INTESTINAL ABSORPTION OF AN ESTER-TYPE PRODRUG, ME3229 —STUDIES ON THE EFFLUX OF METABOLITES FORMED IN THE ENTEROCYTES INTO THE GUT LUMEN—

We iiave evaluated the absorption of ME3229, an ester-type prodrug of a hydrophilic glycoprotein IIb/IIIa antagonist, ME3277. Although Log D value and permeability across Caco-2 cell monolayer of ME3229 became high enough for us to expect good oral absorption, less than 10% of dose was absorbed in rats. To clarify this discrepancy, we have separately evaluated the disappearance rate from the gut lumen (VI), hydrolysis rate in the gut lumen before absorption (Vdeg), uptake rate into the enterocytes (Vuptake) and appearance rate into the mesenteric vein (V2), by using single-pass perfusion technique. The data suggested that ME3229 permeated the apical membrane and was taken up into the enterocytes at the reasonable rate for its lipophilicity, but only a small part reached the mesenteric vein mainly due to the efflux of the metabolites formed in the enterocytes into the lumen. Transport characteristics of ME3277 across rat intestinal tissue suggested the existence of an active efflux system to pump out the metabolite(s) of ME3229.