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

• Published in: Journal of pharmaceutical sciences 2003-01, Vol.92 (1), p.67-76
• Main Authors: Kawabata, Yoshihiro, Nakamura, Hideki, Kamada, Emiko, Furuta, Shigeru, Shinozaki, Yutaka, Kurimoto, Tadashi, Nishigaki, Ryuichiro
• Format: Article
• Language: English
• Subjects: Animals; antagonist; Bile - metabolism; Bile - secretion; Biliary Tract - metabolism; Biliary Tract - secretion; Biological and medical sciences; Biological Transport - physiology; General pharmacology; Indans - chemistry; Indans - pharmacokinetics; Liver - metabolism; Liver - secretion; Male; Medical sciences; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; rat; Rats; Rats, Sprague-Dawley; Receptors, Thromboxane - antagonists & inhibitors; Receptors, Thromboxane - metabolism; Taurine - chemistry; Taurine - pharmacokinetics; Xenobiotics - chemistry; Xenobiotics - pharmacokinetics; Z-335; Z-335-Tau
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.10288

We investigated the mechanism of hepatobiliary transport of a novel thromboxane A2 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 (νbile/Cu,cyt) of Z-335 was markedly decreased in EHBRs, whereas νbile/Cu,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 νbile/Cu,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.