The disposition and metabolism of tiazofurin in rodents, rabbits, and dogs

Drug Metab Dispos. 1984 Mar-Apr;12(2):165-73.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Chromatography, High Pressure Liquid
  • Dogs
  • Dose-Response Relationship, Drug
  • Feces / analysis
  • In Vitro Techniques
  • Kinetics
  • Leukemia P388 / metabolism
  • Male
  • Mice
  • Models, Biological
  • Rabbits
  • Rats
  • Rats, Inbred Strains
  • Ribavirin / analogs & derivatives
  • Ribavirin / blood
  • Ribavirin / metabolism*
  • Ribavirin / urine
  • Ribonucleosides / metabolism*
  • Species Specificity
  • Tissue Distribution

Substances

  • Ribonucleosides
  • Ribavirin
  • tiazofurin