Detection and identification of 6-methylmercapto-8-hydoxypurine, a major metabolite of 6-mercaptopurine, in plasma during intravenous administration

Abstract

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.

Measurement of thiopurine S-methyltransferase activity in human blood samples based on high-performance liquid chromatography: reference values in erythrocytes from children

“…These plots also showed a very good correlation with the number of cells analysed (rˆ0¢984 for RBC, rˆ0 ¢994 for Molt-F4 cells and rˆ0 ¢990 for pMNC). Linearity was observed between 5610 7 and 10610 7 RBC, 2610 6 and 3610 6 Molt-F4 cells and 2610 6 and 3610 6 pMNC. Speci¢c TPMT activities of RBC samples were expressed in pmol/10 7 cells per h and those of pMNC and Molt-F4 cells in pmol/10 6 cells per h.…”

“…2^6 It is converted rapidly to 6MP in vivo and may be further converted by various pathways: it may be metabolized to 6-thioguanine nucleotides, a multi-step conversion initially catalysed by hypoxanthine -guanine phosphoribosyltransferase; it may be converted to 6mercapto-8-hydroxypurine and thiouric acid by xanthine dehydrogenase; or it may be 6-S-methylated to 6-methylmercaptopurine (6MeMP) by TPMT. 7 It is known that a marked variation exists in TPMT activity between individuals, controlled by an allelic polymorphism for either normal or de¢cient enzyme activity. 8^10 The frequency distribution of TPMT activity is tri-modal.…”

In Vitro Study of 6-mercaptopurine Oxidation Catalysed by Aldehyde Oxidase and Xanthine Oxidase

“…However, during intravenous infusion, which bypasses intestinal XO, either 6-MP or 6-thioguanine are mostly oxidized at 8 position. 34) Although these reactions could be oxidized by either XO or AO, the diŠerence in metabolite proˆle between oral and intravenus administration indicates that AO may be the major enzyme in 8-hydroxylation. 16) In addition, the results obtained in the present study and a higher capability of AO to produce 8-hydroxy metabolites from guanine and purine analogs compared with XO, 10,23) provide more support for the involvment of AO in the matabolism of thioxanthine to thiouric acid as the major enzyme.…”

Novel pharmacogenetic markers for treatment outcome in azathioprine‐treated inflammatory bowel disease

“…[33][34][35] It is therefore thought to have additional functions over and above its contribution to purine catabolism. 36 AO acts on azathioprine, MP and other thiopurine metabolites, contributing to the catabolism of thiopurines 18,34,37 ( Figure 1). However, the functional significance of the thiopurine metabolites generated by AO is poorly understood.…”