Distinct tissue distribution of metabolites of the novel glutathione-activated thiopurine prodrugs cis-6-(2-acetylvinylthio)purine and trans-6-(2-acetylvinylthio)guanine and 6-thioguanine in the mouse.
The compounds cis-6-(2-acetylvinylthio)purine (cis-AVTP) and trans-6-(2-acetylvinylthio)guanine (trans-AVTG) are glutathione-activated prodrugs of 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG), respectively, that have comparable or lower IC50 values in tumor cells than 6-MP and 6-TG. Previously, we showed that cis-AVTP- and trans-AVTG-treated mice exhibited less bone marrow and intestinal toxicity and excreted a lower fraction of the administered dose in urine than did mice treated with equivalent 6-TG doses. To explain these results, the tissue distribution and levels of metabolites of cis-AVTP, trans-AVTG, and 6-TG were examined at 15, 30, and 45 min after i.p. treatment of mice with equimolar doses of these compounds. After prodrug treatment, the thiopurines, the corresponding thiopurine ribosides and nucleotides, thioxanthine (TX), and thiouric acid (TU) were quantitated in plasma, red blood cells, liver, and intestine. Thiopurine and thiopurine riboside and nucleotide area under the curve between 15 and 45 min [AUC(15-45)] values were generally comparable after cis-AVTP and trans-AVTG treatments but were lower than those after 6-TG treatment. A higher liver/plasma metabolite ratio was evident after trans-AVTG treatment than after cis-AVTP or 6-TG treatments, which exhibited similar liver/plasma ratios. Treatment with cis-AVTP yielded the highest AUC(15-45) for TX and TU in plasma, liver, and intestine. Prodrug treatment did not change the concentration of reduced or oxidized glutathione in tissue homogenates. Collectively, these results show distinct patterns of metabolites depending upon the compound used and suggest that differences in metabolite levels and composition after cis-AVTP, trans-AVTG, and 6-TG treatments may partially explain the different toxicity and urinary metabolite excretion profiles previously observed among cis-AVTP, trans-AVTG, and 6-TG.
Gunnarsdottir
Sjofn
S
Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, 2015 Linden Drive, Madison, WI 53706, USA.
Elfarra
Adnan A
AA
D000818:Animals; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D004912:Erythrocytes / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D006147:Guanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D011355:Prodrugs / Q000493:pharmacokinetics*; D011687:Purines / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013866:Thioguanine / Q000097:blood / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014970:Xanthines / Q000097:blood / Q000378:metabolism
C451721:6-(2-acetylvinylthio)guanine; C451722:6-(2-acetylvinylthio)purine; D011355:Prodrugs; D011687:Purines; D014970:Xanthines; D006147:Guanine; D013866:Thioguanine; D005978:Glutathione