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Vol. 287, Issue 2, 791-799, November 1998
Department of Drug Metabolism and Molecular Toxicology, School of
Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji-shi, Tokyo 192-03, Japan
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.
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