Abstract
Sixteen deaths occurred among patients orally co-administered the new antiviral, sorivudine, with fluoropyrimidine anticancer agents in Japan 1993. The objective of our present research is to investigate the mechanism for the severe toxicity exerted by simultaneous administration of sorivudine and the typical fluoropyrimidine, tegafur (FT) in rats. When rats were co-administered FT with sorivudine for 6 days, a remarkable decrease in body weight and death of the animals were induced. A marked suppression of bone marrow, marked decreases in white blood cells and platelets and marked atrophy in jejunal mucosa were observed in the co-administered rats. Administration of FT alone did not induce such toxicological changes in the rat. The toxic effects were demonstrated to be caused by the accumulation of 5-fluorouracil (5-FU) in the co-administered rats, i.e. AUC and Cmax of 5-FU in co-administered rat plasma were 10 and 17.5 times higher than those in FT-treated rats, respectively. Hepatic dihydropyrimidine dehydrogenase (DPD), a rate-limiting factor for the catabolism of 5-FU, was significantly inactivated in rats repeatedly administered with sorivudine as well as with 5-bromovinyluracil (BVU), a major metabolite of the antiviral in gut flora, resulting in a marked accumulation of 5-FU from FT co-administered. An in vitro study using DPD purified from rat liver indicated that in the presence of NADPH the radioactivity of [14C]BVU was incorporated into the DPD protein in manner of covalent binding stoichiometrically with complete loss of its activity. Sorivudine had no activity to inactivate purified DPD under the same conditions. These results demonstrated that the lethal toxicity exerted by co-administration of FT and sorivudine was due to the marked accumulation of 5-FU, which resulted from inactivation of DPD by its modification with a reactive metabolite formed from BVU.
