PT - JOURNAL ARTICLE AU - Haruhiro Okuda AU - Takahito Nishiyama AU - Kenichiro Ogura AU - Sekio Nagayama AU - Kazumasa Ikeda AU - Shuji Yamaguchi AU - Yoshimasa Nakamura AU - Yasuro Kawaguchi AU - Tadashi Watabe TI - Lethal Drug Interactions of Sorivudine, a New Antiviral Drug, with Oral 5-Fluorouracil Prodrugs DP - 1997 Feb 01 TA - Drug Metabolism and Disposition PG - 270--273 VI - 25 IP - 2 4099 - http://dmd.aspetjournals.org/content/25/2/270.short 4100 - http://dmd.aspetjournals.org/content/25/2/270.full SO - Drug Metab Dispos1997 Feb 01; 25 AB - Rats were orally co-administered sorivudine (SRV: 1-β-d-arabinofuranosyl-(E)-5-(2-bromovinyl)uracil), a new oral antiviral drug for herpes zoster, with the oral anticancer drug tegafur (FT: 1-(2-tetrahydrofuryl)-5-fluorouracil) as a prodrug of 5-flourouracil (5-FU) once daily to investigate a toxicokinetic mechanism of 15 Japanese patients’ deaths recently caused within a brief period by the drug interaction of these drugs. All the rats showed extremely elevated levels of 5-FU in plasma and tissues, including bone marrow and small intestine, and died within 10 days, whereas the animals given the same dose of SRV or FT alone were still alive over 20 days without any appreciable toxic symptom. Before their death, there was marked damage of bone marrow, marked atrophy of intestinal membrane mucosa, marked decreases in white blood cells and platelets, diarrhea with bloody flux, and severe anorexia as reported with the Japanese patients. Data obtained by in vivo andin vitro studies strongly suggested that (E)-5-(2-bromovinyl)uracil generated from SRV by gut flora was reduced in the presense of NADPH to a reactive form by hepatic dihydropyrimidine dehydrogenase (DPD), a key enzyme determining the tissue 5-FU levels, bound covalently to DPD as a suicide inhibitor, and markedly retarded the catabolism of 5-FU. The American Society for Pharmacology and Experimental Therapeutics