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.
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.
Kawabata
Yoshihiro
Y
Central Research Laboratories, ZERIA Pharmaceutical Corporation, Ltd, 2512-1, Oshikiri, Kohnan-Machi, Ohsato-Gun, Saitama 360-0111, Japan. yoshihiro-kawabata@zeria.co.jp
Nakamura
Hideki
H
Kamada
Emiko
E
Furuta
Shigeru
S
Shinozaki
Yutaka
Y
Kurimoto
Tadashi
T
Nishigaki
Ryuichiro
R
D000818:Animals; D001646:Bile / Q000378:metabolism; D001659:Biliary Tract / Q000378:metabolism*; D001692:Biological Transport / Q000502:physiology; D007189:Indans / Q000737:chemistry / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013654:Taurine / Q000737:chemistry / Q000493:pharmacokinetics*; D015262:Xenobiotics / Q000737:chemistry / Q000493:pharmacokinetics
D007189:Indans; D017482:Receptors, Thromboxane; D015262:Xenobiotics; C115527:Z 335; D013654:Taurine