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, strongly suggested that in the patients who received both SRV and the
5-FU prodrug, tissue levels of highly toxic
5-FU markedly increased as a result of irreversible inactivation of DPD in the presence of
NADPH by
5-(2-bromovinyl)uracil (BVU), a metabolite formed from SRV by gut flora in rats and humans. Recombinant human (h) DPD was also irreversibly inactivated by [14C] BVU in the presence of
NADPH. MALDI-TOF MS analysis of radioactive tryptic fragments from the radiolabeled and inactivated hDPD demonstrated that a Cys residue located at position 671 in the
pyrimidine-binding domain of hDPD was modified with an
allyl bromide type of reactive metabolite, dihydro-BVU. Thus artificial
DPD deficiency caused by BVU from SRV led to patient deaths when coadministered with the
5-FU prodrug. Human population studies using healthy volunteers have demonstrated that there are poor and extensive
5-FU metabolizers who have very low and high DPD activities, respectively. Administration of a clinical dose of
5-FU or its
prodrug to poor
5-FU metabolizers may cause death unless DPD activity is determined using their peripheral blood mononuclear cells prior to the administration of the anticancer
drug.