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 conversi on 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 or al absorption, less than 10% of the dose was absorbed in rats. To clarify t his unexpected outcome, we evaluated the rate of its disappearance from the gut lumen (V1), its degradation in the gut lumen (V-deg), uptake into ente rocytes (V-uptake), and appearance in the mesenteric vein (V2) by using a s ingle-pass perfusion technique in combination with an in vitro metabolism s tudy. Our data suggested that ME3229 crossed the apical membrane and was ta ken up into enterocytes at a rate compatible with its lipophilicity, but th at only a small fraction of the metabolites formed in enterocytes reached t he mesenteric vein, primarily attributable to efflux into the intestinal lu men. 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.