[Molecular toxicological mechanism of the lethal interactions of the new antiviral drug, sorivudine, with 5-fluorouracil prodrugs and genetic deficiency of dihydropyrimidine dehydrogenase].

@article{Watabe2002MolecularTM,
  title={[Molecular toxicological mechanism of the lethal interactions of the new antiviral drug, sorivudine, with 5-fluorouracil prodrugs and genetic deficiency of dihydropyrimidine dehydrogenase].},
  author={Tadashi Watabe and Kenichiro Ogura and Takahito Nishiyama},
  journal={Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan},
  year={2002},
  volume={122 8},
  pages={
          527-35
        }
}
  • T. Watabe, K. Ogura, T. Nishiyama
  • Published 1 August 2002
  • Biology, Chemistry, Medicine
  • Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan
In 1993, there were 18 acute deaths in Japanese patients who had the viral disease herpes zoster and were treated with the new antiviral drug sorivudine (SRV, 1-beta-D-arabinofuranosyl-(E)-5-(2-bromovinyl)uracil). All the dead patients had received a 5-fluorouracil (5-FU) prodrug as anticancer chemotherapy concomitant with SRV administration. Studies on toxicokinetics in rats and on hepatic dihydropyrimidine dehydrogenase (DPD), a rate-limiting enzyme for 5-FU catabolism in rats and humans… 
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In 1993 eighteen Japanese patients with cancer and herpes zoster, a viral disease, died from interactions of the new oral antiviral drug, sorivudine (SRV:
A possible mechanism of eighteen patient deaths caused by interactions of sorivudine, a new antiviral drug, with oral 5-fluorouracil prodrugs.
A toxicokinetic study was performed using rats to investigate the possible mechanism of 18 acute deaths in Japanese patients with cancer and herpes zoster by interactions of the new oral antiviral
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TLDR
Data obtained by in vivo and in vitro studies strongly suggested that (E)-5-(2-bromovinyl)uracil generated from SRV by gut flora was reduced in the presense of NADPH to a reactive form by hepatic dihydropyrimidine dehydrogenase (DPD), a key enzyme determining the tissue 5-FU levels, bound covalently to DPD as a suicide inhibitor, and markedly retarded the catabolism of5-FU.
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TLDR
DPD activity was determined in 50 pairs of tumor and uninvolved liver specimens in Chinese cancer patients with hepatocellular carcinoma and hepatomas were found to have relatively high DPD activity, providing an explanation for the relative 5-fluorouracil resistance of hepatoma.
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TLDR
It appears that total DPD deficiency is a very rare event, and pre-treatment DPD activity cannot be a useful indicator for improving 5-FU dose adaptation strategy, but the identification of partial D PD deficiency could lead to starting the treatment with a markedly reduce 5-fu dose.
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TLDR
A sensitive, accurate, and precise DPD assay and a storage method to stabilize DPD activity are developed, permitting large scale DPD screening in cancer patients and a normal distribution (Gaussian distribution) of human D PD activity from peripheral blood mononuclear cells (PBM-DPD) in a population study.
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The pig and human dihydropyrimidine dehydrogenase (DPD) cDNAs were cloned and sequenced and the DPD appears to be derived from at least three distinct domains.
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