title: The disposition and metabolism of tiazofurin in rodents, rabbits, and dogs.
abstract: The pharmacokinetics and metabolism of tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide) have been examined in the mouse, rat, rabbit, and dog using tritiated drug as a marker. In all four species, tiazofurin, given as a single bolus iv injection, is removed from the circulation in a triphasic manner, with a generally prolonged terminal half-life. In all cases, the mean concentration of unchanged drug prevailing during this terminal phase was well within the cytotoxic range (IC50 vs. P388 cells is 2 microM in vitro). Urinary excretion accounted for between approximately 40 and 90% of the administered dose in all four species, with only minor quantities (less than 3%) of drug-derived radioactivity detected in the feces. The metabolism of tiazofurin was examined in mice and rats: although no evidence was uncovered for hydroxylation of tiazofurin at carbon atom 5 of the thiazole ring, phosphorylation of the drug at its 5'-hydroxyl was demonstrable in nearly every organ of both species, but, liver, striated muscles, and kidney were the only tissues catalyzing the synthesis of thiazole-4-carboxamide adenine dinucleotide to any prominent degree. This synthesis did not appear to be a saturated process, even at doses as high as 8000 mg/m2. Since rodent skeletal muscle accumulated high concentrations of tiazofurin phosphates in vivo, it is suggested that musculature may serve as a reservoir for the drug, and contribute to its rather protracted terminal half-life in plasma.
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005243:Feces / Q000032:analysis; D066298:In Vitro Techniques; D007700:Kinetics; D007941:Leukemia P388 / Q000378:metabolism; D008297:Male; D051379:Mice; D008954:Models, Biological; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D012254:Ribavirin / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism* / Q000652:urine; D012263:Ribonucleosides / Q000378:metabolism*; D013045:Species Specificity; D014018:Tissue Distribution
chemical_list: D012263:Ribonucleosides; D012254:Ribavirin; C033706:tiazofurin