Lethal drug interactions of the new antiviral, sorivudine, with anticancer prodrugs of 5-fluorouracil

In 1993 eighteen Japanese patients with cancer and herpes zoster, a viral disease, died from interactions of the new oral antiviral drug, sorivudine (SRV: 1-beta-D-arabinofuranosyl-(E)-5-(2-bromovinyl)uracil), with oral anticancer prodrugs of 5-fluorouracil (5-FU) within 40 d after SRV was approved by the Japanese government and began to be used clinically. Before the death, most of these patients had severe symptoms of toxicity, including diarrhea with bloody flux and marked decreases in white blood cell and platelet counts. All of these patients received SRV daily for several days while being administered long-term anticancer chemotherapy with one of the oral 5-FU prodrugs. There was no acute toxic symptom in patients who received SRV alone or SRV and the other types of anticancer drugs. A toxicokinetic study was carried out using rats to investigate the mechanism of the acute death in the patients caused by drug interactions between SRV and 5-FU prodrugs. Rats were orally coadministered SRV with tegafur (FT: 1-(2-tetrahydrofuryl)-5-fluorouracil), a 5-FU prodrug that most of the patients were considered to receive before the death. All the rats receiving SRV and FT once daily showed extremely elevated levels of 5-FU in the plasma and tissues, including bone marrow and small intestines, and died within 10 d, while the animals given the same repeated dose of SRV or FT alone were still alive over 20 d without any appreciable toxic symptom. Before their death, there were a marked damage of bone marrow, a marked atrophy of intestinal membrane mucosa, marked decreases in white blood cells and platelets, diarrhea with bloody flux, and severe anorexia as reported for the patients. Data obtained by in vivo and in vitro studies indicated that (E)-5-(2-bromovinyl)uracil (BW), generated from SRV by the gut flora and absorbed through the intestinal membrane, was reduced in the presence of NADPH to a reactive form by hepatic dihydropyrimidine dehydrogenase (DPD), a key enzyme regulating the tissue 5-FU levels from FT, bound covalently to DPD as a suicide inhibitor, and markedly retarded the catabolism of 5-FU. An irreversible inactivation by BVU of rat and human DPDs, expressed in E. coli for the latter, was observed in the presence of NADPH with their purified preparations in a manner reciprocal to radiolabelling of the enzyme proteins with [C-14]BVU. SRV showed no inhibitory effect on the rat and human DPDs in the presence of NADPH.