Z-335

The characteristics of bile canalicular transport processes for xenobiotic taurine conjugates have not yet been clarified. To elucidate the biliary excretion characteristics of xenobiotic taurine conjugates, we investigated the transport of a novel thromboxane A2 receptor antagonist, Z-335, and its taurine conjugate (Z-335-Tau) across the bile canalicular membrane.

We examined the uptake of Z-335 and Z-335-Tau by isolated bile canalicular membrane vesicles (CMVs) from Sprague Dawley and Eisai-hyperbilirubinemic rats (EHBRs) which EHBRs have a hereditary defect of canalicular multidrug resistance-associated protein 2 (Mrp2) function. Also, the in vitro and in vivo kinetics of Z-335-Tau uptake and excretion were compared.

Z-335 uptake by CMVs from normal rats exhibited marked ATP-dependence, whereas ATP-dependent uptake of Z-335 into CMVs from EHBRs was not observed. In contrast, Z-335-Tau uptake into CMVs from both normal rats and EHBRs was ATP dependent. The initial uptake velocity was concentration-dependent, with an in vitro Michaelis constant for initial uptake of 189 microM, which was similar to the in vivo value.

The biliary excretion of Z-335 involves Mrp2, whereas that of Z-335-Tau involves active transport systems that remain intact in EHBRs and show marked ATP dependence, which ATP-dependent transport is involved in the biliary excretion of Z-335-Tau in vivo.

We investigated the mechanism of hepatobiliary transport of a novel thromboxane A(2) receptor antagonist, [2-(4-chlorophenylsulfonylaminomethyl)indan-5-yl]acetate (Z-335), and its taurine conjugate (Z-335-Tau) in normal Sprague-Dawley rats (SDRs) and Eisai hyperbilirubinemic rats (EHBRs). The biliary excretion rate/unbound concentration in the cytosol (nu(bile)/C(u,cyt)) of Z-335 was markedly decreased in EHBRs, whereas nu(bile)/C(u,cyt) values for Z-335-Tau did not differ significantly between EHBRs and SDRs. These results suggest that biliary excretion of Z-335 involves mrp2, whereas Z-335-Tau is excreted by other transporters. The effects of inhibitors on the biliary excretion of Z-335 and Z-335-Tau were also examined in SDRs. After infusion of bromosulfophthalein (BSP), the nu(bile)/C(u,cyt) of Z-335 was significantly decreased, whereas that of Z-335-Tau decreased to 50% of control values by infusion of indocyanine green (ICG) or taurocholate. However, biliary excretion of Z-335-Tau was maintained at a highly concentrative. In conclusion, the biliary excretion of Z-335 involves mrp2, whereas Z-335-Tau is excreted into the bile by active transport systems that remain intact in EHBRs. The mdr2 and/or BSEP/spgp might contribute to a part of total biliary excretion of Z-335-Tau, however, these transporters have not played a major role in the biliary excretion of Z-335-Tau.