[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.
Watabe
Tadashi
T
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
Ogura
Kenichiro
K
Nishiyama
Takahito
T
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