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Vol. 294, Issue 2, 580-587, August 2000
Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., Yokohama,
Japan (N.O., T.T., I.K.); Inveresk Research, Tranent, United Kingdom
(G.C.S.); and Graduate School of Pharmaceutical Sciences, University of
Tokyo, Tokyo, Japan (Y.S.)
The intestinal absorption of a prodrug is affected by a number of
factors, such as its membrane permeability, stability in the gut lumen,
and conversion to the parent drug in enterocytes. We evaluated the
absorption of ME3229, an ester-type prodrug of a hydrophilic
glycoprotein IIb/IIIa antagonist. Although the octanol/water distribution coefficient and permeability across a Caco-2 cell monolayer of ME3229 was high enough for us to expect good oral absorption, less than 10% of the dose was absorbed in rats. To clarify
this unexpected outcome, we evaluated the rate of its disappearance
from the gut lumen (V1), its degradation in the gut lumen
(Vdeg), uptake into enterocytes
(Vuptake), and appearance in the mesenteric
vein (V2) by using a single-pass perfusion technique in combination
with an in vitro metabolism study. Our data suggested that ME3229
crossed the apical membrane and was taken up into enterocytes at a rate
compatible with its lipophilicity, but that only a small fraction of
the metabolites formed in enterocytes reached the mesenteric vein,
primarily attributable to efflux into the intestinal lumen. Transport
of the main metabolite across rat intestinal tissue mounted on an
Ussing chamber suggested that an active efflux system pumped out any
ionic metabolite(s) present.
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