Metabolism of intravenously administered high-dose 6-mercaptopurine with and without allopurinol treatment in patients with non-Hodgkin lymphoma.
OBJECTIVE
We investigated the metabolism of high dose 6 mercaptopurine (HD-6MP) infusions and its influence on the metabolism by allopurinol, an inhibitor of xanthine oxidase, the enzyme that catabolizes 6MP into thioxanthine and thiouric acid.


METHODS
Nine patients (aged 2-11 years) with non-Hodgkin lymphoma (NHL) were treated with HD-6MP (1300 mg/m(2).24h) within a therapeutic window after diagnosis. Four patients received oral allopurinol (200 mg/m(2).day) to prevent urate nephropathy, and five did not. Plasma and RBC were isolated before and 4, 20, 24, 28, and 48h after the start of the infusion. All measurements were performed with HPLC.


RESULTS
Considerable variations were found in the plasma levels of 6MP, thioxanthine, and thiouric acid and of RBC-MeTIN levels. 6MP-riboside was not detectable, and MeMP and MeMPR levels were <1.3 muM in the plasma. In general, 6MP, thioxanthine, and MeMP levels in plasma were higher, and thiouric acid plasma levels and RBC-MeTIN levels were lower in the patients treated with allopurinol compared to those who did not receive allopurinol.


CONCLUSIONS
6MP is extensively metabolized in patients with NHL treated with HD-6MP. Thiopurine methylation, at the levels of nucleotide, nucleoside, and base, is an important metabolic pathway after HD-6MP. Co-administration of allopurinol can result in both a decreased catabolism and anabolism of 6MP compared to treatment with HD-6MP alone. This observation may have consequences for the therapeutic efficacy and toxic effects of 6MP in combination with allopurinol.
Keuzenkamp-Jansen
C W
CW
Center for Pediatric Oncology S.E., University Hospital Nigmegen, The Netherlands.
DeAbreu
R A
RA
Bökkerink
J P
JP
Lambooy
M A
MA
Trijbels
J M
JM
D000493:Allopurinol / Q000097:blood / Q000627:therapeutic use*; D000964:Antimetabolites, Antineoplastic / Q000097:blood / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000097:blood* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000097:blood / Q000627:therapeutic use*; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D006801:Humans; D019271:Hypoxanthine; D007042:Hypoxanthines / Q000097:blood; D007206:Individuality; D007262:Infusions, Intravenous; D008228:Lymphoma, Non-Hodgkin / Q000097:blood* / Q000188:drug therapy*; D008297:Male; D015122:Mercaptopurine / Q000097:blood* / Q000627:therapeutic use; D008778:Methylthioinosine / Q000097:blood; D009711:Nucleotides / Q000097:blood; D019820:Xanthine; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors; D014970:Xanthines / Q000097:blood
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007042:Hypoxanthines; D009711:Nucleotides; D014970:Xanthines; D019820:Xanthine; D019271:Hypoxanthine; D008778:Methylthioinosine; D000493:Allopurinol; D015122:Mercaptopurine; D014969:Xanthine Oxidase