PMID- 9923818
OWN - NLM
STAT- MEDLINE
DCOM- 19990208
LR  - 20171116
IS  - 0344-5704 (Print)
IS  - 0344-5704 (Linking)
VI  - 43
IP  - 2
DP  - 1999
TI  - Metabolism of 6-mercaptopurine in the erythrocytes, liver, and kidney of rats 
      during multiple-dose regimens.
PG  - 133-40
AB  - 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 x 10(8) 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.
FAU - Innocenti, F
AU  - Innocenti F
AD  - Department of Oncology, University of Pisa, Italy.
FAU - Danesi, R
AU  - Danesi R
FAU - Bocci, G
AU  - Bocci G
FAU - Fogli, S
AU  - Fogli S
FAU - Di Paolo, A
AU  - Di Paolo A
FAU - Del Tacca, M
AU  - Del Tacca M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Germany
TA  - Cancer Chemother Pharmacol
JT  - Cancer chemotherapy and pharmacology
JID - 7806519
RN  - 0 (Antimetabolites)
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 0 (Enzyme Inhibitors)
RN  - 49717AWG6K (Ribavirin)
RN  - E7WED276I5 (Mercaptopurine)
RN  - X6Q56QN5QC (Hydroxyurea)
SB  - IM
MH  - Animals
MH  - Antimetabolites/pharmacology
MH  - Antimetabolites, Antineoplastic/*administration & dosage/*pharmacokinetics
MH  - Area Under Curve
MH  - Biotransformation
MH  - Chromatography, High Pressure Liquid
MH  - Enzyme Inhibitors/pharmacology
MH  - Erythrocytes/*metabolism
MH  - Female
MH  - Hydroxyurea/pharmacology
MH  - Kidney/*metabolism
MH  - Liver/*metabolism
MH  - Mercaptopurine/*administration & dosage/*pharmacokinetics
MH  - Rats
MH  - Rats, Wistar
MH  - Regression Analysis
MH  - Ribavirin/pharmacology
EDAT- 1999/01/29 00:00
MHDA- 1999/01/29 00:01
CRDT- 1999/01/29 00:00
PHST- 1999/01/29 00:00 [pubmed]
PHST- 1999/01/29 00:01 [medline]
PHST- 1999/01/29 00:00 [entrez]
AID - 10.1007/s002800050873 [doi]
PST - ppublish
SO  - Cancer Chemother Pharmacol. 1999;43(2):133-40. doi: 10.1007/s002800050873.