ISSN:
1432-0843
Keywords:
Key words 6-MP
;
6-TG
;
Rat tissues
;
Pharmacokinetics
;
Ribavirin
;
Hydroxyurea
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract Purpose: To describe the metabolism of 6-mercaptopurine (6-MP) in erythrocytes and tissues of rats after repeated administration of 6-MP at two dose levels and to provide evidence that in vivo modulation of 6-MP anabolism can be obtained by simultaneous treatment with ribavirin or hydroxyurea, two inhibitors of enzymes involved in the bioactivation of 6-MP to the active 6-thioguanine nucleotides (6-TGN). Methods: Rats were treated i.p. with 6-MP at 12.5 and 25 mg/kg daily for 12 days and erythrocyte, liver, and kidney levels of 6-mercaptopurine nucleotides (6-MPN) and 6-TGN were investigated during the accumulation phase and for 50 days after the end of treatment. In combination studies, ribavirin at 75 and 100 mg/kg per day (for 6-MP, 25 and 12.5 mg/kg per day) or hydroxyurea at 200 mg/kg per day were given i.p. for 12 days. The measurements of thionucleotide levels in rat samples were performed by high-pressure liquid chromatography (HPLC). Results: The maximal concentration (Cmax) and the area under the concentration versus time curve (AUC) of 6-MPN and 6-TGN in erythrocytes and tissues increased significantly after the administration of 6-MP at 25 mg/kg per day as compared with 12.5 mg/kg per day. In particular, the Cmax and AUC of 6-TGN in erythrocytes of rats treated with 6-MP at 25 mg/kg per day were approximately 5-fold higher than the 6-TGN values observed following treatment at 12.5 mg/kg per day. Moreover, 6-TGN levels in erythrocytes were significantly higher than those of 6-MPN (910.9 ± 53.1 and 286.8 ± 23.4 pmol/8 × 108 cells for 6-TGN and 6-MPN, respectively, P 〈 0.05) after treatment with 6-MP at 25 mg/kg per day. The administration of ribavirin, an inhibitor of inosine monophosphate dehydrogenase, in association with 6-MP increased the amount of 6-MPN detected in erythrocytes and tissues while reducing 6-TGN levels in samples. The production and accumulation of 6-MPN and 6-TGN were increased in erythrocytes and tissues by hydroxyurea, an inhibitor of ribonucleotide reductase. Finally, a significant correlation between thionucleotide concentrations and erythrocyte counts was observed. Conclusion: The overall results demonstrate that 6-MP is actively metabolized in rats and that its biotransformation can be modulated by agents acting on enzymes of the purine metabolism, resulting in significant changes in erythrocyte and tissue levels of 6-MPN and 6-TGN. These findings provide evidence that the rat is a suitable model for investigation of the metabolism of 6-MP and its possible pharmacologic modulation.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/s002800050873
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