Author: Nakahata, Norimichi ; Honma, Shigeyoshi ; Ohkubo, Satoko ; Shimura, Tokuro ; Sato, Yukari ; Tanaka, Takao ; Yoshida, Makoto ; Kurimoto, Tadashi

The effect of a novel thromboxane A2 receptor (TP) antagonist, (±)-sodium[2-(4-chlorophenylsulfonylaminomethyl)- indan-5-yl]acetate monohydrate (Z-335), on the U46619-induced responses was compared between rabbit platelets and aorta. Z-335 inhibited platelet shape change induced by U46619 with higher efficacy than SQ29548, a common TP antagonist. The U46619-induced platelet aggregation was inhibited by Z-335 in a noncompetitive manner, while it was competitively inhibited by SQ29548. Z-335 inhibited U46619-induced vasoconstriction of rabbit aorta with higher efficacy than SQ29548. The pA2 value of Z-335 in aortic vasoconstriction was significantly higher than in platelet shape change. The competitive binding study showed the higher pKi value of Z-335 against [3H]-SQ29548 binding in rabbit aortic smooth muscle cells than in platelets. These data suggest that Z-335 has useful characteristics of TP antagonism.

01 Mar 2004·Pharmaceutical ResearchQ3 · MEDICINE

ATP-Dependent Transport of a Novel Thromboxane A₂Receptor Antagonist, [2-(4-Chlorophenylsulfonylaminomethyl)-Indan-5-yl]Acetate (Z-335) and Its Xenobiotic Taurine Conjugate (Z-335-Tau) by Rat Bile Canalicular Membrane Vesicles

Q3 · MEDICINE

Article

Author: Kurimoto, Tadashi ; Nishigaki, Ryuichiro ; Kamada, Emiko ; Takei, Mineo ; Furuta, Shigeru ; Kawabata, Yoshihiro ; Okudaira, Kazuho

PURPOSEThe 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.METHODSWe 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.RESULTSZ-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.CONCLUSIONSThe 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.

01 Jan 2003·Journal of Pharmaceutical SciencesQ3 · MEDICINE

Mechanism of Hepatobiliary 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) in Rats

Q3 · MEDICINE

Article

Author: Nishigaki, Ryuichiro ; Kurimoto, Tadashi ; Furuta, Shigeru ; Shinozaki, Yutaka ; Kawabata, Yoshihiro ; Kamada, Emiko ; Nakamura, Hideki

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.

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Indication	Highest Phase	Country/Location	Organization	Date
Arterial Occlusive Diseases	Phase 2	JP	Zeria Usa, Inc.	-
Arterial Occlusive Diseases	Phase 2	-	Zeria Pharmaceutical Co., Ltd.	-

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