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ATP-Dependent Transport of a Novel Thromboxane A2 Receptor Antagonist, [2-(4-Chlorophenylsulfonylaminomethyl)-Indan-5-yl]Acetate (Z-335) and Its Xenobiotic Taurine Conjugate (Z-335-Tau) by Rat Bile Canalicular Membrane Vesicles

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Abstract

Purpose. 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.

Methods. 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.

Results. 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 μM, which was similar to the in vivo value.

Conclusions. 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.

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Authors and Affiliations

  1. Central Research Laboratories, ZERIA Pharmaceutical Co., Ltd., Oshikiri, Kohnan-Machi, Ohsato-Gun, Saitama, 360-0111, Japan

    Yoshihiro Kawabata, Emiko Kamada, Shigeru Furuta, Mineo Takei & Tadashi Kurimoto

  2. School of Pharmaceutical Sciences, Toho University, Miyama, Funabashi, Chiba, 274-8510, Japan

    Yoshihiro Kawabata, Kazuho Okudaira & Ryuichiro Nishigaki

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  1. Yoshihiro Kawabata
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  2. Emiko Kamada
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  3. Shigeru Furuta
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  4. Mineo Takei
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  7. Ryuichiro Nishigaki
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Correspondence to Yoshihiro Kawabata.

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Kawabata, Y., Kamada, E., Furuta, S. et al. ATP-Dependent Transport of a Novel Thromboxane A2 Receptor Antagonist, [2-(4-Chlorophenylsulfonylaminomethyl)-Indan-5-yl]Acetate (Z-335) and Its Xenobiotic Taurine Conjugate (Z-335-Tau) by Rat Bile Canalicular Membrane Vesicles. Pharm Res 21, 467–475 (2004). https://doi.org/10.1023/B:PHAM.0000019301.97624.5b

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