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Multidrug Resistance Protein 2-Mediated Estradiol-17β-D-glucuronide Transport Potentiation: In Vitro-in Vivo Correlation and Species Specificity

Solvo Biotechnology, Szeged, Hungary (K.H.-S., H.G., E.K., D.M., G.B., P.K.); Chemical Research Institute, HAS, Budapest, Hungary (Z.V., L.K., K.J.); and Aicuris, Wuppertal, Germany (O.v.R.)

Multidrug resistance protein 2 (MRP2) is a multispecific organic anion transporter expressed at important pharmacological barriers, including the canalicular membrane of hepatocytes. At this location it is involved in the elimination of both endogenous and exogenous waste products, mostly as conjugates, to the bile. Estradiol-17β-D-glucuronide (E₂17βG), a widely studied endogenous substrate of MRP2, was shown earlier to recognize two binding sites of the transporter in vesicular transport assays. MRP2 modulators (substrates and nonsubstrates) potentiate the transport of E₂17βG by MRP2. We correlated data obtained from studies of different complexities and investigated the species-specific differences between rat and human MRP2-mediated transport. We used vesicular transport assays, sandwich-cultured primary hepatocytes, and in vivo biliary efflux in rats. Our results demonstrate that the rat Mrp2 transporter, unlike the human MRP2, transports E₂17βG according to Michaelis-Menten type kinetics. Nevertheless, in the presence of modulator drugs E₂17βG transport mediated by the rat transporter also shows cooperative kinetics as potentiation of E₂17βG transport was observed in the vesicular transport assay. We also demonstrated that the potentiation exists both in rat and in human hepatocytes and in vivo in rats.