concentrations in plasma during high-dose 6-mercaptopurine infusions (1300 mg/m2 in 24 h). This previously unknown compound was identified by reversed-phase HPLC with absorbance detection and by gas chromatography-mass spectrometry. The pathways leading to 6-methylmercapto-8-hydroxypurine in vivo are not yet fully understood. In a group of 17 patients treated with four courses of high-dose 6-mercaptopurine infusions according to the ALL-8 treatment protocol of the Dutch Childhood Leukemia Study Group, the steady-state concentrations of 6-methylmercapto-8-hydroxypurine in plasma were one-fifth of the parent drug concentrations, with wide interindividual variation. The formation of high concentrations of 6-methylmercapto-8-hydroxypurine in plasma, especially during the infusion, probably indicates another catabolic pathway of high-dose 6-mercaptopurine, apart from its conversion into thiouric acid.
Keuzenkamp-Jansen
C W
CW
Center for Pediatric Oncology SE Netherlands, St. Radboud University Hospital Nijmegen, The Netherlands.
van Baal
J M
JM
De Abreu
R A
RA
de Jong
J G
JG
Zuiderent
R
R
Trijbels
J M
JM
D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000378:metabolism* / Q000627:therapeutic use; D002648:Child; D002851:Chromatography, High Pressure Liquid; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007262:Infusions, Intravenous; D015122:Mercaptopurine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism* / Q000627:therapeutic use; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood* / Q000188:drug therapy*
C098430:6-methylmercapto-8-hydroxypurine; D000964:Antimetabolites, Antineoplastic; D015122:Mercaptopurine