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Vol. 28, Issue 4, 467-474, April 2000
Graduate School of Pharmaceutical Sciences, University of Tokyo,
Tokyo, Japan (S.K., Y.S.); School of Pharmaceutical Sciences, Kitasato
University, Tokyo, Japan (K.I.); School of Pharmacy, Tokyo University
of Pharmacy and Life Science, Tokyo, Japan (H.O., K.O., T.W.); and
Division of GI Oncology, National Cancer Center Hospital, Tokyo, Japan
(K.M.)
The fatal drug-drug interaction between sorivudine, an antiviral
drug, and 5-fluorouracil (5-FU) has been shown to be caused by a
mechanism-based inhibition. In this interaction, sorivudine is
converted by gut flora to (E)-5-(2-bromovinyl)uracil (BVU), which is
metabolically activated by dihydropyrimidine dehydrogenase (DPD), and
the activated BVU irreversibly binds to DPD itself, thereby
inactivating it. In an attempt to predict this interaction in vivo from
in vitro data, inhibition of 5-FU metabolism by BVU was investigated by
using rat and human hepatic cytosol and human recombinant DPD.
Whichever enzyme was used, increased inhibition was observed that
depended on the preincubation time of BVU and enzyme in the presence of
NADPH and BVU concentration. The kinetic parameters obtained for
inactivation represented by kinact and K'app were 2.05 ± 1.52 min
1, 69.2 ± 60.8 µM (rat hepatic cytosol),
2.39 ± 0.13 min1, 48.6 ± 11.8 µM (human
hepatic cytosol), and 0.574 ± 0.121 min1, 2.20 ± 0.57 µM (human recombinant DPD). The drug-drug interaction in vivo was predicted quantitatively based on a physiologically based
pharmacokinetic model, using pharmacokinetic parameters obtained from
the literature and kinetic parameters for the enzyme inactivation
obtained in the in vitro studies. In rats, DPD was predicted to be
completely inactivated by administration of BVU and the area under the
curve of 5-FU was predicted to increase 11-fold, which agreed
well with the reported data. In humans, a 5-fold increase in the area
under the curve of 5-FU was predicted after administration of
sorivudine, 150 mg/day for 5 days. Mechanism-based inhibition of drug
metabolism is supposed to be very dangerous. We propose that such in
vitro studies should be carried out during the drug-developing phase so
that in vivo drug-drug interactions can be predicted.
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