RT Journal Article
SR Electronic
T1 Lethal Drug Interactions of Sorivudine, a New Antiviral Drug, with Oral 5-Fluorouracil Prodrugs
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 270
OP 273
VO 25
IS 2
A1 Haruhiro Okuda
A1 Takahito Nishiyama
A1 Kenichiro Ogura
A1 Sekio Nagayama
A1 Kazumasa Ikeda
A1 Shuji Yamaguchi
A1 Yoshimasa Nakamura
A1 Yasuro Kawaguchi
A1 Tadashi Watabe
YR 1997
UL http://dmd.aspetjournals.org/content/25/2/270.abstract
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