A study of the intestinal absorption of an ester-type prodrug, ME3229, in rats: active efflux transport as a cause of poor bioavailability of the active drug.

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 (V(deg)), uptake into enterocytes (V(uptake)), 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.