[Molecular toxicological mechanism of the lethal interactions of the new antiviral drug, sorivudine, with 5-fluorouracil prodrugs and genetic deficiency of dihydropyrimidine dehydrogenase].
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.
Department of Drug Metabolism and Molecular Toxicology, School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji City, Tokyo 192-0392, Japan. watabet@ps.toyaku.ac.jp
Tadashi
T
Watabe
Kenichiro
K
Ogura
Takahito
T
Nishiyama
D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D001976:Bromouracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D042943:Dihydrouracil Dehydrogenase (NADP); D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005472:Fluorouracil / Q000493:pharmacokinetics; D006801:Humans; D009249:NADP; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics*; D011355:Prodrugs / Q000493:pharmacokinetics; D051381:Rats
D000998:Antiviral Agents; D011355:Prodrugs; D001086:Arabinofuranosyluracil; D001976:Bromouracil; D009249:NADP; C046140:5-(2-bromovinyl)uracil; C031368:sorivudine; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil