A Possible Mechanism of Eighteen Patient Deaths Caused by Interactions of Sorivudine, a New Antiviral Drug, with Oral 5-Fluorouracil Prodrugs

A toxicokinetic study was performed using rats to investigate the possible mechanism of 18 acute deaths in Japanese patients with cancer and herpes zoster by interactions of the new oral antiviral drug, sorivudine (SRV), with one of the oral 5-fluorouracil (5-FU) prodrugs within 40 days after approval of the use of SRV. Tegafur, an anticancer 5-FU prodrug suggested to be used by most of the patients who died, and SRV were orally administered to rats simultaneously once daily. All of these rats died within 10 days, whereas rats given SRV or tegafur alone under the same dosage conditions showed no appreciable change over 20 days compared with controls. In the rats given both drugs, bone marrow and intestinal membrane mucosa were greatly damaged at an early stage of the coadministration, and before death, the animals showed marked decreases in white blood cell and platelet counts, diarrhea with bloody flux, and severe anorexia, as was also manifested by the patients who subsequently died. In the rats given both drugs for 6 days, extremely enhanced 5-FU levels were observed from the first day of administration in plasma and in all tissues examined, including bone marrow and intestines. The extreme enhancement of the tissue 5-FU levels was attributable to the facile inactivation by (E)-5-(2-bromovinyl)uracil (BVU) of hepatic dihydropyrimidine dehydrogenase (DPD), a key enzyme regulating the systemic 5-FU level in the rat and human. BVU, a major metabolite formed from SRV by gut flora, was found at considerable levels in the liver of rats orally administered SRV alone or SRV and tegafur, and there was a marked decrease in hepatic DPD activity. In the presence of NADPH, DPD purified from rat liver cytosol was rapidly and irreversibly inactivated by [14C]BVU as a suicide inhibitor with concomitant incorporation of the radioactivity into the enzyme protein, although SRV showed no inhibitory effect on DPD under the same conditions. Human liver DPD was recently demonstrated by us to be inactivated with BVU in a manner very similar to rat DPD.