Contribution of serum protein association to discrepancy between the in vivo and in vitro UDS results for 6,7-dimethyl-2,4-di-1-pyrrolidinyl-7H-pyrrolo[2,3-d]pyrimidine (U-89843).

  title={Contribution of serum protein association to discrepancy between the in vivo and in vitro UDS results for 6,7-dimethyl-2,4-di-1-pyrrolidinyl-7H-pyrrolo[2,3-d]pyrimidine (U-89843).},
  author={Z Y Zhao and Kenneth Koeplinger and G. E. Padbury and C. S. Aaron and Philip R. Harbach and J. K. Mayo and W. B. Mattes and Gordon Bundy},
  journal={Mutation research},
  volume={395 2-3},
U-89843 has been shown to undergo biotransformation, both in vitro and in vivo, to form U-97924 as a major primary metabolite. U-89843 was found to be positive in an in vitro UDS mutagenesis screen conducted with primary rat hepatocytes in serum-free media. In contrast to in vitro results, no evidence of genetic toxicity of U-89843 was observed in rats in the in vivo/in vitro version of the UDS test with single oral doses up to 1400 mg/kg. The negative results may be related to more robust in… Expand
2 Citations
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In vitro and in vivo biotransformation of 6,7-dimethyl-2,4-di-1-pyrrolidinyl-7H-pyrrolo[2,3-D]pyrimidine (U-89843) in the rat.
Although significant levels of U-89843, U-97924, and U-97865 were observed in vivo in rat plasma, only a minor amount of the carboxylic acid together with larger amounts of unidentified polar metabolites were excreted in urine and feces. Expand
Bioactivation of 6,7-dimethyl-2,4-di-1-pyrrolidinyl-7H-pyrrolo[2,3-d]pyrimidine (U-89843) to reactive intermediates that bind covalently to macromolecules and produce genotoxicity.
Observations suggest that the positive in vitro UDS results of U-89843 are mediated by the bioactivation of the novel pyrrolo[2,3-d]pyrimidine antioxidant, leading to reactive electrophilic intermediates derived from the (hydroxymethyl)pyrrole metabolite U-97924. Expand
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