Polarized efflux of mono- and diacid metabolites of ME3229, an ester-type prodrug of a glycoprotein IIb/IIIa receptor antagonist, in rat small intestine

ME3229 is an ester-type prodrug of a glycoprotein IIb/IIIa receptor antagon ist ME3277. In our previous study, it was shown that only a small part of t he drug taken up into the enterocytes reached the mesenteric vein, mainly d ue to transporter-mediated efflux of its hydrolyzed metabolites formed in t he cells. To characterize the efflux transport system for the metabolites, the transport of the diacid metabolite ME3277 and the monoacid metabolites PM-10 and PM-11 were studied. ME3277 and PM-10 were preferentially transpor ted in the serosal-to-mucosal direction across the rat small intestine in t he presence of glucose. Permeability of ME3277 across monolayer of Caco-2 c ells with P-glycoprotein (P-gp) and indomethacin-sensitive efflux pump expr ession did not show any directionality and verapamil, an inhibitor of P-gp, and indomethacin did not affect the permeability of ME3277 across rat inte stinal tissue. Directional transport was not site specific and was observed in the Eisai hyperbilirubinemic rat whose canalicular multispecific organi c anion transporter/multidrug resistance-associated protein (cMOAT/MRP2) is hereditarily defective as well as in normal rats. The efflux transport of ME3277 was inhibited by 1-naphthol, 1-choloro-2,4-dinitrobenzene, and sulfo bromophthalein, and efflux of ME3277 and monoacid metabolites from intestin al tissue preloaded with ME3229 fell in the presence of 1-naphthol and sulf obromophthalein. These results demonstrate that mono- and diacid metabolite s of ME3229 were pumped out into the gut lumen by an energy-dependent trans port system located on the mucosal membrane of intestinal tissue and distin ct from either P-gp, indomethacin-sensitive efflux pump or canalicular mult ispecific organic anion transporter/MRP2. An inhibition study suggested tha t this unknown transporter has a substrate specificity similar to that of M RP transporter families.