Sorivudine Fluorouracil

Lethal drug interactions of new antiviral, sorivudin [l-(3-D-arabinofuranosyl-( )-5-(2-bromvinyl)uracil], with anticancer prodrugs of 5-fluorouracil structure 97YZ910. 

Okuda H, Nishiyama T, Ogura K et al. Lethal drug interactions of sorivudine, a new antiviral drug, with oral 5-fluorouracil prodrugs. DrugMetab Dispos 1997 25 270-273. 

A similar model was employed to predict the DDIs between 5-fluorouracil and sorivudine (124). Sorivudine is converted by gut flora to (E)-5-(2-bromovinyl) uracil, which inactivates dihydropyrimidine dehydrogenase and impairs the metabolism of 5-fluorouracil by this enzyme. This interaction led to 15 deaths in Japan from 5-fluorouracil toxicity due to elevated exposure to the drug. Using a fcE of 0.00018 min, a fivefold increase in the AUC of 5-fluorouracil was predicted after administration of sorivudine (150 mg/day for 5 days), which was close to the observed data in patients. 

Sorivudine and 5-fluorouracil (5-FU) interaction, leading to severe or fatal gastrointestinal and bone marrow toxicities. Soruvidine was withdrawn from the market in 1993. Sorivudine inhibits dihydropyrimidine dehydrogenase, an enzyme pathway responsible forfluoropyrimidine metabolism. 48... 

Diasio RB. Sorivudine and 5-fluorouracil A clinically significant drug-drug interaction due to inhibition of dihydropyrimidine dehydrogenase. Br J Clin Pharmacol. 1998 46 1-4. 

Marked and rapidly fatal toxicity, attributed to fluorouracil toxicity, has been seen in patients given tegafur or other fluorouracil prodrugs with sorivudine. Fluorouracil is expected to interact similarly. 

Sorivudine appears to be converted in the gut into a metabolite (BVU or bromovinyluraeil) that is a potent inhibitor of dihydropyrimidine dehydrogenase (DPD), an enzyme involved in the metabolism of fluorouracil (which is derived from tegafiir and other fluorouracil prodrugs). There is some evidence that DPD activity is genetically determined, and that there are poor fluorouracil metabolisers with low DPD activity, who would be expected to be more susceptible to this interaction. ... 

Information appears to be limited to these reports but the interaction appears to be established and of clinical importance. The concurrent use of inhibitors of DPD (such as sorivudine and brivudine) and oral fluorouracil prodrugs such as capecitabine and tegafur is contraindicated. Note that sorivudine was withdrawn from the market following confirmation of this interaction. 

Watabe T, Okuda H, Ogura K. Lethal drug intemetiens of the new antiviral, sorivudine, with anticancer prodrugs of 5-fluorouracil. YakugakuZa hi 99T) 117,910-21. (In Japanese). 

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