Mechanism of Hepatobiliary Transport of a Novel Thromboxane A2Receptor Antagonist, [2-(4-Chlorophenylsulfonylaminomethyl)indan-5-yl]acetate (Z-335), and its Xenobiotic Taurine Conjugate (Z-335-Tau) in Rats

Autor: Kawabata, Yoshihiro, Nakamura, Hideki, Kamada, Emiko, Furuta, Shigeru, Shinozaki, Yutaka, Kurimoto, Tadashi, Nishigaki, Ryuichiro
Zdroj: Journal of Pharmaceutical Sciences; January 2003, Vol. 92 Issue: 1 p67-76, 10p
Abstrakt: We investigated the mechanism of hepatobiliary transport of a novel thromboxane A2receptor 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 (νbile/Cu,cyt) of Z-335 was markedly decreased in EHBRs, whereas νbile/Cu,cytvalues 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 νbile/Cu,cytof 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.
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